WSGR Docket No. 41223-754.601 ORALLY-BIOAVAILABLE NUCLEOSIDE ANALOGS CROSS-REFERENCE [0001] This application claims the benefit of U. S. Provisional Application Serial No.63/387,392 filed December 14, 2022 which is hereby incorporated by reference in its entirety. BACKGROUND [0002] Remdesivir is a parenterally administered prodrug that was previously developed for the treatment of Ebola virus disease and more recently received emergency use authorization for the treatment of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection (Eastman, R.T., Roth, J.S., Brimacombe, K.R., Simeonov, A., Shen, M., Patnaik, S., and Hall, M.D. (2020). Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci 6, 672-683). The parent compound is a 1′-cyano modified adenosine C- nucleoside analog (GS-441524) that is phosphorylated by intracellular nucleotide kinases to the active tri-phosphorylated form (GS-443902). GS-443902 inhibits viral replication by competing with adenosine 5’-triphosphate for incorporation into nascent RNA chains by the virally-encoded RNA-dependent RNA polymerase leading to a delayed chain termination that can occur three nucleotides downstream from its position (Kokic et a., 2021; Nature Communications 12:279). In full-length read-through transcripts, the presence of GS-443902 residues in the template strand significantly compromises the incorporation of uridine residues during second-strand synthesis (Tchesnokov et al.2020 Journal of Biological Chemistry 295(47):16156-16165). Remdesivir (GS-5734) is a monophosphoramidate prodrug of GS-441524 and demonstrates broad spectrum antiviral activity against a wide range of different RNA virus families including: filoviruses (e.g. Ebola viruses, Marburg virus), paramyxoviruses (e.g. parainfluenza type II virus, Nipah virus, Hendra virus, measles morbillivirus, mumps virus), coronaviruses (e.g. SARS-CoV, SARS-CoV-2, MERS-CoV), and pneumoviruses (e.g. respiratory syncytial virus) (Cho, A., Saunders, O.L., Butler, T., Zhang, L., Xu, J., Vela, J.E., Feng, J.Y., Ray, A.S., and Kim, C.U. (2012). Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett 22, 2705-2707). [0003] Coronaviruses (CoV) are a large family of viruses that typically infect the upper respiratory tract causing mild to moderate disease in humans. Infections with human coronaviruses: 229E, NL63, OC43 and HKU1 account for approximately 5-30% of “common” colds. There are several hundred coronaviruses that circulate in animals such as pigs, camels, bats, and cats. In the past twenty years, at least three coronaviruses have jumped from one or more of these animal reservoirs into humans in what is known as a spillover event. One example is “Middle East Respiratory Syndrome Coronavirus” (MERS-CoV or MERS) which was first reported in Saudi Arabia in 2012. Another example is SARS- CoV, the coronavirus responsible for “Severe Acute Respiratory Syndrome” (SARS) that was first identified in China in 2002. Still another example is SARS-CoV-2, the causative agent of COVID-19
WSGR Docket No. 41223-754.601 (Coronavirus Disease of 2019). All three of these beta-coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, have shown the potential to replicate in the lower respiratory tract and cause more serious illnesses in humans giving rise to a viral pneumonia that can be fatal. Other clinical manifestations and organ system complications (i.e., cardiac, neurologic, hematologic) have also been described in patients who are infected with SARS-CoV-2. SUMMARY [0004] The present disclosure relates to small-molecule compounds that can be used as a monotherapy or in combination with additional antivirals and/or other agents in the treatment of a viral infection. [0005] The present disclosure relates to small-molecule compounds that block coronavirus and filovirus replication with the potential to be used as a monotherapy or in combination with additional antivirals and/or other agents. [0006] Disclosed herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (IIa) as defined herein. [0007] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier. [0008] Also disclosed herein is a method of treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. [0009] In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papillomavirus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Poxviridae, Potyviridae, Reoviridae, Retroviridae, Rhabdoviridae, Tectiviridae, Togaviridae, orthopoxvirus, coronavirus, influenza virus,
WSGR Docket No. 41223-754.601 sendai virus (SeV), sindbis virus (SINV), vaccinia viruses, West Nile virus, Hantavirus, viruses which cause the common cold, and any combination thereof. [0010] In some embodiments, the viral infection is caused by coronavirus disease 2019 (SARS-CoV- 2). [0011] In some embodiments, the viral infection is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). [0012] In some embodiments, the viral infection is caused by one Ebolavirus. [0013] In some embodiments, the method further comprises administering at least one antiviral agent. [0014] In some embodiments, the at least one antiviral agent is nirmatrelvir/ritonavir. INCORPORATION BY REFERENCE [0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publica tion, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION Definitions [0016] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. [0017] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. [0018] The terms below, as used herein, have the following meanings, unless indicated otherwise: [0019] “Oxo” refers to =O. [0020] “Amino” refers to -NH
2;
WSGR Docket No. 41223-754.601 [0021] “Hydroxy” refers to -OH; [0022] “Carboxyl” refers to -COOH. [0023] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C
1-C
6 alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C
1-C
10 alkyl. In some embodiments, the alkyl is a C
1-C
6 alkyl. In some embodiments, the alkyl is a C
1-C
5 alkyl. In some embodiments, the alkyl is a C
1-C
4 alkyl. In some embodiments, the alkyl is a C
1-C
3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. [0024] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH
2), 1-propenyl (-CH
2CH=CH
2), isopropenyl [-C(CH
3)=CH
2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C
2-C
6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
WSGR Docket No. 41223-754.601 [0025] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C
2-C
6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. [0026] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, - NH
2, or -NO
2. In some embodiments, the alkylene is optionally substituted with one or more halogen, - CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0027] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH
2, or -NO
2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0028] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or
WSGR Docket No. 41223-754.601 heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF
3, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF
3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. [0029] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and/or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C
3-C
15 fully saturated cycloalkyl or C
3-C
15 cycloalkenyl), from three to ten carbon atoms (e.g., C
3-C
10 fully saturated cycloalkyl or C
3-C
10 cycloalkenyl), from three to eight carbon atoms (e.g., C
3-C
8 fully saturated cycloalkyl or C
3-C
8 cycloalkenyl), from three to six carbon atoms (e.g., C
3-C
6 fully saturated cycloalkyl or C
3-C
6 cycloalkenyl), from three to five carbon atoms (e.g., C
3-C
5 fully saturated cycloalkyl or C
3-C
5 cycloalkenyl), or three to four carbon atoms (e.g., C
3-C
4 fully saturated cycloalkyl or C
3-C
4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7 -dimethyl- bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF
3, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF
3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0030] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0031] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [0032] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.
WSGR Docket No. 41223-754.601 [0033] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [0034] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. [0035] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD
3, CH
2D, CHD
2, CH
2CD
3, CD
2CD
3, CHDCD
3, CH
2CH
2D, or CH
2CHD
2. In some embodiments, the deuteroalkyl is CD
3. [0036] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus , or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C
1-C
6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C
1-C
6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH
2OCH
3, -CH
2CH
2OCH
3, -CH
2CH
2OCH
2CH
2OCH
3, - CH(CH
3)OCH
3, -CH
2NHCH
3, -CH
2N(CH
3)
2, -CH
2CH
2NHCH
3, or -CH
2CH
2N(CH
3)
2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF
3, -OH, -OMe, -NH
2, or - NO
2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo , halogen, methyl, ethyl, -CN, -CF
3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. [0037] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three
WSGR Docket No. 41223-754.601 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C
2-C
15 fully saturated heterocycloalkyl or C
2-C
15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C
2-C
10 fully saturated heterocycloalkyl or C
2-C
10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C
2-C
8 fully saturated heterocycloalkyl or C
2-C
8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C
2-C
7 fully saturated heterocycloalkyl or C
2-C
7 heterocycloalkenyl), from two to six carbon atoms (e.g., C
2-C
6 fully saturated heterocycloalkyl or C
2-C
7 heterocycloalkenyl), from two to five carbon atoms (e.g., C
2-C
5 fully saturated heterocycloalkyl or C
2-C
5 heterocycloalkenyl), or two to four carbon atoms (e.g., C
2-C
4 fully saturated heterocycloalkyl or C
2-C
4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 - to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered
WSGR Docket No. 41223-754.601 heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF
3, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF
3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [0038] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments , the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may b e optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 -benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2- oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1- phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl,
WSGR Docket No. 41223-754.601 pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF
3, -OH, -OMe, -NH
2, or -NO
2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF
3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. [0039] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH
2CH
3), fully substituted (e.g., -CF
2CF
3), mono-substituted (e.g., -CH
2CH
2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH
2CHF
2, - CH
2CF
3, -CF
2CH
3, -CFHCHF
2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons. [0040] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. [0041] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. [0042] “Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
WSGR Docket No. 41223-754.601 [0043] “Coronavirus infection” refers to any and all conditions deriving from infection with coronaviruses, including but not limited to SARS-CoV, SARS-CoV-2, and MERS-CoV, preferably SARS-CoV-2. Compounds [0044] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of viral infections. In some embodiments, the viral infection is a coronavirus infection. [0045] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (I); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
WSGR Docket No. 41223-754.601 R
12 is -C(=O)NR
22R
23; R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro; R
15 is hydrogen, -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; each R
15a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
15a on the same atom are taken together to form an oxo; R
25 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
25a; each R
25a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)2R
a, -S(=O)2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
25a on the same atom are taken together to form an oxo;
WSGR Docket No. 41223-754.601 or two R
25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
16 is hydrogen, -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a; each R
16a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
16a on the same atom are taken together to form an oxo; R
26 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a; each R
26a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
26a on the same atom are taken together to form an oxo; or two R
26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each R
a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
WSGR Docket No. 41223-754.601 each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo. [0046] In some aspect, the compound of Formula (I) gets metabolized in vivo. [0047] In some aspect, the compound of Formula (I) gets metabolized in vivo to a compound of Formula (I-M). [0048] Disclosed herein is a compound of Formula (I-M), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (I-M); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is -C(=O)NR
22R
23;
WSGR Docket No. 41223-754.601 R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C1-C6alkyl; R
14 is -OH or fluoro; R
17 is hydrogen,
, , or
R
7 is hydrogen or a counterion; each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
WSGR Docket No. 41223-754.601 C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo. [0049] In some embodiments of a compound of Formula
[0050] In some embodiments of a compound of Formula (I) or (I-M), X is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), X is -CN. [0051] In some embodiments of a compound of Formula (I) or (I-M), R
13 is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), R
13 is C
1-C
6alkyl. [0052] In some embodiments of a compound of Formula (I) or (I-M), R
14 is -OH. In some embodiments of a compound of Formula (I) or (I-M), R
14 is fluoro. [0053] In some embodiments of a compound of Formula (I) or (I-M), R
11 is hydrogen, -C(=O)R
21, or C
1-C
6alkyl optionally substituted with one or more R
11a. In some embodiments of a compound of Formula (I) or (I-M), R
11 is hydrogen or -C(=O)R
21. In some embodiments of a compound of Formula (I) or (I-M), R
11 is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), R
11 is - C(=O)R
21.
WSGR Docket No. 41223-754.601 [0054] In some embodiments of a compound of Formula (I) or (I-M), each R
11a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (I) or (I-M), each R
11a is independently halogen. [0055] In some embodiments of a compound of Formula (I) or (I-M), R
21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a. In some embodiments of a compound of Formula (I) or (I-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [0056] In some embodiments of a compound of Formula (I) or (I-M), each R
21a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (I) or (I-M), each R
21a is independently halogen, -OH, - OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [0057] In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl).
[0058] In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl or C
1- C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
22 is C
1-C
6alkyl. [0059] In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen, C
1-C
6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl),
WSGR Docket No. 41223-754.601 C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [0060] In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen, C
1-C
6alkyl, or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen or C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
23 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (I) or (I-M), R
23 is C
1-C
6alkyl. In some embodiments of a compound of Formula (I) or (I-M), R
23 is hydrogen. [0061] In some embodiments of a compound of Formula (I) or (I-M), each R
22a is independently halogen, -CN, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, - C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl.
[0062] In some embodiments of a compound of Formula (I) or (I-M), each R
22a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (I) or (I-M), each R
22a is independently halogen, -OH, - OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (I) or (I- M), each R
22a is independently halogen, -OC(=O)R
a, or -NR
cR
d. In some embodiments of a compound of Formula (I) or (I-M), each R
22a is independently -OC(=O)R
a or -NR
cR
d. In some embodiments of a compound of Formula (I) or (I-M), each R
22a is independently -OC(=O)R
a. [0063] In some embodiments of a compound of Formula
[0064] In some embodiments of a compound of Formula (I), R
15 is hydrogen, -C(=O)R
25, or -CH
2-O- C(=O)R
25. In some embodiments of a compound of Formula (I), R
15 is hydrogen or -C(=O)R
25. In some embodiments of a compound of Formula (I), R
15 is -C(=O)R
25. In some embodiments of a compound of Formula (I), R
15 is hydrogen. [0065] In some embodiments of a compound of Formula (I), each R
15a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (I), each R
15a is independently halogen. [0066] In some embodiments of a compound of Formula (I), R
25 is C1-C6alkyl, C1-C6aminoalkyl, C1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
WSGR Docket No. 41223-754.601 optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (I), R
25 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (I), R
25 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
25a. [0067] In some embodiments of a compound of Formula (I), each R
25a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (I), each R
25a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [0068] In some embodiments of a compound of Formula (I), R
15 is
, or
. In some embodiments of a compound of Formula (I), R
15
. In some embodiments of a compound of Formula (I), R
15 is
. In some embodiments of a compound of Formula (I), R
15 is
. In some embodiments of a compound of Formula (I), R
15 is
. In some embodiments of a compound of Formula (I), R
15 is not
. In some embodiments of a compound of Formula (I), R
15 is not
. In some embodiments of a compound of Formula (I), R
15 is not
. [0069] In some embodiments of a compound of Formula (I), R
16 is hydrogen, -C(=O)R
26, or -CH
2-O- C(=O)R
26. In some embodiments of a compound of Formula (I), R
16 is hydrogen or -C(=O)R
26. In some embodiments of a compound of Formula (I), R
16 is -C(=O)R
26. In some embodiments of a compound of Formula (I), R
16 is hydrogen. In some embodiments of a compound of Formula (I), R
16 is -CH
2-O- C(=O)R
26. [0070] In some embodiments of a compound of Formula (I), each R
16a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (I), each R
16a is independently halogen.
WSGR Docket No. 41223-754.601 [0071] In some embodiments of a compound of Formula (I), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (I), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (I), R
26 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
26a. [0072] In some embodiments of a compound of Formula (I), each R
26a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (I), each R
26a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [0073] In some embodiments of a compound of Formula (I), R
16 is
. In some embodiments of a compound of Formula (I), R
16 is
. In some embodiments of a compound of Formula (I), R
16 is
. In some embodiments of a compound of Formula (I), R
16 is not
. In some embodiments of a compound of Formula (I), R
16 is not
. In some embodiments of a compound of Formula (I), R
16 is not
. In some embodiments of a compound of Formula
some embodiments of a
WSGR Docket No. 41223-754.601 compound of Formula
some embodiments of a compound of
. ,
[0074] In some embodiments of a compound of Formula (I-M), R
7 is hydrogen. In some embodiments of a compound of Formula (I-M), R
7 is a counterion. In some embodiments of a compound of Formula (I-M), R
7 is Na
+. In some embodiments of a compound of Formula (I-M), R
7 is Li
+. In some embodiments of a compound of Formula (I-M), R
7 is Mg
2+. [0075] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (II); wherein: X is hydrogen or -CN;
WSGR Docket No. 41223-754.601
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C1-C6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C1-C6alkyl optionally substituted with one or more R
12a; each R
12a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
12a on the same atom are taken together to form an oxo; R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl,
WSGR Docket No. 41223-754.601 C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro; R
15 is hydrogen, -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; each R
15a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
15a on the same atom are taken together to form an oxo; R
25 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
25a; each R
25a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
25a on the same atom are taken together to form an oxo; or two R
25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26; R
26 is C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a; each R
26a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - SH, -SR
a, -S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -NR
bC(=O)NR
cR
d, -NR
bC(=O)R
a, - NR
bC(=O)OR
b, -NR
bS(=O)
2R
a, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R
26a on the same atom are taken together to form an oxo; or two R
26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
WSGR Docket No. 41223-754.601 each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [0076] In some aspect, the compound of Formula (II) gets metabolized in vivo. [0077] In some aspect, the compound of Formula (II) gets metabolized in vivo to a compound of Formula (II-M). [0078] Disclosed herein is a compound of Formula (II-M), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (II-M); wherein: X is hydrogen or -CN;
WSGR Docket No. 41223-754.601 R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; each R
12a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
12a on the same atom are taken together to form an oxo; R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)2R
a, -S(=O)2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo;
WSGR Docket No. 41223-754.601 or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro;
R
7 is hydrogen or a counterion; each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo.
WSGR Docket No. 41223-754.601 [0079] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula
[0080] In some embodiments of a compound of Formula (II) or (II-M), X is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), X is -CN. [0081] In some embodiments of a compound of Formula (II) or (II-M), R
13 is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), R
13 is C1-C6alkyl. [0082] In some embodiments of a compound of Formula (II) or (II-M), R
14 is -OH. In some embodiments of a compound of Formula (II) or (II-M), R
14 is fluoro. [0083] In some embodiments of a compound of Formula (II): R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0084] In some embodiments of a compound of Formula (II), R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is hydrogen, -C(=O)R
25, -C(=O)OR
25, -CH2-O-C(=O)R
25, -CH2-O-C(=O)OR
25, or C1-C6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0085] In some embodiments of a compound of Formula (II),
WSGR Docket No. 41223-754.601 R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, or -C(=O)NR
22R
23, C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is hydrogen, -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0086] In some embodiments of a compound of Formula (II), R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0087] In some embodiments of a compound of Formula (II), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH2-O-C(=O)R
25, -CH2-O-C(=O)OR
25, or C1-C6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0088] In some embodiments of a compound of Formula (II), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is hydrogen, -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0089] In some embodiments of a compound of Formula (II), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, -CH
2-O-C(=O)OR
25, or C
1-C
6alkyl optionally substituted with one or more R
15a; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26. [0090] In some embodiments of a compound of Formula (II) or (II-M), R
11 is hydrogen, -C(=O)R
21, or C
1-C
6alkyl optionally substituted with one or more R
11a. In some embodiments of a compound of Formula (II) or (II-M), R
11 is hydrogen or -C(=O)R
21. In some embodiments of a compound of Formula
WSGR Docket No. 41223-754.601 (II) or (II-M), R
11 is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), R
11 is - C(=O)R
21. [0091] In some embodiments of a compound of Formula (II) or (II-M), each R
11a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (II) or (II-M), each R
11a is independently halogen. [0092] In some embodiments of a compound of Formula (II) or (II-M), R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a. In some embodiments of a compound of Formula (II) or (II-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [0093] In some embodiments of a compound of Formula (II) or (II-M), each R
21a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (II) or (II-M), each R
21a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [0094] In some embodiments of a compound of Formula (II) or (II-M), R
12 is hydrogen, -C(=O)R
22, - C(=O)OR
22, or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R
12 is - C(=O)R
22, -C(=O)OR
22, or C
1-C
6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R
12 is hydrogen or -C(=O)R
22. In some embodiments of a compound of Formula (II) or (II-M), R
12 is - C(=O)R
22. In some embodiments of a compound of Formula (II) or (II-M), R
12 is hydrogen, or - C(=O)OR
22. In some embodiments of a compound of Formula (II) or (II-M), R
12 is hydrogen or C
1- C
6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R
12 is -C(=O)NR
22R
23. [0095] In some embodiments of a compound of Formula (II) or (II-M), each R
12a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (II) or (II-M), each R
12a is independently halogen. [0096] In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. [0097] In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl,
WSGR Docket No. 41223-754.601 C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [0098] In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl or C
1- C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl optionally substituted with one R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6alkyl substituted with one R
22a. [0099] In some embodiments of a compound of Formula (II) or (II-M), R
22 is C
1-C
6heteroalkyl. [00100] In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00101] In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen, C
1-C
6alkyl, or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen or C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
23 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (II) or (II-M), R
23 is C
1-C
6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R
23 is hydrogen. [00102] In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently halogen, -CN, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, - C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. [00103] In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently halogen, -OH,
WSGR Docket No. 41223-754.601 -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently halogen, -OC(=O)R
a, or -NR
cR
d. In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently -OC(=O)R
a or -NR
cR
d. In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently -OC(=O)R
a. In some embodiments of a compound of Formula (II) or (II-M), each R
22a is independently -OR
a. In some embodiments of a compound of Formula (II) or (II-M), R
22a is -OR
a.
[00105] In some embodiments of a compound of Formula
[00106] In some embodiments of a compound of Formula (II) or (II-M), R
12 is
, ,
. , . embodiments of a compound of Formula (II) or (II-M), R
12 is
. In some embodiments of a compound of Formula
[00107] In some embodiments of a compound of Formula (II), R
15 is hydrogen, -C(=O)R
25, or -CH
2-O- C(=O)R
25. In some embodiments of a compound of Formula (II), R
15 is hydrogen or -C(=O)R
25. In some embodiments of a compound of Formula (II), R
15 is -C(=O)R
25. In some embodiments of a compound of Formula (II), R
15 is hydrogen. [00108] In some embodiments of a compound of Formula (II), each R
15a is independently halogen, - CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (II), each R
15a is independently halogen.
WSGR Docket No. 41223-754.601 [00109] In some embodiments of a compound of Formula (II), R
25 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (II), R
25 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (II), R
25 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
25a. [00110] In some embodiments of a compound of Formula (II), each R
25a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (II), each R
25a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00111] In some embodiments of a compound of Formula (II), R
15 is
, or
. In some embodiments of a compound of Formula (II), R
15 is
. In some embodiments of a compound of Formula (II), R
15 is
. In some embodiments of a compound of Formula (II), R
15 is
. In some embodiments of a compound of Formula (II), R
15 is . In some embodiments of a compound of Formula (II), R
15 is
. In some embodiments of a compound of Formula (II), R
15 is
. In some embodiments of a compound of Formula (II), R
15 is not
. In some embodiments of a compound of Formula (II), R
15 is not
. In some embodiments of a compound of Formula (II), R
15 is not
. [00112] In some embodiments of a compound of Formula (II), R
16 is -C(=O)R
26. In some embodiments of a compound of Formula (II), R
16 is -C(=O)OR
26. In some embodiments of a compound of Formula (II), R
16 is -CH
2-O-C(=O)R
26.
WSGR Docket No. 41223-754.601 [00113] In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1- C
6alkylene(cycloalkyl) or C
1-C
6alkylene(aryl). In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independe ntly substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1- C
6alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. [00114] In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C1alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. [00115] In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(3- to 8-membered cycloalkyl). In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(4- to 7-membered cycloalkyl). In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(4- to 6-membered cycloalkyl). In some embodiments of a compound of Formula (II), R
26 is C
1alkylene(5- to 6-membered cycloalkyl). [00116] In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (II), R
26 is C
1-C
6alkylene(phenyl); wherein the alkylene and phenyl is optionally and independently substituted with one or more R
26a. [00117] In some embodiments of a compound of Formula (II), each R
26a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R
26a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl.
WSGR Docket No. 41223-754.601 [00118] In some embodiments of a compound of Formula (II), R
16 is
, ,
. In some embodiments of a compound of Formula (II), R
16 is
. In some embodiments of a compound of Formula (II), R
16 is
. In some embodiments of a compound
. [00119] In some embodiments of a compound of Formula (II), R
15 is
; R
12 is -C(=O)R
22; and R
22 is C
1-C
6heteroalkyl. [00120] In some embodiments of a compound of Formula (II), R
15 is
; R
12 is -C(=O)R
22; R
22 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a; and each R
22a is independently -OR
a. [00121] In some embodiments of a compound of Formula (II), R
15 is
,
WSGR Docket No. 41223-754.601 [00122] In some embodiments of a compound of Formula (II-M), R
17 is
,
some embodiments of a compound of Formula
some embodiments of a compound of Formula
. ,
. [00123] In some embodiments of a compound of Formula (II-M), R
7 is hydrogen. In some embodiments of a compound of Formula (II-M), R
7 is a counterion. In some embodiments of a compound of Formula (II-M), R
7 is Na
+. In some embodiments of a compound of Formula (II-M), R
7 is Li
+. In some embodiments of a compound of Formula (II-M), R
7 is Mg
2+.
WSGR Docket No. 41223-754.601 [00124] In some embodiments, the compound of Formula (II) is of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (IIa); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
32 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl;
WSGR Docket No. 41223-754.601 R
14 is -OH or fluoro; R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, or -CH
2-O-C(=O)OR
26; R
26 is C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a; each R
26a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - SH, -SR
a, -S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -NR
bC(=O)NR
cR
d, -NR
bC(=O)R
a, - NR
bC(=O)OR
b, -NR
bS(=O)
2R
a, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R
26a on the same atom are taken together to form an oxo; or two R
26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00125] In some embodiments, the compound of Formula (IIa) gets metabolized in vivo to a compound of Formula (IIa-M):
WSGR Docket No. 41223-754.601
Formula (IIa-M); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
32 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro;
WSGR Docket No. 41223-754.601
R
7 is hydrogen or a counterion; each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00126] In some embodiments of a compound of Formula (IIa) or (IIa-M), G is
some embodiments of a compound of Formula (IIa) or (IIa-M), G is
WSGR Docket No. 41223-754.601 some embodiments of a compound of Formula (IIa) or (IIa-M), G is
. [00127] In some embodiments of a compound of Formula (IIa) or (IIa-M), X is hydrogen. In some embodiments of a compound of Formula (IIa) or (IIa-M), X is -CN.
[00128] In some embodiments of a compound of Formula (IIa) or (IIa-M), R
13 is hydrogen. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
13 is C
1-C
6alkyl.
[00129] In some embodiments of a compound of Formula (IIa) or (IIa-M), R
14 is -OH. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
14 is fluoro. [00130] In some embodiments of a compound of Formula (IIa) or (IIa-M), R
11 is hydrogen, -C(=O)R
21, or C1-C6alkyl optionally substituted with one or more R
11a. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
11 is hydrogen or -C(=O)R
21. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
11 is hydrogen. In some embodiments of a compound of Formula (IIa) or (IIa- M), R
11 is -C(=O)R
21. [00131] In some embodiments of a compound of Formula (IIa) or (IIa-M), each R
11a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (IIa) or (IIa-M), each R
11a is independently halogen. [00132] In some embodiments of a compound of Formula (IIa) or (IIa-M), R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (IIa) or (IIa-M), R
21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00133] In some embodiments of a compound of Formula (IIa) or (IIa-M), each R
21a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IIa) or (IIa-M), each R
21a is independently halogen, - OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl.
WSGR Docket No. 41223-754.601 [00134] In some embodiments of a compound of Formula (IIa) or (IIa-M), R
32 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, or C
1-C
6heteroalkyl; wherein the alkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
32 is C
1-C
6alkyl or C
1-C
6haloalkyl; wherein the alkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IIa) or (IIa-M), R
32 is C
1-C
6alkyl optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IIa), R
32 is C
1-C
6alkyl.
[00136] In some embodiments of a compound of Formula (IIa), R
16 is -C(=O)R
26. In some embodiments of a compound of Formula (IIa), R
16 is -C(=O)OR
26. In some embodiments of a compound of Formula (IIa), R
16 is -CH
2-O-C(=O)R
26. [00137] In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1- C
6alkylene(cycloalkyl) or C
1-C
6alkylene(aryl). In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(cycloalkyl). In some embodiments of a compound of Formula (IIa), R
26 is C
1- C
6alkylene(aryl). In some embodiments of a compound of Formula (IIa), R
26 is C
1- C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(4- to
WSGR Docket No. 41223-754.601 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. [00138] In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
26a. [00139] In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(3- to 8-membered cycloalkyl). In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(4- to 7-membered cycloalkyl). In some embodiments of a compound of Formula (IIa), R
26 is C1alkylene(4- to 6-membered cycloalkyl). In some embodiments of a compound of Formula (IIa), R
26 is C
1alkylene(5- to 6-membered cycloalkyl). [00140] In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (IIa), R
26 is C
1-C
6alkylene(phenyl); wherein the alkylene and phenyl is optionally and independently substituted with one or more R
26a. [00141] In some embodiments of a compound of Formula (IIa), each R
26a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (IIa), each R
26a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl.
[00142] In some embodiments of a compound of Formula (IIa), R
16 is
, ,
WSGR Docket No. 41223-754.601
. , . embodiments of a compound of Formula (IIa), R
16 is
. In some embodiments of a compound
. [00143] In some embodiments of a compound of Formula (IIa-M), R
17 is
,
. In some embodiments of a compound of Formula
some embodiments of a compound of Formula
WSGR Docket No. 41223-754.601 . In some embodiments of a compound of Formula (IIa-M), R
17 is
[00144] In some embodiments of a compound of Formula (IIa-M), R
7 is hydrogen. In some embodiments of a compound of Formula (IIa-M), R
7 is a counterion. In some embodiments of a compound of Formula (IIa-M), R
7 is Na
+. In some embodiments of a compound of Formula (IIa-M), R
7 is Li
+. In some embodiments of a compound of Formula (IIa-M), R
7 is Mg
2+. [00145] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (III); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a;
WSGR Docket No. 41223-754.601 each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; each R
12a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
12a on the same atom are taken together to form an oxo; each R
22 is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; R
25 is C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a;
WSGR Docket No. 41223-754.601 each R
25a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - SH, -SR
a, -S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -NR
bC(=O)NR
cR
d, -NR
bC(=O)R
a, - NR
bC(=O)OR
b, -NR
bS(=O)
2R
a, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R
25a on the same atom are taken together to form an oxo; or two R
25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
16 is hydrogen, -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a; each R
16a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
16a on the same atom are taken together to form an oxo; R
26 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a; each R
26a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
26a on the same atom are taken together to form an oxo; or two R
26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl,
WSGR Docket No. 41223-754.601 heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00146] In some aspect, the compound of Formula (III) gets metabolized in vivo. [00147] In some aspect, the compound of Formula (III) gets metabolized in vivo to a compound of Formula (II-M). [00148] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a
[00149] In some embodiments of a compound of Formula (III), X is hydrogen. In some embodiments of a compound of Formula (III), X is -CN.
[00150] In some embodiments of a compound of Formula (III), R
13 is hydrogen. In some embodiments of a compound of Formula (III), R
13 is C
1-C
6alkyl. [00151] In some embodiments of a compound of Formula (III), R
14 is -OH. In some embodiments of a compound of Formula (III), R
14 is fluoro. [00152] In some embodiments of a compound of Formula (III), R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a;
WSGR Docket No. 41223-754.601 R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a. [00153] In some embodiments of a compound of Formula (III), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is hydrogen, -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a. [00154] In some embodiments of a compound of Formula (III), R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is hydrogen, -C(=O)R
26, -C(=O)OR
26, -CH2-O-C(=O)R
26, -CH2-O-C(=O)OR
26, or C1-C6alkyl optionally substituted with one or more R
16a. [00155] In some embodiments of a compound of Formula (III), R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a. [00156] In some embodiments of a compound of Formula (III), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is hydrogen, -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a. [00157] In some embodiments of a compound of Formula (III), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a;
WSGR Docket No. 41223-754.601 R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is hydrogen, -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a. [00158] In some embodiments of a compound of Formula (III), R
11 is -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; and R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a. [00159] In some embodiments of a compound of Formula (III), R
11 is hydrogen, -C(=O)R
21, or C
1- C
6alkyl optionally substituted with one or more R
11a. In some embodiments of a compound of Formula (III), R
11 is hydrogen or -C(=O)R
21. In some embodiments of a compound of Formula (III), R
11 is hydrogen. In some embodiments of a compound of Formula (III), R
11 is -C(=O)R
21. [00160] In some embodiments of a compound of Formula (III), each R
11a is independently halogen, - CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (III), each R
11a is independently halogen. [00161] In some embodiments of a compound of Formula (III), R
21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a. In some embodiments of a compound of Formula (III), R
21 is C
1-C
6alkyl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R
21 is C
1-C
6alkyl, C
1- C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00162] In some embodiments of a compound of Formula (III), each R
21a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (III), each R
21a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00163] In some embodiments of a compound of Formula (III), R
12 is hydrogen, -C(=O)R
22, - C(=O)OR
22, or C
1-C
6alkyl. In some embodiments of a compound of Formula (III), R
12 is -C(=O)R
22, - C(=O)OR
22, or C
1-C
6alkyl. In some embodiments of a compound of Formula (III), R
12 is hydrogen or - C(=O)R
22. In some embodiments of a compound of Formula (III), R
12 is hydrogen, or -C(=O)OR
22. In some embodiments of a compound of Formula (III), R
12 is hydrogen or C
1-C
6alkyl. In some embodiments of a compound of Formula (III), R
12 is -C(=O)OR
22. In some embodiments of a compound of Formula (III), R
12 is -C(=O)NR
22R
23.
WSGR Docket No. 41223-754.601 [00164] In some embodiments of a compound of Formula (III), each R
12a is independently halogen, - CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (III), each R
12a is independently halogen. [00165] In some embodiments of a compound of Formula (III), R
22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (III), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00166] In some embodiments of a compound of Formula (III), R
22 is C
1-C
6alkyl or C
1- C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (III), R
22 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. [00167] In some embodiments of a compound of Formula (III), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (III), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00168] In some embodiments of a compound of Formula (III), R
23 is hydrogen, C
1-C
6alkyl, or C
1- C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (III), R
23 is hydrogen or C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (III), R
23 is C1-C6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (III), R
23 is C
1-C
6alkyl. In some embodiments of a compound of Formula (III), R
23 is hydrogen.
WSGR Docket No. 41223-754.601 [00169] In some embodiments of a compound of Formula (III), each R
22a is independently halogen, - CN, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, - C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00170] In some embodiments of a compound of Formula (III), each R
22a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R
22a is independently halogen, -OH, -OR
a, - NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (III), each R
22a is independently halogen, -OC(=O)R
a, or -NR
cR
d. In some embodiments of a compound of Formula (III), each R
22a is independently -OC(=O)R
a or -NR
cR
d. In some embodiments of a compound of Formula (IV), each R
22a is independently -OC(=O)R
a. [00171] In some embodiments of a compound of Formula (III), R
12 is
, , ,
some embodiments of a compound of Formula
. [00173] In some embodiments of a compound of Formula (III), R
15 is -C(=O)R
25. In some embodiments of a compound of Formula (III), R
15 is -C(=O)OR
25. In some embodiments of a compound of Formula (III), R
15 is -CH
2-O-C(=O)R
25. [00174] In some embodiments of a compound of Formula (III), R
25 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (III), R
25 is C
1- C
6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (III), R
25 is C
1-C
6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R
25a. [00175] In some embodiments of a compound of Formula (III), each R
25a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (III), each R
25a is independently halogen, -OH, -OR
a, -NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. [00176] In some embodiments of a compound of Formula (III), R
16 is hydrogen, -C(=O)R
26, or -CH
2- O-C(=O)R
26. In some embodiments of a compound of Formula (III), R
16 is hydrogen or -C(=O)R
26. In some embodiments of a compound of Formula (III), R
16 is -C(=O)R
26. In some embodiments of a
WSGR Docket No. 41223-754.601 compound of Formula (III), R
16 is hydrogen. In some embodiments of a compound of Formula (III), R
16 is -CH
2-O-C(=O)R
26. [00177] In some embodiments of a compound of Formula (III), each R
16a is independently halogen, - CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (III), each R
16a is independently halogen. [00178] In some embodiments of a compound of Formula (III), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (III), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
26a. In some embodiments of a compound of Formula (III), R
26 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R
26a. [00179] In some embodiments of a compound of Formula (III), each R
26a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (III), each R
26a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl.
R
16 is not . In some embodiments of a compound of Formula (III), R
16 is not . In some embodiments of a compound of Formula (III), R
16 is not
. [00181] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
WSGR Docket No. 41223-754.601 Formula (IV); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; each R
12a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
12a on the same atom are taken together to form an oxo; R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a;
WSGR Docket No. 41223-754.601 or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro; R
15 is -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; R
25 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
25a; each R
25a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
25a on the same atom are taken together to form an oxo; or two R
25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl,
WSGR Docket No. 41223-754.601 heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00182] In some aspect, the compound of Formula (IV) gets metabolized in vivo. [00183] In some aspect, the compound of Formula (IV) gets metabolized in vivo to a compound of Formula (IV-M). [00184] Also disclosed herein is a compound of Formula (IV-M), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (IV-M); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo; R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl,
WSGR Docket No. 41223-754.601 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; each R
12a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
12a on the same atom are taken together to form an oxo; R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl; R
14 is -OH or fluoro; R
17 is hydrogen,
; R
7 is hydrogen or a counterion;
WSGR Docket No. 41223-754.601 each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00185] In some embodiments of a compound of Formula
embodiments of a compound of Formula
some embodiments of a compound of Formula
WSGR Docket No. 41223-754.601 [00186] In some embodiments of a compound of Formula (IV) or (IV-M), X is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), X is -CN. In some embodiments of a compound of Formula (IV) or (IV-M), R
13 is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), R
13 is C
1-C
6alkyl. [00187] In some embodiments of a compound of Formula (IV) or (IV-M), R
14 is -OH. In some embodiments of a compound of Formula (IV) or (IV-M), R
14 is fluoro. [00188] In some embodiments of a compound of Formula (IV) or (IV-M), R
11 is hydrogen, -C(=O)R
21, or C
1-C
6alkyl optionally substituted with one or more R
11a. In some embodiments of a compound of Formula (IV) or (IV-M), R
11 is hydrogen or -C(=O)R
21. In some embodiments of a compound of Formula (IV) or (IV-M), R
11 is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), R
11 is -C(=O)R
21.
[00189] In some embodiments of a compound of Formula (IV) or (IV-M), each R
11a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (IV) or (IV-M), each R
11a is independently halogen. [00190] In some embodiments of a compound of Formula (IV) or (IV-M), R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a. In some embodiments of a compound of Formula (IV) or (IV-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R
21 is C
1-C
6alkyl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00191] In some embodiments of a compound of Formula (IV) or (IV-M), each R
21a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (IV) or (IV-M), each R
21a is independently halogen, - OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00192] In some embodiments of a compound of Formula (IV) or (IV-M), R
12 is -C(=O)R
22, - C(=O)OR
22, or C
1-C
6alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R
12 is - C(=O)R
22. In some embodiments of a compound of Formula (IV) or (IV-M), R
12 is -C(=O)OR
22. In some embodiments of a compound of Formula (IV) or (IV-M), R
12 is C
1-C
6alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R
12 is -C(=O)NR
22R
23. [00193] In some embodiments of a compound of Formula (IV) or (IV-M), each R
12a is independently halogen, -CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (IV) or (IV-M), each R
12a is independently halogen. [00194] In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-
WSGR Docket No. 41223-754.601 C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. [00195] In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. [00196] In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00197] In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl or C
1- C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (IV) or (IV-M), R
22 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. [00198] In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00199] In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen, C
1-C
6alkyl, or C
1-C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen or C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is C1-C6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is C
1-C
6alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R
23 is hydrogen.
WSGR Docket No. 41223-754.601 [00200] In some embodiments of a compound of Formula (IV) or (IV-M), each R
22a is independently halogen, -CN, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, - C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00201] In some embodiments of a compound of Formula (IV) or (IV-M), each R
22a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) or (IV-M), each R
22a is independently halogen, - OH, -OR
a, - NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (IV) or (IV-M), each R
22a is independently halogen, -OC(=O)R
a, or -NR
cR
d. In some embodiments of a compound of Formula (IV) or (IV-M), each R
22a is independently -OC(=O)R
a or -NR
cR
d. In some embodiments of a compound of Formula (IV) or (IV-M), each R
22a is independently -OC(=O)R
a. [00202] In some embodiments of a compound of Formula (IV) or (IV-M), R
12 is
, ,
[00203] In some embodiments of a compound of Formula
[00204] In some embodiments of a compound of Formula (IV), R
15 is -C(=O)R
25. In some embodiments of a compound of Formula (IV), R
15 is -C(=O)OR
25. In some embodiments of a compound of Formula (IV), R
15 is -CH
2-O-C(=O)R
25. In some embodiments of a compound of Formula (IV), R
25 is C
1-C
6alkylene(cycloalkyl) or C
1-C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (IV), R
25 is C
1-C
6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
25a. In some embodiments of a compound of Formula (IV), R
25 is C
1-C
6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R
25a.
[00205] In some embodiments of a compound of Formula (IV), each R
25a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), each R
25a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl.
WSGR Docket No. 41223-754.601 [00206] In some embodiments of a compound of Formula (IV), R
15 is
,
. In some embodiments of a compound of Formula (IV), R
15 is
. In some embodiments of a compound of Formula (IV), R
15 is
. In some embodiments of a compound of Formula (IV), R
15 is
. In some embodiments of a compound of Formula (IV), R
15 is
. In some embodiments of a compound of Formula (IV), R
15 is not
. In some embodiments of a compound of Formula (IV), R
15 is not
. In some embodiments of a compound of Formula (IV), R
15 is not
. [00207] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula (IV-M), R
17 is
WSGR Docket No. 41223-754.601
.
[00208] In some embodiments of a compound of Formula (IV-M), R
7 is hydrogen. In some embodiments of a compound of Formula (IV-M), R
7 is a counterion. In some embodiments of a compound of Formula (IV-M), R
7 is Na
+. In some embodiments of a compound of Formula (IV-M), R
7 is Li
+. In some embodiments of a compound of Formula (IV-M), R
7 is Mg
2+. [00209] Also disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (V); wherein: X is hydrogen or -CN;
R
11 is hydrogen, -C(=O)R
21, -C(=O)OR
21, or C
1-C
6alkyl optionally substituted with one or more R
11a; each R
11a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
11a on the same atom are taken together to form an oxo;
WSGR Docket No. 41223-754.601 R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a; each R
21a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
21a on the same atom are taken together to form an oxo; or two R
21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
12 is -C(=O)R
22, -C(=O)OR
22, -C(=O)NR
22R
23, or C
1-C
6alkyl optionally substituted with one or more R
12a; each R
12a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
12a on the same atom are taken together to form an oxo; R
22 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a; or R
22 and R
23 are taken together to form a heterocycloalkyl optionally substituted with one or more R
22a; each R
22a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
22a on the same atom are taken together to form an oxo; or two R
22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
13 is hydrogen or C
1-C
6alkyl;
WSGR Docket No. 41223-754.601 R
14 is -OH or fluoro; R
15 is hydrogen, -C(=O)R
25, -C(=O)OR
25, -CH
2-O-C(=O)R
25, or -CH
2-O-C(=O)OR
25; R
25 is C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
25a; each R
25a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
25a on the same atom are taken together to form an oxo; or two R
25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R
16 is -C(=O)R
26, -C(=O)OR
26, -CH
2-O-C(=O)R
26, -CH
2-O-C(=O)OR
26, or C
1-C
6alkyl optionally substituted with one or more R
16a; each R
16a is independently halogen, -CN, -OH, -OR
a, -NR
cR
d, cycloalkyl, or heterocycloalkyl; or two R
16a on the same atom are taken together to form an oxo; R
26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1- C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a; each R
26a is independently halogen, -CN, -NO
2, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, - S(=O)R
a, -S(=O)
2R
a, -S(=O)
2NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R
26a on the same atom are taken together to form an oxo; or two R
26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each R
a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
WSGR Docket No. 41223-754.601 each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more R; R
c and R
d are each independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, C
2-C
6alkenyl, C
2-C
6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkyl(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH
3, -S(=O)CH
3, -S(=O)
2CH
3, -S(=O)
2NH
2, - S(=O)
2NHCH
3, -S(=O)
2N(CH
3)
2, -NH
2, -NHCH
3, -N(CH
3)
2, -C(=O)CH
3, -C(=O)OH, -C(=O)OCH
3, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, and C
1-C
6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00210] In some aspect, the compound of Formula (V) gets metabolized in vivo. [00211] In some aspect, the compound of Formula (V) gets metabolized in vivo to a compound of Formula (IV-M). [00212] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a
[00213] In some embodiments of a compound of Formula (V), X is hydrogen. In some embodiments of a compound of Formula (V), X is -CN.
WSGR Docket No. 41223-754.601 [00214] In some embodiments of a compound of Formula (V), R
13 is hydrogen. In some embodiments of a compound of Formula (V), R
13 is C
1-C
6alkyl. [00215] In some embodiments of a compound of Formula (V), R
14 is -OH. In some embodiments of a compound of Formula (V), R
14 is fluoro. [00216] In some embodiments of a compound of Formula (V), R
11 is hydrogen, -C(=O)R
21, or C
1- C
6alkyl optionally substituted with one or more R
11a. In some embodiments of a compound of Formula (V), R
11 is hydrogen or -C(=O)R
21. In some embodiments of a compound of Formula (V), R
11 is hydrogen. In some embodiments of a compound of Formula (V), R
11 is -C(=O)R
21. [00217] In some embodiments of a compound of Formula (V), each R
11a is independently halogen, - CN, -OH, -OR
a, or -NR
cR
d. In some embodiments of a compound of Formula (V), each R
11a is independently halogen. [00218] In some embodiments of a compound of Formula (V), R
21 is C
1-C
6alkyl, C
1-C
6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
21a. In some embodiments of a compound of Formula (V), R
21 is C
1-C
6alkyl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R
21 is C1-C6alkyl, C1- C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00219] In some embodiments of a compound of Formula (V), each R
21a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound of Formula (V), each R
21a is independently halogen, -OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00220] In some embodiments of a compound of Formula (V), R
12 is -C(=O)R
22, -C(=O)OR
22, or C
1- C
6alkyl. In some embodiments of a compound of Formula (V), R
12 is -C(=O)R
22. In some embodiments of a compound of Formula (V), R
12 is -C(=O)OR
22. In some embodiments of a compound of Formula (V), R
12 is C
1-C
6alkyl. In some embodiments of a compound of Formula (V), R
12 is -C(=O)NR
22R
23. [00221] In some embodiments of a compound of Formula (V), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. [00222] In some embodiments of a compound of Formula (V), R
22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments
WSGR Docket No. 41223-754.601 of a compound of Formula (V), R
22 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). In some embodiments of a compound of Formula (V), R
22 is C
1-C
6alkyl or C
1- C
6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (V), R
22 is C
1-C
6alkyl optionally and independently substituted with one or more R
22a. [00223] In some embodiments of a compound of Formula (V), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (V), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1- C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C
6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R
23 is hydrogen, C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl).
[00224] In some embodiments of a compound of Formula (V), R
23 is hydrogen, C
1-C
6alkyl, or C
1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (V), R
23 is hydrogen or C
1-C
6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (V), R
23 is C1-C6alkyl optionally and independently substituted with one or more R
22a. In some embodiments of a compound of Formula (V), R
23 is C
1-C
6alkyl. In some embodiments of a compound of Formula (V), R
23 is hydrogen. [00225] In some embodiments of a compound of Formula (V), each R
22a is independently halogen, - CN, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, - C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00226] In some embodiments of a compound of Formula (V), each R
22a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00227] In some embodiments of a compound of Formula (V), each R
22a is independently halogen, - OH, -OR
a, - NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00228] In some embodiments of a compound of Formula (V), each R
22a is independently halogen, - OC(=O)R
a, or -NR
cR
d. In some embodiments of a compound of Formula (V), each R
22a is independently -OC(=O)R
a or -NR
cR
d. In some embodiments of a compound of Formula (V), each R
22a is independently -OC(=O)R
a.
WSGR Docket No. 41223-754.601
some embodiments of a compound of Formula (V), R
12 is
, or
.
[00231] In some embodiments of a compound of Formula (V), R
15 is hydrogen. In some embodiments of a compound of Formula (V), R
15 is -C(=O)R
25. In some embodiments of a compound of Formula (V), R
15 is -C(=O)OR
25. [00232] In some embodiments of a compound of Formula (V), R
25 is C
1-C
6alkylene(cycloalkyl) or C
1- C
6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R
25a. [00233] In some embodiments of a compound of Formula (V), R
25 is C
1-C
6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R
25a. [00234] In some embodiments of a compound of Formula (V), R
25 is C
1-C
6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R
25a. [00235] In some embodiments of a compound of Formula (V), each R
25a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00236] In some embodiments of a compound of Formula (V), each R
25a is independently halogen, - OH, -OR
a, -NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00237] In some embodiments of a compound of Formula (V), R
15 is
, , , or
. In some embodiments of a compound of Formula (V), R
15 is
embodiments of a compound of Formula (V), R
15 is
. In some embodiments of a compound of Formula (V), R
15 is
. In some embodiments of a compound of Formula (V), R
15 is
. In
WSGR Docket No. 41223-754.601 some embodiments of a compound of Formula (V), R
15 is not . In some embodiments of a compound of Formula (V), R
15 is not
. In some embodiments of a compound of Formula (V), R
15 is not
. [00238] In some embodiments of a compound of Formula (V), R
16 is -C(=O)R
26. [00239] In some embodiments of a compound of Formula (V), R
16 is -C(=O)OR
26. [00240] In some embodiments of a compound of Formula (V), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R
26a. [00241] In some embodiments of a compound of Formula (V), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1- C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). [00242] In some embodiments of a compound of Formula (V), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1- C6alkylene(heteroaryl). [00243] In some embodiments of a compound of Formula (V), R
26 is C
1-C
6alkyl, C
1-C
6aminoalkyl, aryl, C
1-C
6alkylene(cycloalkyl), or C
1-C
6alkylene(aryl). [00244] In some embodiments of a compound of Formula (V), R
26 is C
1-C
6alkyl or C
1-C
6aminoalkyl. [00245] In some embodiments of a compound of Formula (V), each R
26a is independently halogen, - CN, -OH, -OR
a, -OC(=O)R
a, -OC(=O)OR
b, -OC(=O)NR
cR
d, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, - C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00246] In some embodiments of a compound of Formula (V), each R
26a is independently halogen, - CN, -OH, -OR
a, -NR
cR
d, -C(=O)R
a, -C(=O)OR
b, -C(=O)NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00247] In some embodiments of a compound of Formula (V), each R
26a is independently halogen, - OH, -OR
a, - NR
cR
d, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00248] In some embodiments of a compound of Formula (V), each R
26a is independently -OC(=O)R
a, or -NR
cR
d.
WSGR Docket No. 41223-754.601
. In some embodiments of a compound of Formula (V), R
16 is not . In some embodiments of a compound of Formula (V), R
16 is not
. [00249] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkyl(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkyl(aryl), or C
1-C
6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
a is independently C
1-C
6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
a is independently C
1-C
6alkyl, C
1-C
6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
a is independently C
1-C
6alkyl or C
1-C
6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
a is independently C
1-C
6alkyl. [00250] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed
WSGR Docket No. 41223-754.601 herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently hydrogen, C
1-C
6alkyl or C
1-C
6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently hydrogen or C
1-C
6alkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is hydrogen. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
b is independently C
1-C
6alkyl. [00251] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
1-C
6aminoalkyl, C
1-C
6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C
1-C
6alkylene(cycloalkyl), C
1-C
6alkylene(heterocycloalkyl), C
1-C
6alkylene(aryl), or C
1-C
6alkyl(heteroaryl). In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently hydrogen, C
1-C
6alkyl, C
1-C
6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently hydrogen, C
1-C
6alkyl or C
1-C
6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently hydrogen or C
1-C
6alkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are hydrogen. In some embodiments of a
WSGR Docket No. 41223-754.601 compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R
c and R
d are independently C
1-C
6alkyl. [00252] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R
c and R
d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. [00253] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC
1-C
6alkyl, -NH
2, - NHC
1-C
6alkyl, -N(C
1-C
6alkyl)
2, -NHC(=O)OC
1-C
6alkyl, -C(=O)C
1-C
6alkyl, -C(=O)OH, - C(=O)OC
1-C
6alkyl, -C(=O)NH
2, -C(=O)N(C
1-C
6alkyl)
2, -C(=O)NHC
1-C
6alkyl, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC
1-C
6alkyl, -NH
2, - C(=O)C
1-C
6alkyl, -C(=O)OH, -C(=O)OC
1-C
6alkyl, -C(=O)NH
2, C
1-C
6alkyl, or C
1-C
6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC
1-C
6alkyl, -NH
2, C
1-C
6alkyl, or C
1-C
6haloalkyl. [00254] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00255] Described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound in Table 1. Table 1. Exemplary compounds.
WSGR Docket No. 41223-754.601
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Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [00256] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or
WSGR Docket No. 41223-754.601 interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds [00257] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as
2H,
3H,
13C,
14C,
l5N,
18O,
17O,
31P,
32P,
35S,
18F, and
36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as
3H and
14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,
3H and carbon-14, i.e.,
14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,
2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. [00258] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [00259] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods
WSGR Docket No. 41223-754.601 disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [00260] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof , or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [00261] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosu lfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate. [00262] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 - carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
WSGR Docket No. 41223-754.601 [00263] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N
+(C
1-4 alkyl)
4, and the like. [00264] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [00265] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [00266] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers [00267] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Prodrugs [00268] “Prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an
WSGR Docket No. 41223-754.601 active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam). Prodrugs are delivered through any known methods described herein, including but not limited to orally, intravenously, intraperitoneal, or other method of administration known by those skilled in the art. [00269] A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. [00270] The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. In some embodiments, prodrugs include any group bound to a heteroatom, such as the nitrogen of a pyridine which is cleaved in vivo to form the active compound or metabolite thereof. Examples of prodrugs include, but are not limited to, acetate, formate phosphate, and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like. [00271] In some embodiments, a prodrug is a salt. In some embodiments, a prodrug is a phosphate salt. In some embodiments, a prodrug is an alkyl phosphate salt. In some embodiments, a prodrug is an alkylated heteroaromatic salt. In some embodiments, a prodrug is a pyridinium salt. In some embodiments, a prodrug is a pyridinium alkylphosphate salt. In some embodiments, a prodrug is a pyridinium methylphosphate salt. In some embodiments, a prodrug comprises an alkyl phosphate bound to a heteroatom. In some embodiments, a prodrug comprises an alkyl phosphate bound to a heteroatom of a heterocycle. [00272] In some embodiments, a prodrug is any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each. In other embodiments, prodrugs are formed using groups attached to functionality, e.g., HO—, HS—, HOOC—, NHR—, associated with the drug or active compounds, that cleave in vivo. In some embodiments, prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol, and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated above are exemplary, not exhaustive, and other varieties of prodrugs are possible. Such prodrugs of disclosed compounds fall within this scope. In some embodiments, the compounds of the present
WSGR Docket No. 41223-754.601 application are prodrugs themselves and are converted into other forms, including the biologically active compound forms, when administered to a biological system. [00273] In some embodiments, prodrugs undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, more, or less than the intended active drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc. Prodrug forms of compounds are utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992, Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed. by E. B. Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press, Oxford, 1980. [00274] In some embodiments, prodrugs comprise phosphorus moieties includ ing phosphates or derivatives thereof. One such class of prodrugs is the aryl amidate (McGuigan) type. One report disclosed pharmacokinetic evaluation in the cynomolgus monkey of an aryl amidate prodrug of abacavir. (C. McGuigan et al., “Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency,” J. Med. Chem. 2005, 48, 3504-3515). [00275] In some embodiments, the compounds of the present application comprise a prodrug moiety that is carbamate, thiocarbamate, or urea to mask an amino or hydroxy group on the active compound. In some embodiments, the prodrug moiety of carbamate, thiocarbamate, or urea is metabolized in vivo to afford the free amino or hydroxy moiety on the active compound. Method of Treatment [00276] In one aspect, the disclosure provides a method of treating, preventing and/or reducing the severity or extent of viral infections by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound. [00277] The compounds described herein find use in a variety of applications for human and animal health. In some embodiments, the compounds described herein are inhibitors of coronavirus. [00278] In some embodiments, the efficacy of treatment is determined using quantification of viral load or other evidence of infection. [00279] In some embodiments, the compounds described herein reduce viral load in an individual suffering from a coronavirus infection.
WSGR Docket No. 41223-754.601 [00280] As used herein, the term “administering” or “administration” refers to any route of introducing or delivering the composition or formulation to perform the intended function or treatment. Administration can be carried out by any route suitable for the delivery of composition or formulation. Thus, delivery routes can include intravenous, intramuscular, intraperitoneal, or subcutaneous delivery. Administration includes self-administration and the administration by another. [00281] As used herein, he terms “patient” “subject” “individual” and the like are used interchangeably, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject, or individual is a human. [00282] As used herein, the terms “prevent” and “prevention” refer to acting prior to overt disease or disorder onset, to prevent the disease or disorder from developing, or to minimize the extent of the disease or disorder, or to slow its course of development. [00283] As used herein, the term “cure” refers to heal, to make well, or to restore to good health or to allow a time without recurrence of disease so that the risk of recurrence is small. [00284] The subjects receiving the therapy described herein (e.g. a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising the compound) may experience as a result of the therapy a reduction of virus count or improvement of at least one symptom associated with the virus infection, including, for example, fever, coughing, fatigue, pain, etc. [00285] In one aspect, the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection and associated disease from an RNA or DNA virus that includes but is not limited to coronaviruses, respiratory syncytial virus, influenza viruses, flaviviruses, hemorrhagic fever viruses, alphaviruses, polyomaviruses, herpesviruses, and poxviruses. [00286] In one aspect, the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection, including, for example, a single-stranded positive sense RNA virus, coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, and Human immunodeficiency virus type 1. In another aspect, the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection, including, for example, a DNA virus, equine herpesvirus type 1, pseudorabies virus, BK polyomavirus, and porcine circovirus 2. COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV). [00287] In one aspect, the disclosure provides a method for treating, preventing and/or reducing the severity or extent of viral infection and associated disease from an RNA or DNA virus that includes but is not limited to coronaviruses, respiratory syncytial virus, influenza viruses, flaviviruses, hemorrhagic fever viruses, alphaviruses, polyomaviruses, herpesviruses, and poxviruses.
WSGR Docket No. 41223-754.601 [00288] Also disclosed herein is a method of treating an infection in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00289] Also disclosed herein is a method of treating an infection in a subject, comprising administering to the subject a pharmaceutical composition disclosed herein. [00290] In some embodiments, the infection is a viral infection. In some embodiments, the viral infection is caused by the SARS-CoV or SARS-CoV-2 virus. In some embodiments, the viral infection is COVID, or COVID-19. In some embodiments, the viral infection is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). [00291] In some embodiments, the viral infection is caused by a filovirus. In some embodiments the viral infection is caused by the Ebola virus. In some embodiments the viral infection is caused by the Marburg virus. [00292] In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyavirid ae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papillomavirus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Poxviridae, Potyviridae, Reoviridae, Retroviridae, Rhabdoviridae, Tectiviridae, Togaviridae, orthopoxvirus, coronavirus, influenza virus, sendai virus (SeV), sindbis virus (SINV), vaccinia viruses, West Nile virus, Hantavirus, viruses which cause the common cold, and any combination thereof. [00293] In some embodiments, the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Adenoviridae, Arenaviridae, Arteriviridae, Astroviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae, Coronaviridae, Deltavirus, Filoviridae, Flaviviridae, Hepadnaviridae, Papovaviridae, Paramyxoviridae, Parvoviridae, Poxviridae, Reoviridae, Retroviridae, Rhabdoviridae, Togaviridae, and viruses which cause the common cold, and any combination thereof. [00294] Zaire ebolavirus is one of five known species (Bundibugyo ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, and Reston ebolavirus) within the genus Ebolavirus. With the exception of Reston ebolavirus, the other four known ebolaviruses can infect humans and cause a severe and often fatal hemorrhagic fever known as Ebola virus disease (EVD). In some embodiments the viral infection is caused by one ebolavirus. Compositions/Formulations [00295] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds of this
WSGR Docket No. 41223-754.601 invention may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration. [00296] In another aspect, provided herein are pharmaceutical compositions comprising a compound describe herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharm aceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00297] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof. [00298] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. [00299] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee -making, levigating, emulsifying, encapsulating, entrapping, or compression processes. [00300] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee
WSGR Docket No. 41223-754.601 cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [00301] Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. [00302] Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontox ic glyceryl esters, and any combinations thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms. [00303] As used herein, the term “composition” or “pharmaceutical composition” refers to a composition comprising a therapeutically effective compound and a pharmaceutically acceptable carrier and optionally, other materials, e.g., one or more inert components (for example, a detectable agent or label) or one or more active components. The pharmaceutical composition facilitates administration of the therapeutically effective compound to a subject. [00304] As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle in which the pharmaceutical composition is administered. Pharmaceutically acceptable carriers may include one or more solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible. Compositions can include components such as diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, or mixtures thereof. Examples of pharmaceutically acceptable carriers include but are not limited to water, saline, phosphate buffered saline, aqueous dextrose solutions, glycerol solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, dextrose, gelatin, mannitol, cellulose malt, rice, flour, chalk, silica gel, sodium stearate, glycerol
WSGR Docket No. 41223-754.601 monostearate, talc, sodium chloride, milk powder, glycerol, propylene, glycol, water, ethanol, and the like. [00305] Carriers may also encompass a buffer or pH adjusting agent such as a salt prepared from an organic acid or base optionally mixed with a nontoxic surfactant. Examples of buffers include but are not limited to organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, and phosphate buffers. Additional carriers may include polymeric excipients or additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-.quadrature.- cyclodextrin), polyethylene glycols, flavoring agents such as cherry or wintergreen flavor, antimicrobial agents, sweeteners, antioxidants, antistatic agents. The compositions may include a pharmaceutical carrier or excipient and a compound disclosed herein, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, binding agents etc. A pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc. [00306] The compositions can take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, solutions, suspensions, emulsion, aerosols, gels, implants, microneedles, tablets, pills, capsules, soft elastic or hard gelatin capsules, dermal patch, gummy bears, powders, suspensions, extended-release formulations, and the like, for example, in unit dosage forms suitable for simple administration of precise dosages. In one embodiment the composition takes the forms of tablets, capsules, liquid caps, sublingual dissolving tablets, sublingual spray, nasal spray, gummy bear and/or dermal patch. [00307] In one aspect, the composition is a liquid-based formulation including but not limited to an emulsion, suspension, solution, elixirs, or syrup in which the disclosed compound is dissolved and/or suspended, or in the form of a liquid-containing capsule in which the disclosed compound is dissolved and/or suspended in the liquid portion of the capsule core. The composition may be a capsule filled with an effective therapeutic amount of the liquid pharmaceutical formulation. Combination [00308] Disclosed herein are methods of treating a virus infection using a compound disclosed herein in combination with additional therapeutic agents. [00309] Disclosed herein are methods of treating coronavirus infection using a compound disclosed herein in combination with additional therapeutic agents useful for treating coronavirus infection. [00310] In some embodiments, the compound disclosed herein in combination with additional therapeutic agents useful for treating a coronavirus infection are administered simultaneously. In some embodiments, the compound disclosed herein in combination with additional therapeutic agents useful for treating a coronavirus infection are administered sequentially.
WSGR Docket No. 41223-754.601 [00311] In some embodiments, for the treatment of Arenaviridae virus infections or coronavirus infection, the additional therapeutic agent is also active against Arenaviridae virus infections, particularly including Lassa and Junin virus, coronavirus infection and Junin virus infections. [00312] Non-limiting examples of additional therapeutic agents include ribavirin, favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof. [00313] The compounds and compositions of the present disclosure are also intended for use with general care provided to patients with Arenaviridae 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 K and zinc sulfate), anti-inflammatory agents (such as ibuprofen, corticosteroids, kinase inhibitors or monoclonal antibodies targeting cytokines and other immunomodulatory signaling or checkpoint ligands/receptors), 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. [00314] In some embodiments, the additional therapeutic agent is an influenza antiviral agent (oseltamivir, zanamivir, baloxavir marboxil). In some embodiments, the additional therapeutic agent is an RSV antiviral agent (palivizumab). In some embodiments, the additional therapeutic agent is a monoclonal antibody cocktail. In some embodiments, the additional therapeutic agent is a monoclonal antibody cocktail for Ebolavirus disease (atoltivimab/maftivimab/odesivimab, Ebanga
TM). In some embodiments, the additional therapeutic agent is a steroid. [00315] In some embodiments, the additional therapeutic agent is a ribonucleic acid (RNA)-dependent RNA polymerase inhibitor, a checkpoint inhibitor or PD-1/PD-L1 inhibitor, a therapeutic vaccine, an RNA interference (RNAi) therapeutic, an antisense-based therapeutic, an coronavirus entry inhibitor, a TLR agonist, an RIG-I agonist, or an interferon. [00316] It is also possible to combine any compound of the disclosure with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. [00317] Co-administration of a compound of the disclosure with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the disclosure and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound
WSGR Docket No. 41223-754.601 of the disclosure and one or more other active therapeutic agents are both present in the body of the patient. [00318] Co-administration includes administration of unit dosages of the compounds of the disclosure before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the disclosure within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the disclosure can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the disclosure within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the disclosure first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the disclosure. [00319] The combination therapy may provide “synergy” and “synergistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co - formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills, or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect denotes an inhibitory activity that is greater than predicted additive activity of the individual compounds acting alone.. [00320] Additional non-limiting examples of additional therapeutic agents useful for treating coronavirus infections include: TLR Agonists [00321] In some embodiments, the compound described herein is used in combination with a TLR agonist (TLR7, 8 and/or 9). In some embodiments, the TLR agonist is RG7795, GS-9620, SM360320, or AZD 8848. RIG-I agonists [00322] In some embodiments, the compound described herein is used in combination with a RIG-I agonist. In some embodiments, the RIG-I agonist is inarigivir. Interferons [00323] In some embodiments, the compound described herein is used in combination with an interferon. In some embodiments, the interferon is interferon alpha (IFN-a), interferon alpha-2a,
WSGR Docket No. 41223-754.601 recombinant interferon alpha-2a, peginterferon alpha-2a, interferon alpha-2b, recombinant interferon alpha- 2b, interferon alpha-2b XL, peginterferon alpha-2b, glycosylated interferon alpha-2b, interferon alpha-2c, recombinant interferon alpha-2c, interferon beta, interferon beta- la, peginterferon beta- la, interferon delta, interferon lambda (IFN-l), peginterferon lambda-1, interferon omega, interferon tau, interferon gamma (IFN-g), interferon alfacon-l, interferon alpha-nl, interferon alpha-n3, albinterferon alpha-2b, BLX-883, DA-3021, PI 101 (also known as AOP2014), PEG- infergen, belerofon, INTEFEN- IFN, albumin/interferon alpha 2a fusion protein, rHSA-IFN alpha 2a, rHSA-IFN alpha 2b, PEG-IFN-SA, interferon alpha biobetter; in particular, peginterferon alpha-2a, peginterferon alpha-2b, glycosylated interferon alpha-2b, peginterferon beta-la, or peginterferon lambda-1. Antiviral agents [00324] In some embodiments, the compound described herein is used in combination with an antiviral agent. In some embodiments, the antiviral agent is abacavir, acyclovir, adefovir, brivudine, cidofovir, didanosine, edoxudine, emtricitabine, entecavir, famciclovir, favipiravir, ganciclovir, idoxuridine, lamivudine, molnupiravir, nirmatrelvir, penciclovir, remdesivir, ribavirin, sofosbuvir, ST-193, stavudine, T-705 diphosphate,T-705 monophosphate, T-705 triphosphate, telbivudine, tenofovir alafenamide, tenofovir disoproxil, trifluridine, valaciclovir, valganciclovir, vidarabine, zalcitabine, zidovudine, or any combinations thereof. In some embodiments, the antiviral agent is molnupiravir. In some embodiments, the antiviral agent is nirmatrelvir/ritonavir. Monoclonal antibodies [00325] In some embodiments, the compound described herein is used in combination with a monoclonal antibody. In some embodiments, the monoclonal antibody is bamlanivimab, REGEN-COV (casirivimab and imdevimab, administered together), bamlanivimab and etesevimab (administered together), sotrovimab, or tocilizumab. Other Antiviral Agents [00326] In some embodiments, the compound described herein is used in combination with a Guanosine Nucleotide Analog. In some embodiments, the Guanosine Nucleotide Analog is AT-527. [00327] In some embodiments, the compound described herein is used in combination with a protease inhibitor. In some embodiments, the protease inhibitor is nirmatrelvir, ritonavir, or a combination thereof. Preparation of Compounds [00328] The size and scale of the synthetic methods will vary depending on the desired amount of end product. It is understood that while specific reactants and amounts are provided in the Examples, one of skill in the art knows other alternative and equally feasible sets of reactants that will also yield the same compounds. Thus, where general oxidizers, reducers, solvents of various nature (aprotic, apolar, polar, etc.) are utilized, equivalents will be known in the art and are herein contemplated for use in the present methods.
WSGR Docket No. 41223-754.601 [00329] For instance, in all instances, where a drying agent is used, contemplated drying agents include all those reported in the literature and known to one of skill, such as, but not limited to, magnesium sulfate, sodium sulfate, calcium sulfate, calcium chloride, potassium chloride, potassium hydroxide, sulfuric acid, quicklime, phosphorous pentoxide, potassium carbonate, sodium, silica gel, aluminum oxide, calcium hydride, lithium aluminum hydride (LAH), potassium hydroxide, and the like. (See, Burfield et al., “Desiccant Efficiency in Solvent Drying. A Reappraisal by Application of a Novel Method for Solvent Water Assay,” J. Org. Chem., 42(18):3060-3065, 1977). The amount of drying agent to add in each work up may be optimized by one of skill in the art and is not particularly limited. Further, although general guidance is provided for work-up of the intermediates in each step, it is generally understood by one of skill that other optional solvents and reagents may be equally substituted during the work-up steps. However, in some exceptional instances, it was found the very specific work-up conditions are required to maintain an unstable intermediate. Those instances are indicated below in the steps in which they occur. [00330] Many of the steps below indicate various work-ups following termination of the reaction. A work-up involves generally quenching of a reaction to terminate any remaining catalytic activity and starting reagents. This is generally followed by addition of an organic solvent and separation of the aqueous layer from the organic layer. The product is typically obtained from the organic layer and unused reactants and other spurious side products and unwanted chemicals are generally trapped in the aqueous layer and discarded. The work-up in standard organic synthetic procedures found throughout the literature is generally followed by drying the product by exposure to a drying agent to remove any excess water or aqueous byproducts remaining partially dissolved in the organic layer and concentration of the remaining organic layer. Concentration of product dissolved in solvent may be achieved by any known means, such as evaporation under pressure, evaporation under increased temperature and pressure, and the like. Such concentrating may be achieved by use of standard laboratory equipment such as rotary- evaporator distillation, and the like. This is optionally followed by one or more purification steps which may include, but is not limited to, flash column chromatography, filtration through various media and/or other preparative methods known in the art. (See, for instance, Addison Ault, “Techniques and Experiments for Organic Chemistry,” 6
th Ed., University Science Books, Sausalito, Calif., 1998, Ann B. McGuire, Ed., pp.45-59). Though certain organic co-solvents and quenching agents may be indicated in the steps described below, other equivalent organic solvents and quenching agents known to one of skill may be employed equally as well and are fully contemplated herein. Further, most of the work -ups in most steps may be further altered according to preference and desired end use or end product. Drying and evaporation, routine steps at the organic synthetic chemist bench, need not be employed and may be considered in all steps to be optional. The number of extractions with organic solvent may be as many as one, two, three, four, five, or ten or more, depending on the desired result and scale of reaction. Except where specifically noted, the volume, amount of quenching agent, and volume of organic solvents used in
WSGR Docket No. 41223-754.601 the work-up may be varied depending on specific reaction conditions and optimized to yield the best results. [00331] Additionally, where inert gas or noble gas is indicated, any inert gas commonly used in the art may be substituted for the indicated inert gas, such as argon, nitrogen, helium, neon, etc. EXAMPLES [00332] Examples below are intended to illustrate the general procedures used for preparing the compounds of the present invention. [00333] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. Example 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4- (2-methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (1).
Step 1. Synthesis of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (1.2).
WSGR Docket No. 41223-754.601 [00334] To a solution of compound 1.1 (prepared according to Siegel, D., et al., J. Med. Chem. 2017, 60, 1648−1661, 5.00 g, 17.2 mmol) in DMPU (15 mL) was added HCl/1,4-dioxane (8.6 mL) at 0 °C. The mixture solution was stirred for 10 min, and cyclohexylacetyl chloride (5.3 mL, 34.4 mmol) was added into the flask vessel dropwise. The reaction mixture was stirred at 0 °C for 2 h. The mixture was adjusted to pH 8 with aqueous NaHCO
3. The mixture was diluted with water (150 mL) and extracted with EtOAc (150 mL×3). The organic phase was washed with brine water (50 mL×3), then dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The crude product was purified by chromatography (SiO
2, dichloromethane/methanol = 0% to 6%) to obtain compound 1.2 (6.30 g, 83.7% yield) as a white solid. MS (ESI): mass calcd. for C
20H
25N
5O
5, 415.19, m/z found 416.2 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.92 (br s, 3H), 6.91 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.31 (d, J = 6 Hz, 1H), 5.37 (d, J = 6 Hz, 1H), 4.68 (d, J = 5.2 Hz, 1H), 4.22 (d, J = 6 Hz, 1H), 3.9-4.15 (m, 2H), 3.92 (m, 1H), 2.07 (m, 2H), 1.5 (br m, 6H), 1.0-1.2 (m, 3H), 0.86-1.1 (m, 2H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-((2- cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanoate (1.3). [00335] To a solution of compound 1.2 (6.00 g, 14.4 mmol) in THF (200 mL) was added (2S)-2-{[(tert- butoxy)carbonyl]amino}-3-methylbutanoic acid (3.14 g, 14.4 mmol), EDCI (8.28 g, 43.2 mmol) and DMAP (5.28 mg, 43.2 mmol), the mixture was stirred at 25 ℃ for 16 h. After completion, the mixture was concentrated in vacuo to afford a residue. Then the reaction residue was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford a crude. The residue was purified by prep -HPLC [Gradient: 5-65% ACN in water (0.1% formic acid (FA))] to obtain compound 1.3 (2.65 g, 28.5% yield) as a white solid. MS (ESI): mass calcd. for C
31H
44N
6O
8, 813.47, found 814.60 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.46 – 7.89 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 4.4 Hz, 1H), 6.65 (d, J = 5.6 Hz, 1H), 5.11 (dd, J = 8.0, 5.2 Hz, 2H), 4.41 (d, J = 4.0 Hz, 1H), 4.30 (dd, J = 12.0, 3.2 Hz, 1H), 4.18 (dd, J = 12.0, 5.2 Hz, 1H), 4.06 (dd, J = 8.4, 6.0 Hz, 1H), 2.29 – 2.08 (m, 3H), 1.57 (s, 6H), 1.39 (s, 9H), 1.24 – 1.03 (m, 3H), 0.93 – 0.78 (m, 8H). Step 3: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (1.4). [00336] To a solution of 2-methoxy-2-methylpropanoic acid (70.0 mg, 0.593 mmol) in THF (40 mL) was added HATU (120 mg, 0.889 mmol), the solution was stirred at 25 ℃ for 1 h. To the above solution was added 1.3 (200 mg, 0.326 mmol) and DIEA (230 mg, 1.78 mmol), the mixture was stirred at 25 ℃ for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The organic phase was washed with brine water (50 mL×3), then dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The crude product was purified by chromatography (SiO2, Petroleum
WSGR Docket No. 41223-754.601 ether/ Ethyl acetate from 0% to 30%) to obtain compound 1.4 (120 mg, 65% purity, 18% yield) as a white solid. MS (ESI): mass calcd. for C
35H
50N
6O
10, 714.36, found 715.20 [M+H]
+. Step 4: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (1). [00337] To a solution of compound 1.4 (70.0 mg, 0.0979 mmol) in DCM (1 mL) was added HCl in dioxane (1 mL, 4 M) at 0 ℃, then the reaction was stirred at 20 ℃ for 1 h. After completion, the mixture was concentrated in vacuo to afford a residue, the residue was diluted with ACN (2 mL) and purified by prep-HPLC (mobile phase: ACN–H
2O (0.1% FA), 5%-60%) to obtain compound 1 (28.81 mg, 46.9% yield) as a white solid. MS (ESI): mass calcd. for C
30H
42N
6O
8, 614.31, found 615.20 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.85 – 6.65 (m, 1H), 5.18 – 5.13 (m, 1H), 5.12 – 5.08 (m, 1H), 4.50 (dd, J = 8.0, 4.0 Hz, 1H), 4.33 – 4.26 (m, 1H), 4.25 – 4.14 (m, 1H), 3.29 (s, 3H), 3.25 (d, J = 5.2 Hz, 1H), 2.17 – 2.08 (m, 2H), 2.04 – 1.95 (m, 1H), 1.62 – 1.50 (m, 6H), 1.44 (s, 6H), 1.20 – 1.02 (m, 3H), 0.97 – 0.90 (m, 3H), 0.88 – 0.80 (m, 5H). Example 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (2).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (2.2). [00338] Compound 2.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using phenylacetyl chloride in place of cyclohexylacetyl chloride. Compound 2.1 was converted to the title compound 2.2 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C
35H
44N
6O
10, 708.31, m/z found 709.15 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (2). [00339] The title compound was prepared from carbamate 2.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C30H36N6O8, 608.26, m/z found 609.10 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.30 – 7.23 (m, 3H), 7.21 – 7.16 (m, 3H), 7.13 (d, J = 4.8 Hz, 1H), 6.72 – 6.70 (m, 1H), 5.15 (dd, J = 5.2, 4.0 Hz, 1H), 5.05 – 5.02 (m, 1H), 4.51 – 4.49 (m, 1H), 4.29 (dd, J = 14.0,
WSGR Docket No. 41223-754.601 4.0 Hz, 2H), 3.66 (s, 2H), 3.30 (s, 3H), 3.24 (d, J = 5.2 Hz, 1H), 2.05 – 1.97 (m, 1H), 1.44 (s, 6H), 0.89 (dd, J = 27.2, 6.8 Hz, 6H). Example 3. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (3).
Step 1: Synthesis of (2R,3R,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (3.1) [00340] To a solution of compound 1.3 (100 mg, 0.163 mmol) and pyridine (0.16 mL, 1.95 mmol) in DCM (1 mL) was added TMSCl (53.0 mg, 0.488 mmol) at 0 ℃, the mixture was stirred at 20 ℃ for 1 h. 2-Ethylbutanoyl chloride (32.9 mg, 0.244 mmol) was added to the reaction at 0 ℃, the mixture was stirred at 0 ℃ for 1 h, then the reaction was quenched by water (50 mL) and extracted with DCM (50 mL x3). The organic phase was washed with brine water (50 mL x3), then dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The crude product was purified by chromatography (SiO2, petroleum ether/ethyl acetate from 0% to 14%) to obtain compound 3.1 (70.0 mg, 49% yield) as a white solid. MS (ESI): m/z calcd. for C
39H
60N
6O
9Si, 784.42, found 785.40 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.42 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 5.26 (d, J = 5.2 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.51 (dd, J = 8.8, 5.2 Hz, 1H), 4.35 (dd, J = 12.4, 2.8 Hz, 1H), 4.25 (dd, J = 12.4, 4.8 Hz, 1H), 4.04 (dd, J = 8.4, 6.0 Hz, 1H), 2.82 – 2.70 (m, 1H), 2.22 – 2.08 (m, 3H), 1.67 – 1.47 (m, 10H), 1.39 (s, 9H), 1.15 – 1.05 (m, 3H), 0.95 – 0.82 (m, 14H), 0.06 (s, 9H). Step 2: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (3) [00341] The title compound was prepared according to the procedure of Example 1, Step 4, using 3.1. MS (ESI): mass calcd. for C
31H
44N
6O
7, 612.33, found 613.25 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.42 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 6.92 – 6.57 (m, 1H), 5.18 – 5.12 (m, 1H), 5.12 – 5.07 (m, 1H), 4.53 – 4.47 (m, 1H), 4.33 – 4.18 (m, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.81 – 2.73 (m, 1H), 2.18 – 2.06 (m, 2H), 2.04 – 1.95 (m, 1H), 1.68 – 1.49 (m, 10H), 1.17 – 1.01 (m, 3H), 0.97 – 0.80 (m, 14H). Example 4. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (4).
WSGR Docket No. 41223-754.601
Step 1: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (4.1). [00342] The title compound was prepared according to the procedure of Example 1, Step 3, using 1.3 and 2-ethoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
36H
52N
6O
10, 728.37, found 729.25 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 8.49 (s, 1H), 7.27 – 7.10 (m, 3H), 6.78 (d, J = 6.4 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 5.12 – 5.03 (m, 1H), 4.47 (d, J = 4.0 Hz, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.19 (dd, J = 12.4, 4.8 Hz, 1H), 4.07 (dd, J = 7.6, 5.2 Hz, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.22 (dd, J = 13.2, 6.4 Hz, 1H), 2.12 (t, J = 6.4 Hz, 2H), 1.61 – 1.51 (m, 6H), 1.45 (s, 6H), 1.40 (s, 9H), 1.26 – 1.21 (m, 3H), 1.08 (t, J = 6.8 Hz, 3H), 0.95 – 0.78 (m, 8H). Step 2: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (4). [00343] The title compound was prepared from compound 4.1. according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C31H44N6O8, 628.32, found 629.30 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.82 – 6.65 (m, 1H), 5.18 – 5.13 (m, 1H), 5.10 (d, J = 5.2 Hz, 1H), 4.53 – 4.47 (m, 1H), 4.30 – 4.20 (m, 2H), 3.49 (q, J = 7.2 Hz, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.22 – 2.09 (m, 2H), 2.05 – 1.95 (m, 1H), 1.61 – 1.50 (m, 6H), 1.45 (s, 6H), 1.22 (t, J = 7.2 Hz, 3H), 1.17 – 1.05 (m, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.88 – 0.79 (m, 5H). Example 5. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (5).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (5.1). [00344] The title compound 5.1 was prepared according to the procedure of Example 1, Step 3, using 2.1 and 2-ethoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C36H46N6O10, 722.33, m/z found 723.1 [M+H]
+.
WSGR Docket No. 41223-754.601 Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (5). [00345] The title compound was prepared according to the procedure of Example 1, Step 4, using compound 5.1. MS (ESI): mass calcd. for C
31H
38N
6O
8, 622.28, m/z found 623.25 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 7.30 – 7.25 (m, 3H), 7.20 – 7.15 (m, 3H), 7.13 (d, J = 4.8 Hz, 1H), 6.76 – 6.73 (m, 1H), 5.15 (t, J = 4.8 Hz, 1H), 5.05 (d, J = 5.2 Hz, 1H), 4.54 – 4.50 (m, 1H), 4.30 (dd, J = 16.4, 4.0 Hz, 2H).3.66 (s, 2H), 3.50 (q, J = 6.8 Hz, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.06 – 1.96 (m, 1H), 1.45 (s, 6H), 1.22 (t, J = 6.8 Hz, 3H), 0.89 (dd, J = 27.2, 6.8 Hz, 6H). Example 6. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4- (3-isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (6).
Step 1: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (6.1). [00346] To a solution of compound 1.3 (120 mg, 0.195 mmol) and pyridine (46.3 mg, 0.586 mmol) in DMA (1 mL) was added 2-isocyanatopropane (24.9 mg, 0.293 mmol) at 20 ℃, the mixture was stirred at 60 ℃ for 16 h. After completion, the mixture was concentrated in vacuo to afford a residue, the residue was diluted with ACN (2 mL) and purified by prep-HPLC (mobile phase: ACN-H
2O (0.1% FA), 20%- 70%) to obtain compound 6.1 (40.0 mg, 27.8% yield) as a white solid. MS (ESI): mass calcd. for C
34H
49N
7O
9, 699.36, found 700.20 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.33 (d, J = 7.2 Hz, 1H), 8.30 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 6.76 (d, J = 6.8 Hz, 1H), 5.18 – 5.10 (m, 1H), 5.08 – 4.99 (m, 1H), 4.45 (d, J = 4.0 Hz, 1H), 4.27 (dd, J = 12.4, 3.2 Hz, 1H), 4.17 (dd, J = 12.4, 4.8 Hz, 1H), 4.06 (dd, J = 8.4, 5.6 Hz, 1H), 3.93 (dq, J = 12.8, 6.4 Hz, 1H), 2.27 – 2.16 (m, 1H), 2.13 – 2.03 (m, 2H), 1.63 – 1.50 (m, 6H), 1.39 (s, 9H), 1.21 (d, J = 6.4 Hz, 6H), 1.17 – 1.02 (m, 3H), 0.96 – 0.80 (m, 8H). Step 2: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (6). [00347] The title compound was prepared from compound 6.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
29H
41N
7O
7, 599.31, found 600.05 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.33 (d, J = 6.4 Hz, 1H), 8.30 (s, 1H), 7.50 (d, J = 4.4 Hz, 1H), 7.03 (d, J = 4.4 Hz, 1H), 6.77 – 6.68 (m, 1H), 5.16 – 5.10 (m, 1H), 5.07 – 5.03 (m, 1H), 4.51 – 4.45 (m, 1H), 4.31 – 4.15 (m, 2H), 3.93 (dd, J = 13.2, 6.8 Hz, 1H), 3.23 (d, J = 5.2 Hz, 1H), 2.17 – 2.05 (m, 2H), 2.03 – 1.94 (m, 1H), 1.62 – 1.48 (m, 6H), 1.21 (d, J = 6.4 Hz, 6H), 1.17 – 1.03 (m, 3H), 0.99 – 0.72 (m, 8H).
WSGR Docket No. 41223-754.601 Example 7. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran- 3-yl L-valinate (7).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((R)-2-methylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (7.1). [00348] Title compound 7.1 was prepared according to the procedure of Example 1, Step 3, using compound 2.1 and (R)-2-methylbutanoic acid. MS (ESI): mass calcd. for C
35H
44N
6O
9, 692.32, m/z found 693.2 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((R)-2-methylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (7). [00349] The title compound was prepared from carbamate 7.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
36N
6O
7, 592.26, m/z found 593.1 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.41 (s, 1H), 7.26 – 7.16 (m, 4H), 7.19 (dd, J = 7.6, 5.6 Hz, 2H), 7.09 (d, J = 4.8 Hz, 1H), 6.72 – 6.65 (m, 1H),5.21 – 5.12 (m, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.51 (dd, J = 8.0, 4.0 Hz, 1H), 4.38 – 4.21 (m, 2H), 3.66 (s, 2H), 3.23 (d, J = 5.2 Hz, 1H), 2.94 – 2.90 (m, 1H), 2.13 – 1.95 (m, 1H), 1.78 – 1.61 (m, 1H), 1.58 – 1.40 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.98 – 0.89 (m, 6H), 0.86 (d, J = 6.8 Hz, 3H). Example 8. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((S)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran- 3-yl L-valinate (8).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((S)-2-methylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (8.1). [00350] Title compound 8.1 was prepared from compound 2.1 according to the procedure of Example 1, Step 3, using (S)-2-methylbutanoic acid. MS (ESI): mass calcd. for C
35H
44N
6O
9, 692.32, m/z found 693.2 [M+H]
+.
WSGR Docket No. 41223-754.601 Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-((S)-2-methylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (8). [00351] The title compound was prepared from carbamate 8.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
36N
6O
7, 592.26, m/z found 593.15 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.41 (s, 1H), 7.34 – 7.21 (m, 4H), 7.20 – 7.16 (m, 2H), 7.09 (d, J = 4.8 Hz, 1H), 6.71 – 6.68 (m, 1H), 5.18 – 5.11 (m, 1H), 5.05 – 5.02 (m, 1H), 4.51 (dd, J = 8.0, 4.4 Hz, 1H), 4.29 – 4.25 (m, 2H), 3.66 (s, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.97 – 2.91 (m, 1H), 2.10 – 2.08 (m, 1H), 1.72 – 1.64 (m, 1H), 1.46 – 1.40 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.94 – 0.85 (m, 9H). Example 9. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4- ((R)-2-methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (9).
Step 1: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (9.1). [00352] The title compound was prepared from compound 1.3 according to the procedure of Example 1, Step 3, using (R)-2-methylbutanoic acid. MS (ESI): mass calcd. for C
35H
50N
6O
9, 698.36, found 699.25 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.42 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.75 (d, J = 6.4 Hz, 1H), 5.17 – 5.13 (m, 1H), 5.11 – 5.05 (m, 1H), 4.46 (d, J = 4.0 Hz, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.18 (dd, J = 12.4, 4.8 Hz, 1H), 4.11 – 4.06 (m, 1H), 2.94 (dd, J = 13.6, 6.8 Hz, 1H), 2.27 – 2.17 (m, 1H), 2.15 – 2.06 (m, 2H), 1.74 – 1.63 (m, 1H), 1.62 – 1.50 (m, 6H), 1.48 – 1.43 (m, 1H), 1.40 (s, 9H), 1.20 – 1.03 (m, 6H), 0.96 – 0.78 (m, 11H). Step 2: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (9). [00353] The title compound was prepared from carbamate 9.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
42N
6O
7, 598.31, m/z found 599.05 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.42 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.82 – 6.65 (m, 1H), 5.19 – 5.12 (m, 1H), 5.11 – 5.05 (m, 1H), 4.50 (dd, J = 8.0, 4.0 Hz, 1H), 4.32 – 4.26 (m, 1H), 4.24 – 4.18 (m, 1H), 3.24 (d, J = 5.2 Hz, 1H), 2.94 (dd, J = 13.6, 6.8 Hz, 1H), 2.20 – 2.08 (m, 2H), 2.06 – 1.95 (m, 1H), 1.73 – 1.64 (m, 1H), 1.62 – 1.50 (m, 6H), 1.48 – 1.39 (m, 1H), 1.17 – 1.03 (m, 6H), 0.99 – 0.79 (m, 11H). Example 10. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (10).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3R,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-2-((2-phenylacetoxy)methyl)-4-((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert-butoxycarbonyl)- L-valinate (10.1). [00354] To a solution of 2.1 (100 mg, 0.164 mmol) and pyridine (157 mg, 1.97 mmol) in DCM (1 mL) was added TMSCl (53.0 mg, 0.488 mmol) at 0 ℃, the mixture was stirred at 20 ℃ for 1 h. The reaction was then treated with 2-ethylbutanoyl chloride (32.9 mg, 0.244 mmol) at 0 ℃, and the mixture was stirred at 0 ℃ for 1 h. The reaction was extracted with DCM (5 mL x 3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE from 0% to 30%) to obtain 10.1 (70.0 mg, 55% yield) as a white solid. MS (ESI): mass calcd. for C
39H
54N
6O
9Si, 778.37, m/z found 779.2 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (10). [00355] The title compound 10 was prepared from carbamate 10.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C31H38N6O7, 606.28, m/z found 607.10 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.42 (s, 1H), 7.27 – 7.17 (m, 6H), 7.10 (d, J = 4.8 Hz, 1H), 6.71 – 6.65 (m, 1H), 5.27 – 5.11 (m, 1H), 5.05 – 5.03 (m, 1H), 4.51 (dd, J = 8.0, 4.4 Hz, 1H), 4.29 – 4.20 (m, 2H), 3.66 (s, 2H), 3.25 (d, J = 5.2 Hz, 1H), 2.81 – 2.75 (m, 1H), 2.01 – 1.98 (m, 1H), 1.67 – 1.49 (m, 4H), 0.93 – 0.84 (m, 12H). Example 11. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((R)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (11).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((R)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (11.1). [00356] The title compound 11.1 was prepared according to the procedure of Example 1, Step 3, using 2.1 and (R)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C
36H
46N
6O
9, 706.33, m/z found 707.15 [M+H]
+.
WSGR Docket No. 41223-754.601 Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((R)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (11). [00357] The title compound was prepared from carbamate 11.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
31H
38N
6O
7, 606.28, m/z found 607.0 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.41 (s, 1H), 7.34 – 7.14 (m, 6H), 7.10 (d, J = 4.8 Hz, 1H), 6.80 – 6.68 (m, 1H), 5.18 – 5.10 (m, 1H), 5.05 (d, J = 5.2 Hz, 1H), 4.51 (dd, J = 8.0, 4.0 Hz, 1H), 4.37 – 4.29 (m, 1H), 4.28 – 4.20 (m, 1H), 3.68 – 3.63 (m, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.83 – 2.75 (m, 1H), 2.11 – 1.96 (m, 1H), 1.95 – 1.85 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.97 – 0.89 (m, 9H), 0.85 (d, J = 6.8 Hz, 3H). Example 12. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4- ((S)-2-methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (12).
[00358] The title compound was prepared from compound 1.3 according to the procedure of Example 1, Steps 3 and 4, using (S)-2-methylbutanoic acid. MS (ESI): mass calcd. for C
30H
42N
6O
7, 598.311, m/z found 599.25 [M+H]
+. Example 13. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-((R)-2,3- dimethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate
[00359] The title compound 13 was prepared from compound 1.3 according to the procedure of Example 1, Steps 3 and 4, using (R)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C
31H
44N
6O
8, 612.327, m/z found 613.20 [M+H]
+. Example 14. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-((S)-2,3- dimethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (14).
WSGR Docket No. 41223-754.601
[00360] The title compound was prepared from compound 1.3 according to the procedure of Example 1, Steps 3 and 4, using (S)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C
31H
44N
6O
8, 612.327, m/z found 613.20 [M+H]
+. Example 15. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(3-isopropylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (15).
[00361] The title compound was prepared from compound 2.1 according to the procedure of Example 6. MS (ESI): mass calcd. for C
29H
35N
7O
7, 593.260, m/z found 594.15 [M+H]
+. Example 16. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-cyclohexylacetate (16).
Step 1. Synthesis of (6aR,8R,9R,9aS)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-9-hydroxy-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocine-8-carbonitrile (16.2).
WSGR Docket No. 41223-754.601 [00362] To a solution of compound 16.1 (4 g, 0.013 mol) and imidazole (5.6 g, 0.082 mol) in DMF (40 mL) was added chloro[(chlorodiisopropylsilyl)oxy]diisopropylsilane (5.19 g, 0.016 mmol) at 0 °C, the mixture was stirred at 25 °C for 4 h. The reaction was extracted with EtOAc (10 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 30%) to obtain compound 16.2 as a white solid (5.00 g, 65% yield). MS (ESI): mass calcd. for C
24H
39N
5O
5Si
2, 533.78, m/z found 534.2 [M+H]
+. Step 2. Synthesis of (6aR,8R,9R,9aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-cyclohexylacetate (16.3). [00363] To a solution of compound 16.2 (800 mg, 1.50 mmol) in THF (25 mL) was added cyclohexylacetic acid (426 mg, 3.00 mmol), EDCI (862 mg, 4.50 mmol) and DMAP (549 mg, 4.50 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was extracted with EA (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 40%) to obtain compound 16.3 as a white solid (500 mg, 46% yield). MS (ESI): mass calcd. for C
32H
51N
5O
6Si
2, 657.96, m/z found 658.3 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.01 (d, J = 18.8 Hz, 2H), 7.89 (s, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 5.87 (d, J = 5.2 Hz, 1H), 4.54 (dd, J = 8.8, 5.2 Hz, 1H), 4.14 (t, J = 10.4 Hz, 2H), 4.01 – 3.91 (m, 1H), 2.35 (d, J = 6.4 Hz, 2H), 1.88 – 1.72 (m, 3H), 1.62 –1.60 (m, 3H), 1.23 – 1.09 (m, 3H), 1.08 – 0.84 (m, 30H). Step 3. Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4-pentanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-cyclohexylacetate (16.4). [00364] To a solution of compound 16.3 (100 mg, 0.152 mmol) in DCM (2 mL) was added pyridine (144 mg, 1.82 mmol), followed by pentanoyl chloride (45.8 mg, 0.380 mmol) at 0
oC and stirred for 2 hours. The reaction was extracted with DCM (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE from 0% to 30%) to obtain compound 16.4 as a white solid (70.0 mg, 56% yield). MS (ESI): mass calcd. for C
37H
59N
5O
7Si
2, 741.40, m/z found 742.1 [M+H]
+. Step 4. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-cyclohexylacetate (16). [00365] To a solution of compound 16.4 (70 mg, 0.0940 mmol) in THF (1 mL) was added TBAF in THF (0.2 mL, 1 M), the mixture was stirred at 25 °C for 2 h. The reaction was extracted with EtOAc (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford compound 16 (5.67 mg, 12% yield) as a white solid MS (ESI): mass calcd. for C
25H
33N
5O
6, 499.24, m/z found 500.1 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.40 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.58 (d, J = 6.4 Hz, 1H),5.18 (dd, J = 5.6, 4.0 Hz, 1H), 5.04 (t, J = 5.6 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.28 (q, J = 3.6 Hz,
WSGR Docket No. 41223-754.601 1H), 3.67 – 3.49 (m, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.27 (d, J = 6.8 Hz, 2H), 1.92 –1.70 (m, 3H), 1.69 – 1.57 (m, 5H), 1.44 – 1.31 (m, 2H), 1.20 – 1.10 (m, 3H), 0.99 – 0.87 (m, 5H). Example 17. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-methoxy-2-methylpropanoate (17).
Step 1: Synthesis of (6aR,8R,9R,9aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-methoxy-2- methylpropanoate (17.1). [00366] The title compound 17.1 was prepared from compound 16.2 according to the procedure of Example 16, Step 2, using 2-methoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
29H
47N
5O
7Si
2, 633.30, m/z found 634.20 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.13 – 7.83 (m, 3H), 6.93 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 5.88 (d, J = 5.2 Hz, 1H), 4.55 (dd, J = 9.2, 5.2 Hz, 1H), 4.25 – 4.13 (m, 2H), 3.96 (dd, J = 13.6, 2.4 Hz, 1H), 3.25 (s, 3H), 1.46 (d, J = 4.0 Hz, 6H), 1.07 – 1.01 (m, 8H), 0.99 – 0.95 (m, 12H), 0.94 – 0.90 (m, 8H). Step 2: Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4-pentanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-methoxy-2- methylpropanoate (17.2) [00367] The title compound 17.2 was prepared from compound 17.1 according to the procedure of Example 16, Step 3, using pentanoyl chloride. MS (ESI): mass calcd. for C
34H
55N
5O
8Si
2, 717.36, found 718.25 [M+H]
+. Step 3: Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-methoxy-2-methylpropanoate (17). [00368] The title compound 17 was prepared from compound 17.2 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C
22H
29N
5O
7, 475.21, found 476.10 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.40 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.64 (d, J = 6.4 Hz, 1H), 5.28 (dd, J = 5.6, 3.6 Hz, 1H), 5.07 (t, J = 5.6 Hz, 1H), 5.02 (t, J = 6.0 Hz, 1H), 4.31
WSGR Docket No. 41223-754.601 (q, J = 3.6 Hz, 1H), 3.58 (t, J = 4.4 Hz, 2H), 3.22 (s, 3H), 2.72 (t, J = 7.6 Hz, 2H), 2.65 – 1.56 (m, 2H), 1.42 (s, 6H), 1.39 – 1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). Example 18. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-methoxy-2-methylpropanoate (18)
Step 1: Synthesis of (6aR,8R,9R,9aR)-8-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano- 2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-methoxy-2- methylpropanoate (18.1). [00369] To a solution of compound 17.1 (70.0 mg, 0.110 mmol) and pyridine (0.11 mL, 1.32 mmol) in DCM (1 mL) was added benzoyl chloride (23.3 mg, 0.166 mmol) at 0 ℃, the mixture was stirred at 0 ℃ for 2 h. Then the reaction was quenched by water (50 mL) and extracted with DCM (50 mL×3). The organic phase was washed with brine water (50 mL×3), then dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The crude product was purified by chromatography (SiO2, Petroleum ether/Ethyl acetate from 0% to 12%) to obtain compound 18.1 (50.0 mg, 55.3% yield) as a white solid. MS (ESI): mass calcd. for C
36H
51N
5O
8Si
2, 737.33, found 738.40 [M+H]
+ Step 2: Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-methoxy-2-methylpropanoate (18). [00370] The title compound 18 was prepared from 18.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C
24H
25N
5O
7, 495.18, found 496.05 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 11.93 (s, 1H), 8.34 (s, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.13 – 7.07 (m, 2H), 6.63 (d, J = 6.4 Hz, 1H), 5.30 (dd, J = 5.6, 3.2 Hz, 1H), 5.14 – 5.08 (m, 1H) , 5.04 (t, J = 6.0 Hz, 1H), 4.35 – 4.30 (m, 1H) , 3.63 – 3.58 (m, 2H), 3.22 (s, 3H), 1.43 (s, 6H). Example 19. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2- ethylbutanoate (19).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (6aR,8R,9R,9aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-ethylbutanoate (19.1). [00371] To a solution of compound 16.2 (600 mg, 1.124 mmol) in THF (20 mL) was added 2- ethylbutanoic acid (261 mg, 2.25 mmol), EDCI (646 mg, 3.37 mmol) and DMAP (412 mg, 3.37 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was extracted with EtOAc (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (Petroleum ether/Ethyl acetate, from 0% to 30%) to obtain compound 19.1 as a white solid (530 mg, 67% yield). MS (ESI): mass calcd. for C
30H
49N
5O
6Si
2, 631.32, m/z found 632.1 [M+H]
+. Step 2. Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2- f][1,3,5,2,4]trioxadisilocin-9-yl 2-ethylbutanoate (19.2). [00372] The title compound 19.2 was prepared from compound 19.1 according to the procedure of Example 16, Step 3, using pentyl carbonochloridate. MS (ESI): mass calcd. for C
36H
59N
5O
8 Si
2, 745.39, m/z found 746.1 [M+H]
+. Step 3. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- (((pentyloxy)carbonyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2- ethylbutanoate (19). [00373] The title compound 19 was prepared from compound 19.2 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C
24H
33N
5O
7, 503.24, m/z found 504.05 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.36 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.57 (d, J = 6.4 Hz, 1H), 5.23 (dd, J = 5.6, 3.6 Hz, 1H), 5.05 (t, J = 5.6 Hz, 1H), 4.99 (t, J = 6.4 Hz, 1H), 4.27 – 4.25 (m, 1H), 4.17 (t, J = 6.8 Hz, 2H), 3.67 – 3.50 (m, 2H), 2.28 – 2.24.(m, 1H), 1.74 – 1.47 (m, 6H), 1.42 – 1.28 (m, 4H), 0.89 – 0.85 (m, 9H). Example 20. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-ethylbutanoate (20).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4-pentanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-ethylbutanoate (20.1). [00374] To a solution of 19.1 (150 mg, 0.237 mmol) in DCM (2 mL) was added pyridine (225 mg, 2.85 mmol), followed by pentanoyl chloride (71.6 mg, 0.593 mmol) at 0 °C and stirred at 25 °C for 1 h. The reaction was extracted with DCM (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (Petroleum ether/Ethyl acetate, from 0% to 20%) to obtain 20.1 as a white solid (90.0 mg, 48% yield). MS (ESI): mass calcd. for C
35H
57N
5O
7Si
2, 715.38, m/z found 716.1 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-ethylbutanoate (20). [00375] The title compound 20 was prepared from compound 20.1 according to the procedure of Example 16, Step 3. MS (ESI): mass calcd. for C
23H
31N
5O
6, 473.23, m/z found 474.05 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.45 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H), 5.23 (dd, J = 5.6, 3.6 Hz, 1H), 5.05 – 5.00 (m, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.27 (d, J = 3.6 Hz, 1H), 3.57 – 3.50 (m, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.28 – 2.25 (m, 1H), 1.74 – 1.47 (m, 6H), 1.35 – 1.30 (m, 2H), 0.98 – 0.81 (m, 9H). Example 21. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano- 4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-ethylbutanoate (21).
Step 1. Synthesis of (6aR,8R,9R,9aR)-8-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano- 2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-ethylbutanoate (21.1). [00376] The title compound 21.1 was prepared from compound 19.1 according to the procedure of Example 20, Step 1, using benzoyl chloride. MS (ESI): mass calcd. for C
37H
53N
5O
7 Si
2, 735.35, m/z found 736.1 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-ethylbutanoate (21).
WSGR Docket No. 41223-754.601 [00377] The title compound 21 was prepared from compound 21.1 according to the procedure of Example 16, Step 3. MS (ESI): mass calcd. for C
25H
27N
5O
6, 493.20, m/z found 494.05 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 8.38 (s, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 5.25 (dd, J = 5.6, 3.2 Hz, 1H), 5.08 (t, J = 5.6 Hz, 1H), 5.00 (t, J = 6.4 Hz, 1H), 4.28 – 4.25 (M, 1H), 3.56 – 3.50 (m, 2H), 2.29 – 2.25 (m, 1H), 1.70 – 1.49 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H). Example 23. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(3,3- diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (23).
Step 1: Synthesis of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (23.1). [00378] To a solution of 1.1 (2.00 g, 0.006 mol) and 2,2-dimethoxypropane (3.45 g, 0.033 mol) in acetone (50 mL) was added sulfuric acid (0.90 g, 98%) dropwise at 25 °C for 0.5 h, then heated to 45 °C for 0.5 h. The reaction mixture was quenched by saturated aq. NaHCO
3 (10 mL) and extracted with
WSGR Docket No. 41223-754.601 EtOAc (15 mL×3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO
2, MeOH/DCM = 0-5%) to obtain 23.1 (2.30 g, 96% yield) as a white solid. MS (ESI): mass calcd. for C
15H
17N
5O
4331.33, m/z found 332.0 [M+H]
+. Step 2. Synthesis of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(((tert- butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (23.2). [00379] To a mixture of 23.1 (4.00 g, 12.1 mmol) and imidazole (2.06 g, 30.2 mmol) in DCM (20 mL) was added TBSCl (2.19 g, 14.5 mmol) slowly at 0 ℃. The mixture was then stirred at 20 ℃, for 2 h. After completion, the mixture was quenched with water (300 mL) and extracted with DCM (200 mL×3). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (SiO
2, ethyl acetate/petroleum ether = 0- 30%) to obtain 23.2 as a white solid.(4.80 g, 88.4% yield) which was confirmed by
1H NMR and LCMS. MS (ESI): mass calcd. for C
21H
31N
5O
4Si, 445.21, m/z found 446.25 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.94 (s, 3H), 6.90 (d, J = 4.4 Hz, 1H), 6.84 (d, J = 4.4 Hz, 1H), 5.33 (d, J = 6.4 Hz, 1H), 4.85 (dd, J = 6.4, 2.8 Hz, 1H), 4.37 (dd, J = 7.6, 4.8 Hz, 1H), 4.03 (q, J = 7.2 Hz, 1H), 3.70 (dd, J = 4.8, 1.2 Hz, 2H), 1.63 (s, 3H), 1.37 (s, 3H), 0.76 (s, 9H), -0.03 (s, 3H), -0.08 (s, 3H). Step 3. Synthesis of diethylcarbamic chloride (23.4). [00380] To triphosgene (1.24 g, 4.00 mmol) in DCM (11 mL) was added a solution of 23.3 (0.84 g, 11.0 mmol) and pyridine (1.91 g, 2.40 mmol) in DCM (7 mL) at 0 °C, the mixture was stirred at 25 °C for 2 h. After completion, the mixture was quenched with aq. HCl (10 mL, 0.1 M) and extracted with DCM (10 mL×3). The organic layer was then dried over sodium sulfate and concentrated in vacuo to obtain 23.4 as a yellow oil (1.10 g, 63.5% yield).
1H NMR (400 MHz, CDCl
3) δ 3.89 – 3.27 (m, 4H), 1.42 – 1.03 (m, 6H). Step 4. Synthesis of 3-(7-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,1-diethylurea (23.5). [00381] To a solution of 23.2 (300 mg, 0.673 mmol) in THF (6 mL) was added NaH (80.8 mg, 2.02 mmol) at 0
oC for 0.5 h, then to the above solution was added 23.4 (274 mg, 2.02 mmol) at 0
oC and stirred at 25
oC for 1 h. After completion, the mixture was quenched with saturated aq. NH
4Cl (10 mL) and extracted with EtOAc (5 mL×3). The combined organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO
2, ethyl acetate/petroleum ether = 0-30%) to obtain 23.5 as a white solid (220 mg, 54.0% yield). MS (ESI): mass calcd. for C26H40N6O5Si, 544.73, m/z found 545.2 [M+H]
+. Step 5. Synthesis of 3-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,1-diethylurea (23.6). [00382] To a solution of 23.5 (200 mg, 0.367 mmol) in THF (3 mL) was added aq. HCl (1 mL, 12 M), the mixture was stirred at 25
oC for 1 h. The reaction was concentrated under reduced pressure. The
WSGR Docket No. 41223-754.601 crude product was purified by prep-HPLC [Gradient: 5-60% ACN in water (0.1% formic acid (FA))] to afford compound 23.6 (100 mg, 69.1% yield) as a white solid MS (ESI): mass calcd. for C
17H
22N
6O
5, 390.40, m/z found 391.05 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 12.85 (s, 1H), 7.90 (s, 1H), 6.95 – 6.80 (m, 2H), 6.15 (d, J = 6.0 Hz, 1H), 5.23 (d, J = 3.6 Hz, 1H), 4.98 – 4.75 (m, 1H), 4.57 (t, J = 6.0 Hz, 1H), 4.13 – 4.02 (m, 1H), 4.00 – 3.92 (m, 1H), 3.69 – 3.47 (m, 4H), 3.43 – 3.56 (m, 2H), 1.11 (t, J = 7.2 Hz, 6H). Step 6. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-cyclohexylacetate (23.7). [00383] The title compound was prepared from compound 23.6 according to the procedure of Example 1, Step 1, using 2-cyclohexylacetyl chloride. MS (ESI): mass calcd. for C
25H
34N
6O
6, 514.58, m/z found 515.20 [M+H]
+. Step 7. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(3,3- diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (23.8). [00384] The title compound was prepared from compound 23.7 according to the procedure of Example 1, Step 2, using (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C
35H
51N
7O
9, 713.83, m/z found 714.35 [M+H]
+. Step 8. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(3,3- diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (23). [00385] The title compound was prepared from compound 23.8 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
43N
7O
7, 613.72, m/z found 614.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.93 (s, 1H), 6.92 (d, J = 4.8 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 6.76 – 6.55 (m, 1H), 5.15 (t, J = 4.8 Hz, 1H), 5.03 (d, J = 5.2 Hz, 1H), 4.51 – 4.42 (m, 1H), 4.27 (dd, J = 12.0, 3.6 Hz, 1H), 4.21 (dd, J = 12.4, 4.8 Hz, 1H), 3.60 – 3.43 (m, 4H), 3.25 (d, J = 5.2 Hz, 1H), 2.13 (t, J = 6.4 Hz, 2H), 2.04 – 1.96 (m, 1H), 1.62 – 1.53 (m, 6H), 1.17 – 1.07 (m, 9H), 0.94 – 0.82 (m, 8H). Example 26. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((S)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (26).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((S)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (26.1).
WSGR Docket No. 41223-754.601 [00386] The title compound was prepared from compound 2.1 according to the procedure of Example 1, Step 3, using (S)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C
36H
46N
6O
9, 706.80, m/z found 707.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((S)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (26). [00387] The title compound was prepared from compound 26.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
31H
38N
6O
7, 606.68, m/z found 607.05 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.92 (s, 1H), 8.41 (s, 1H), 7.31 – 7.15 (m, 6H), 7.09 (d, J = 4.8 Hz, 1H), 6.71 – 6.65 (m, 1H), 5.14 (t, J = 4.8 Hz, 1H), 5.05 – 5.01 (m, 1H), 4.51 – 4.45 (m, 1H), 4.29 (dd, J = 16.0, 4.0 Hz, 2H), 3.66 (s, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.77 – 2.75 (m, 1H), 2.11 – 1.97 (m, 1H), 1.92 – 1.89 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.93 – 0.90 (m, 9H), 0.85 (d, J = 6.8 Hz, 3H). Example 28. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (28).
Step 1. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (28.1). [00388] The title compound was prepared from compound 23.6 according to the procedure of Example 1, Step 1, using 2-phenylacetyl chloride. MS (ESI): mass calcd. for C
25H
28N
6O
6, 508.54, m/z found 509.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (28.2). [00389] The title compound was prepared from compound 28.1 according to the procedure of Example 1, Step 2, using (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C
35H
45N
7O
9, 707.79, m/z found 708.2 [M+H]
+. Step 3. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (28).
WSGR Docket No. 41223-754.601 [00390] The title compound 28 was prepared from compound 28.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
37N
7O
7, 607.67, m/z found 608.00 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.93 (s, 1H), 7.21 – 7.16 (m, 5H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.50 – 6.28 (m, 1H), 5.16 (dd, J = 5.6, 4.0 Hz, 1H), 4.98 (d, J = 5.6 Hz, 1H), 4.53 – 4.43 (m, 1H), 4.32 (dd, J = 3.6, 12.4 Hz, 1H), 4.25 (dd, J = 5.2, 12.4 Hz, 1H), 3.67 (s, 2H), 3.35 – 3.30 (m, 4H), 3.27 (d, J = 5.2 Hz, 1H), 2.12 –1.96 (m, 1H), 1.12 (t, J = 7.2 Hz, 6H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H). Example 31. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (31).
Step 1. Synthesis of (2R,3R,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((trimethylsilyl)oxy)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (31.2). [00391] Compound 31.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-cycloheptylacetyl chloride in place of cyclohexylacetyl chloride. Compound 31.1 was converted to the title compound 31.2 using the procedure of Example 3, Step 1. MS (ESI): mass calcd. for C
40H
62N
6O
9Si, 798.43, m/z found 799.40 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 11.00 (s, 1H), 8.41 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 7.17 – 7.09 (m, 2H), 5.26 (d, J = 5.2 Hz, 1H), 5.19 – 5.09 (m, 1H), 4.51 (dd, J = 8.8, 5.2 Hz, 1H), 4.34 (dd, J = 12.4, 3.2 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 4.07 – 4.03 (m, 1H), 2.84 – 2.73 (m, 1H), 2.27 – 2.09 (m, 3H), 1.90 – 1.77 (m, 1H), 1.68 – 1.45 (m, 10H), 1.38 (s, 9H), 1.35 – 1.22 (m, 4H), 1.13 – 1.05 (m, 2H), 0.94 – 0.84 (m, 12H), 0.05 (s, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (31). [00392] The title compound was prepared from carbamate 31.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
32H
46N
6O
7, 626.34, m/z found 627.15 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.98 (s, 1H), 8.42 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 6.90 – 6.60 (m, 1H), 5.20 – 5.12 (m, 1H), 5.11 – 5.08 (m, 1H), 4.53 – 4.48 (m, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.27 (d, J = 5.2 Hz, 1H), 2.83 – 2.72 (m, 1H), 2.24 – 2.08 (m, 2H), 2.07 – 1.96 (m, 1H), 1.83 – 1.73 (m, 1H), 1.69 – 1.59 (m, 2H), 1.58 – 1.43 (m, 8H), 1.42 – 1.22 (m, 4H), 1.14 – 0.98 (m, 2H), 0.97 – 0.79 (m, 12H). Example 32. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (32).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (32.2). [00393] Compound 32.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-cyclopentylacetyl chloride in place of cyclohexylacetyl chloride. Compound 32.1 was converted to the title compound 32.2 using the procedure of Example 3, Step 1. MS (ESI): mass calcd. for C
38H
58N
6O
9Si, 771.00, m/z found 771.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (32). [00394] The title compound was prepared from compound 32.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
42N
6O
7, 598.70, m/z found 599.30 [M+H]
+.
1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.43 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 6.73 – 6.60 (m, 1H), 5.20 – 5.13 (m, 1H), 5.10 (d, J = 5.2 Hz, 1H), 4.55 – 4.47 (m, 1H), 4.29 (dd, J = 12.0, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.26 ((d, J = 5.2 Hz, 1H), 2.80 – 2.74 (m, 1H), 2.25 (dd, J =7.6, 3.6 Hz, 2H), 2.05 – 1.97 (m, 2H), 1.71 –1.60 (m, 4H), 1.55 –1.47 (m, 4H), 1.45 – 1.39 (m, 2H), 1.09 – 0.98 (m, 2H), 0.93 – 0.85 (m, 12H). Example 33. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-4-hydroxy-5-(4- (2-methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (33.1). [00395] Compound 31.1 was converted to the title compound 33.1 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C36H52N6O10, 728.37, m/z found 729.35 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.31 (s, 1H), 8.48 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 6.8 Hz, 1H), 5.14 (t, J = 4.8 Hz, 1H), 5.12 – 5.04 (m, 1H), 4.52 – 4.48 (m, 1H),
WSGR Docket No. 41223-754.601 4.29 (dd, J = 12.0, 3.2 Hz, 1H), 4.20 (dd, J = 12.4, 4.8 Hz, 1H), 4.13 – 4.05 (m, 1H), 3.29 (s, 3H), 2.27 – 2.09 (m, 3H), 1.85 – 1.73 (m, 1H), 1.61 – 1.46 (m, 6H), 1.44 (s, 6H), 1.40 (s, 9H), 1.36 – 1.23 (m, 4H), 1.13 – 1.03 (m, 2H), 0.92 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (33). [00396] The title compound was prepared from carbamate 33.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
31H
44N
6O
8, 628.32, m/z found 629.25 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.80 – 6.70 (m, 1H), 5.15 (t, J = 4.8 Hz, 1H), 5.13 – 5.08 (m, 1H), 4.54 – 4.47 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.23 (dd, J = 12.4, 4.8 Hz, 1H), 3.29 (s, 3H), 3.26 (d, J = 5.2 Hz, 1H), 2.23 – 2.11 (m, 2H), 2.08 – 1.97 (m, 1H), 1.84 – 1.74 (m, 1H), 1.60 – 1.46 (m, 6H), 1.44 (s, 6H), 1.41 – 1.22 (m, 4H), 1.16 – 1.03 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). Example 34. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxy-5-(4- (2-methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl D-valinate (34).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (34.2). [00397] Compound 34.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-cyclobutylacetyl chloride in place of cyclohexylacetyl chloride and using (tert-butoxycarbonyl)-D- valine in place of (tert-butoxycarbonyl)-L-valine. Compound 34.1 was converted to the title compound 34.2 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C
33H
46N
6O
10, 686.76, m/z found 687.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl D-valinate (34). [00398] The title compound was prepared from compound 34.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C28H38N6O8, 586.65, m/z found 587.25 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.48 (s, 1H), 7.29 – 7.20 (m, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 5.39 – 5.19 (m, 1H), 5.11 (t, J = 5.6 Hz, 1H), 4.66 – 4.48 (m, 1H), 4.28 (dd, J = 12.4, 4.0 Hz, 1H), 4.20 (dd, J = 12.0, 4.8 Hz, 1H), 3.29 (s, 3H), 3.27 (d, J = 5.2 Hz, 1H), 2.43 – 2.31 (m, 3H), 2.19 – 2.05 (m,
WSGR Docket No. 41223-754.601 1H), 2.02 – 1.93 (m, 2H), 1.81 – 1.72 (m, 2H), 1.67 – 1.54 (m, 2H), 1.44 (s, 6H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). Example 35. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxy-5-(4- (2-methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (35.2). [00399] Compound 35.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-cyclopentylacetyl chloride in place of cyclohexylacetyl chloride. Compound 35.1 was converted to the title compound 35.2 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C
34H
48N
6O
10, 700.34, m/z found 701.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.48 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 6.4 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 5.12 – 5.05 (m, 1H), 4.52 – 4.43 (m, 1H), 4.30 (dd, J = 12.4, 3.2 Hz, 1H), 4.19 (dd, J = 12.4, 4.8 Hz, 1H), 4.11 – 4.06 (m, 1H), 3.29 (s, 3H), 2.30 – 2.19 (m, 3H), 2.07 – 1.99 (m, 1H), 1.72 – 1.60 (m, 2H), 1.57 – 1.48 (m, 2H), 1.44 (s, 6H), 1.43 – 1.34 (m, 11H), 1.09 – 0.98 (m, 2H), 0.96 – 0.87 (m, 6H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (33). [00400] The title compound was prepared from carbamate 35.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
29H
40N
6O
8, 600.29, m/z found 601.00 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.83 – 6.63 (m, 1H), 5.20 – 5.14 (m, 1H), 5.13 – 5.07 (m, 1H), 4.52 – 4.48 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.29 (s, 3H), 3.26 (d, J = 5.2 Hz, 1H), 2.30 – 2.23 (m, 2H), 2.10 – 1.95 (m, 2H), 1.73 – 1.60 (m, 2H), 1.56 – 1.48 (m, 2H), 1.46 – 1.38 (m, 8H), 1.10 – 0.98 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). Example 36. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxy-5-(4- (2-methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl D-valinate (36).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (36.2). [00401] Compound 36.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-cyclopentylacetyl chloride in place of cyclohexylacetyl chloride and (tert-butoxycarbonyl)-D-valine in place of (tert-butoxycarbonyl)-L-valine. Compound 36.1 was converted to the title compound 36.2 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C
34H
48N
6O
10, 700.34, m/z found 701.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl D-valinate (36). [00402] The title compound was prepared from carbamate 36.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
29H
40N
6O
8, 600.29, m/z found 601.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.20 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.71 (d, J = 6.0 Hz, 1H), 5.27 – 5.19 (m, 1H), 5.14 – 5.06 (m, 1H), 4.58 – 4.50 (m, 1H), 4.30 (dd, J = 12.4, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.29 (s, 3H), 3.25 (d, J = 4.8 Hz, 1H), 2.31 – 2.20 (m, 2H), 2.15 – 1.98 (m, 2H), 1.72 – 1.61 (m, 2H), 1.58 – 1.48 (m, 2H), 1.47 – 1.37 (m, 8H), 1.12 – 0.98 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). Example 37. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl D-valinate (37).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-D-valinate (37.2). [00403] Compound 37.1 was prepared according to the procedure of Example 1, Steps 1 and 2, using 2-phenylacetyl chloride in place of cyclohexylacetyl chloride and using (tert-butoxycarbonyl)-D-valine in
WSGR Docket No. 41223-754.601 place of (tert-butoxycarbonyl)-L-valine. Compound 37.1 was converted to the title compound 37.2 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C
35H
44N
6O
10, 708.77, m/z found 709.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl D-valinate (37). [00404] The title compound was prepared from compound 37.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
36N
6O
8, 608.65, m/z found 609.00 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.29 – 7.18 (m, 6H), 7.13 (d, J = 4.8 Hz, 1H), 6.78 – 6.63 (m, 1H), 5.23 (dd, J = 5.6, 4.0 Hz, 1H), 5.13 – 4.98 (m,1H), 4.65 – 4.51 (m, 1H), 4.33 (dd, J = 12.0, 3.6 Hz, 1H), 4.26 (dd, J = 12.0, 4.8 Hz, 1H), 3.66 (d, J = 2.0 Hz, 2H), 3.30 (s, 3H), 3.23 (d, J = 5.2 Hz, 1H), 2.11 – 2.04 (m, 1H), 1.44 (s, 6H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). Example 38. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4- (2-methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl D-valinate (38).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (38.2). [00405] Compound 38.1 was prepared according to the procedure of Example 1, Step 2, using (tert- butoxycarbonyl)-D-valine in place of (tert-butoxycarbonyl)-L-valine. Compound 38.1 was converted to the title compound 38.2 using the procedure of Example 1, Step 3. MS (ESI): mass calcd. for C
34H
48N
6O
10, 700.34, m/z found 701.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.30 (s, 1H), 8.49 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 6.8 Hz, 1H), 5.23 (t, J = 4.8 Hz, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.60 – 4.48 (m, 1H), 4.45 – 4.10 (m, 3H), 3.29 (s, 3H), 2.33 – 2.21 (m, 1H), 2.20 – 2.04 (m, 2H), 1.64 – 1.51 (m, 6H), 1.44 (s, 6H), 1.39 (s, 9H), 1.15 – 1.02 (m, 3H), 0.95 – 0.80 (m, 8H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-(2- methoxy-2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl D-valinate (38). [00406] The title compound was prepared from carbamate 38.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
30H
42N
6O
8, 614.31, m/z found 615.05 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.85 – 6.65 (m, 1H),
WSGR Docket No. 41223-754.601 5.27 – 5.20 (m, 1H), 5.14 – 5.08 (m, 1H), 4.56 – 4.50 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.29 (s, 3H), 3.28 – 3.27 (m, 1H), 2.20 – 2.04 (m, 3H), 1.62 – 1.50 (m, 6H), 1.44 (s, 6H), 1.20 – 1.02 (m, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.85 – 0.75 (m, 2H). Example 39. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2-ethoxy- 2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (39).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (39.1). [00407] Title compound 39.1 was prepared according to the procedure of Example 1, Step 3, using compound 31.1 and 2-ethoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
37H
54N
6O
10, 742.39, m/z found 743.30 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.18 (s, 1H), 8.48 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 6.4 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 5.11 – 5.05 (m, 1H), 4.53 – 4.43 (m, 1H), 4.32 – 4.27 (m, 1H), 4.19 (dd, J = 12.4, 4.8 Hz, 1H), 4.10 – 4.05 (m, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.24 – 2.11 (m, 3H), 1.85 – 1.75 (m, 1H), 1.60 – 1.47 (m, 6H), 1.45 (s, 6H), 1.42 – 1.27 (m, 13H), 1.19 – 1.16 (m, 3H), 1.13 – 1.04 (m, 2H), 0.92 (t, J = 6.8 Hz, 3H), 0.89 (t, J = 6.8 Hz, 3H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (39). [00408] The title compound was prepared from carbamate 39.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
32H
46N
6O
8, 642.34, m/z found 643.15 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.85 – 6.65 (m, 1H), 5.18 – 5.13 (m, 1H), 5.12 – 5.08 (m, 1H), 4.53 – 4.48 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.23 (dd, J = 12.4, 4.8 Hz, 1H), 3.49 (q, J = 6.8 Hz, 2H), 3.28 (d, J = 5.2 Hz, 1H), 2.23 – 2.10 (m, 2H), 2.09 – 1.95 (m, 1H), 1.85 – 1.73 (m, 1H), 1.62 – 1.46 (m, 6H), 1.45 (s, 6H), 1.41 – 1.26 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H), 1.15 – 1.02 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). Example 40. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-5-(4-(2-ethoxy- 2-methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (40).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (40.1). [00409] Title compound 40.1 was prepared according to the procedure of Example 1, Step 3, using compound 35.1 and 2-ethoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
35H
50N
6O
10, 714.36, m/z found 715.30 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.18 (s, 1H), 8.49 (m, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 6.4 Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 5.12 – 5.07 (m, 1H), 4.52 – 4.44 (m, 1H), 4.30 (dd, J = 12.8, 3.6 Hz, 1H), 4.19 (dd, J = 12.4, 4.8 Hz, 1H), 4.12 – 4.06 (m, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.32 – 2.06 (m, 4H), 1.74 – 1.59 (m, 2H), 1.57 – 1.49 (m, 2H), 1.45 (s, 6H), 1.44 – 1.32 (m, 11H), 1.22 (t, J = 6.8 Hz, 3H), 1.09 – 0.99 (m, 2H), 0.97 – 0.85 (m, 6H). Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (40). [00410] The title compound was prepared from carbamate 40.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C30H42N6O8, 614.31, m/z found 615.10 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.90 – 6.60 (m, 1H), 5.21 – 5.14 (m, 1H), 5.13 – 5.05 (m, 1H), 4.56 – 4.46 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.49 (q, J = 6.8 Hz, 2H), 3.28 (d, J = 5.2 Hz, 1H), 2.32 – 2.20 (m, 2H), 2.10 – 1.95 (m, 2H), 1.72 – 1.60 (m, 2H), 1.57 – 1.48 (m, 2H), 1.47 – 1.39 (m, 8H), 1.22 (t, J = 7.2 Hz, 3H), 1.09 – 0.98 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). Example 41. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (41).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (41.1). [00411] Compound 41.1 was prepared according to the procedure of Example 1, Steps 3, using 1.3 and 2-butoxy-2-methylpropanoic acid- MS (ESI): mass calcd. for C
38H
56N
6O
10, 756.90, m/z found 757.40 [M+H]
+ Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (41). [00412] The title compound was prepared from compound 41.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
33H
48N
6O
8, 656.78, m/z found 657.30 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.10 (s, 1H), 8.47 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 5.22 – 5.13 (m, 1H), 5.10 (t, J = 4.4 Hz, 1H), 4.56 – 4.48 (m, 1H), 4.28 (dd, J = 12.4, 3.2 Hz, 1H), 4.22 (dd, J = 12.0, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.27 – 3.26 (m, 1H), 2.17 – 2.09 (m, 2H), 2.04 –1.96 (m, 1H), 1.59 – 1.49 (m, 8H), 1.45 (s, 6H), 1.40 –1.34 (m, 2H), 1.19 – 1.03 (m, 3H), 0.97 – 0.83 (m, 11H). Example 42. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (42).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (42.1). [00413] Title compound 42.1 was prepared according to the procedure of Example 1, Step 3, using compound 31.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
39H
58N
6O
10, 770.42, m/z found 771.45 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.08 (s, 1H), 8.48 (s, 1H), 7.23 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 6.4 Hz, 1H), 5.17 – 5.12 (m, 1H), 5.11 – 5.06 (m, 1H), 4.53 – 4.45 (m, 1H), 4.35 – 4.28 (m, 1H), 4.23 – 4.17 (m, 1H), 4.11 – 4.05 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 2.23 – 2.11 (m, 3H), 1.83 – 1.72 (m, 1H), 1.64 – 1.46 (m, 8H), 1.45 (s, 6H), 1.42 – 1.35 (m, 13H), 1.29 – 1.22 (m, 2H), 1.14 – 1.04 (m, 2H), 0.97 – 0.86 (m, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (42). [00414] The title compound was prepared from carbamate 42.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
34H
50N
6O
8, 670.37, m/z found 671.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.85 – 6.65 (m, 1H), 5.18 – 5.13 (m, 1H), 5.12 – 5.07 (m, 1H), 4.54 – 4.49 (m, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.23 (dd, J = 12.4, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.28 (d, J = 5.2 Hz, 1H), 2.23 – 2.10 (m, 2H), 2.07 – 1.98 (m, 1H), 1.84 – 1.72 (m, 1H), 1.64 – 1.46 (m, 8H), 1.45 (s, 6H), 1.42 – 1.35 (m, 4H), 1.32 – 1.21 (m, 2H), 1.15 – 1.01 (m, 2H), 0.95 – 0.85 (m, 9H). Example 43. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (43).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (43.1). [00415] Compound 43.1 was prepared according to the procedure of Example 1, Step 3, using 34.1 and 2-butoxy-2-methylpropanoic acid- MS (ESI): mass calcd.
728.84, m/z found 729.30 [M+H]
+ Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (43). [00416] The title compound was prepared from compound 43.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
31H
44N
6O
8, 628.73, m/z found 629.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.48 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.82 – 6.66 (m, 1H), 5.29 – 5.18 (m, 1H), 5.16 – 5.05 (m, 1H), 4.60 – 4.46 (m, 1H) 4.28 (dd, J = 12.4, 3.6 Hz, 1H), 4.20 (dd, J = 12.0, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.24 (d, J = 4.8 Hz, 1H), 2.40 – 2.30 (m, 3H), 2.13 – 2.04 (m, 1H), 2.02 – 1.92 (m, 2H), 1.80 – 1.69 (m, 2H), 1.63 – 1.55 (m, 4H), 1.45 (s, 6H), 1.41 – 1.36 (m, 2H), 0.95 – 0.86 (m, 9H). Example 44. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (44).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (44.1). [00417] Title compound 44.1 was prepared according to the procedure of Example 1, Step 3, using compound 35.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
37H
54N
6O
10, 742.39, m/z found 743.30 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (44). [00418] The title compound was prepared from carbamate 44.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
32H
46N
6O
8, 642.34, m/z found 643.30 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.93– 6.58 (m, 1H), 5.20 – 5.14 (m, 1H), 5.10 (d, J = 5.2 Hz, 1H), 4.55 – 4.45 (m, 1H), 4.30 (dd, J = 12.4, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.28 (d, J = 5.2 Hz, 1H), 2.30 – 2.20 (m, 2H), 2.08 – 1.95 (m, 2H), 1.69 – 1.48 (m, 6H), 1.46 – 1.35 (m, 10H), 1.12 – 0.97 (m, 2H), 0.95 – 0.83 (m, 9H). Example 45. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (45).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert-butoxycarbonyl)-D-valinate (45.1). [00419] Title compound 45.1 was prepared according to the procedure of Example 1, Step 3, using compound 36.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
37H
54N
6O
10, 742.39, m/z found 743.20 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (45). [00420] The title compound was prepared from carbamate 45.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
32H
46N
6O
8, 642.34, m/z found 643.20 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.84 – 6.61 (m, 1H), 5.26 – 5.20 (m, 1H), 5.15 – 5.05 (m, 1H), 4.57 – 4.50 (m, 1H), 4.30 (dd, J = 12.4, 3.6 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.26 (d, J = 5.2 Hz, 1H), 2.31 – 2.19 (m, 2H), 2.14 – 1.96 (m, 2H), 1.67 – 1.49 (m, 6H), 1.48 – 1.36 (m, 10H), 1.11 – 0.98 (m, 2H), 0.97 – 0.84 (m, 9H). Example 46. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L- valinate (46).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (46.1). [00421] Compound 46.1 was prepared according to the procedure of Example 1, Step 3, using 2.1 and 2-butoxy-2-methylpropanoic acid- MS (ESI): mass calcd. for C
38H
50N
6O
10, 750.85, m/z found 751.30 [M+H]
+ Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L- valinate (46). [00422] The title compound was prepared from compound 46.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
33H
42N
6O
8, 650.73, m/z found 651.15 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.38 – 7.17 (m, 6H), 7.14 (d, J = 4.8 Hz, 1H), 6.80 – 6.60 (m, 1H), 5.24 – 5.13 (m, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.65 – 4.48 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s, 2H), 3.45 (t, J = 6.4 Hz, 2H), 3.26 (d, J = 5.2 Hz, 1H ), 2.10 – 1.97 (m, 1H), 1.63 – 1.56 (m, 2H), 1.45 (s, 6H), 1.41 – 1.35 (m, 2H), 0.94 – 0.85 (m, 9H). Example 47. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl D- valinate (47).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (47.1). [00423] Title compound 47.1 was prepared according to the procedure of Example 1, Step 3, using compound 37.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
38H
50N
6O
10, 750.36, m/z found 751.25 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.08 (s, 1H), 8.48 (s, 1H), 7.32 – 7.05 (m, 8H), 7.14 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 6.8 Hz, 1H), 5.26 – 5.20 (m, 1H), 5.14 – 4.98 (m, 1H), 4.60 – 4.52 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.27 (dd, J = 12.4, 4.8 Hz, 1H), 3.70 – 3.62 (m, 2H), 3.45 (t, J = 6.4 Hz, 2H), 3.32 (s, 1H), 2.35 – 2.21 (m, 1H), 1.65 – 1.53 (m, 2H), 1.46 (s, 6H), 1.42 – 1.31 (m, 11H), 0.96 – 0.82 (m, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl D- valinate (47). [00424] The title compound was prepared from carbamate 47.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
33H
42N
6O
8, 650.31, m/z found 651.15 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.30 – 7.17 (m, 6H), 7.14 (d, J = 4.8 Hz, 1H), 6.80 – 6.62 (m, 1H), 5.26 – 5.20 (m, 1H), 5.10 – 5.02 (m, 1H), 4.60 – 4.50 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.71 – 3.61 (m, 2H), 3.47 – 3.41 (m, 2H), 3.26 (d, J = 5.2 Hz, 1H), 2.16 – 2.03 (m, 1H), 1.68 – 1.54 (m, 2H), 1.45 (s, 6H), 1.43 – 1.36 (m, 2H), 0.94 – 0.81 (m, 9H). Example 48. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (48).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (48.1). [00425] Title compound 48.1 was prepared according to the procedure of Example 1, Step 3, using compound 38.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
38H
56N
6O
10, 756.41, m/z found 757.25 [M+H]
+. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (48). [00426] The title compound was prepared from carbamate 48.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C
33H
48N
6O
8, 656.35, m/z found 657.25 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 8.47 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.90 – 6.56 (m, 1H), 5.28 – 5.20 (m, 1H), 5.14 – 5.05 (m, 1H), 4.60 – 4.48 (m, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.30 – 3.26 (m, 1H), 2.20 – 2.05 (m, 3H), 1.62 – 1.50 (m, 8H), 1.45 (s, 6H), 1.42 – 1.34 (m, 2H), 1.21 – 1.02 (m, 3H), 0.78 – 0.95 (m, 11H). Example 49. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (49).
WSGR Docket No. 41223-754.601 Step 1. Synthesis of 1-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-isopropylurea (49.1). [00427] Compound 49.1 was prepared according to the procedure of Example 6, Step 1, using 1.1 and 2-isocyanatopropane- MS (ESI): mass calcd. for C
16H
20N
6O
5, 376.37, m/z found 377.20 [M+H]
+. Step 2. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(3-isopropylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (51). [00428] A solution of 49.1 (45.0 mg, 0.119 mmol) in trimethyl phosphate (0.6 mL) was stirred at 0 °C for 10 min. To the above solution was added phosphorus oxychloride (36.7 mg, 0.239 mmol, fresh distilled) dropwise and the mixture was stirring for 2 h under N
2 atmosphere. A mixture of DIEA (61.8 mg, 0.478 mmol) and bis(tributylammonium) pyrophosphate (197 mg, 0.358 mmol) in acetonitrile (1 mL) was added at once. After 25 minutes, the reaction was quenched with water (10 mL), and the clear solution was stirred vigorously for about an h at room temperature. The pH of the solution was adjusted to ~6.53 with tetraethylammonium bromide (TEAB) buffer (2 mL, 1M) and the mixture was vigorous stirred for 3 h. LCMS analysis indicated the formation of the corresponding triphosphate. The reaction mixture was then lyophilized overnight to afford a residue which was purif ied by prep-HPLC (column: Gemini - C18150×21.2 mm, 5um; mobile phase: ACN in 20 mM TEAB; gradient: 0-15%) twice, and subsequently purified via ion column (column: HiPrepTM Q FF 16/10; mobile phase: water in 1M TEAB; gradient: 0-70%) to obtain the total compound 51 (13.81 mg, 0.0224 mmol, 18.7% yield, tris- triethylaminmonium salt) as a white solid. MS (ESI): mass calcd. for C
16H
23N
6O
14P
3, 616.31, m/z found 615.20 [M-H]-.
1H NMR (400 MHz, D
2O) δ 8.16 (s, 1H), 7.12 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 4.98 (d, J = 4.8 Hz, 1H), 4.48 (d, J = 4.0 Hz, 2H), 4.18 – 4.11 (m, 1H), 4.05 – 3.99 (m, 1H), 3.96 – 3.88 (m, 1H), 3.13 (q, J = 7.2 Hz, 19H), 1.24 – 1.17 (m, 34H).
31P NMR (162 MHz, D
2O) δ -10.27 (d, J = 15.2 Hz, 1P), -11.49 (d, J = 20.0 Hz, 1P), -23.07 (t, J = 19.6 Hz, 1P). Example 50. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (50).
WSGR Docket No. 41223-754.601 Step 1. Synthesis of N-(7-((6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-9- ((trimethylsilyl)oxy)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-2-ethylbutanamide (50.1). [00429] Compound 50.1 was prepared according to the procedure of Example 3, Step 1, using 16.2 and 2-ethylbutanoyl chloride. MS (ESI): mass calcd. for C
33H
57N
5O
6Si
3, 704.10, m/z found 704.30 [M+H]
+. Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-ethylbutanamide (50.2). [00430] Compound 50.2 was prepared according to the procedure of Example 16, Step 4, using 52.1.- MS (ESI): mass calcd. for C
18H
23N
5O
5, 389.41, m/z found 390.2 [M+H]
+. Step 3. Synthesis of Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (50). [00431] Compound 50 was prepared according to the procedure of Example 49, Step 2, using 50.2. MS (ESI): mass calcd. for C
18H
26N
5O
14P
3, 629.35, m/z found 628.05 [M-H]-.
1H NMR (400 MHz, D
2O) δ 8.19 (s, 1H), 7.16 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 4.90 (d, J = 4.4 Hz, 1H), 4.41 – 4.39 (m, 2H), 4.08 – 4.03 (m, 1H), 3.98 – 3.93 (m, 1H), 3.04 (q, J = 7.2 Hz, 18H), 2.48 – 2.38 (m, 1H), 1.58 – 1.46 (m, 4H), 1.12 (t, J = 7.2 Hz, 27H), 0.80 (t, J = 7.6 Hz, 6H).
31P NMR (162 MHz, D
2O) δ -8.24 ~ - 10.64 (m, 1H), -11.51 (d, J = 20.0 Hz, 1H), -23.01 (t, J = 18.0 Hz, 1H). Example 51. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (51).
Step 1. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (51). [00432] Compound 51 was prepared according to the procedure of Example 49, Step 2, using 23.6. MS (ESI): mass calcd. for C
17H
25N
6O
14P
3, 630.34, m/z found 629.35 [M-H]-.
1H NMR (400 MHz, D
2O) δ 7.75 (s, 1H), 7.05 – 6.82 (m, 2H), 4.86 (d, J = 4.8 Hz, 1H), 4.41 – 4.38 (m, 2H), 4.09 – 4.03 (m, 1H), 3.99 – 3.92 (m, 1H), 3.39 – 3.26 (m, 4H), 3.04 (q, J = 7.2 Hz, 19H), 1.11 (t, J = 7.2 Hz, 28H), 1.05 – 0.96 (m, 6H).
31P NMR (162 MHz, D
2O) δ -10.39 ~ -8.68 (m, 1P), -11.50 (d, J = 20.0 Hz, 1P), -22.91 (t, J = 19.6 Hz, 1P). Example 52. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (52).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of N-(7-((6aR,8R,9R,9aS)-8-cyano-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro- 6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxy-2- methylpropanamide (52.1). [00433] Compound 52.1 was prepared according to the procedure of Example 1, Step 3, using 16.2 and 2-methoxy-2-methylpropanoic acid- MS (ESI): mass calcd. for C
29H
47N
5O
7Si
2, 633.89, m/z found 634.2 [M+H]
+ Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxy-2- methylpropanamide (52.2). [00434] Compound 52.2 was prepared from compound 52.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C
17H
21N
5O
6, 391.38, m/z found 392.2 [M+H]
+. Step 3. . Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (52). [00435] Compound 52 was prepared according to the procedure of Example 49, Step 2, using 52.2.- MS (ESI): mass calcd. for C
17H
24N
5O
15P
3, 631.32, m/z found 630.25 [M-H]-.
1H NMR (400 MHz, D
2O) δ 8.23 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 4.91 (d, J = 4.4 Hz, 1H), 4.45 – 4.40 (m, 2H), 4.10 – 4.03 (m, 1H), 3.99 – 3.92 (m, 1H), 3.28 (s, 3H), 3.04 (q, J = 7.2 Hz, 19H), 1.39 (s, 6H), 1.12 (t, J = 7.2 Hz, 6H), 1.12 (t, J = 7.2 Hz, 29H).
31P NMR (162 MHz, D
2O) δ -7.90 ~ -10.20 (m, 1H), -11.55 (d, J = 20.0 Hz, 1H), -23.06 (t, J = 20.0 Hz, 1H). Example 53. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (53).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of N-(7-((6aR,8R,9R,9aS)-8-cyano-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro- 6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-ethoxy-2- methylpropanamide (53.1). [00436] Compound 53.1 was prepared according to the procedure of Example 1, Step 3, using 16.2 and 2-ethoxy-2-methylpropanoic acid. - MS (ESI): mass calcd. for C
30H
49N
5O
7Si
2, 647.92, m/z found 648.20 [M+H]
+. Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-ethoxy-2- methylpropanamide (53.2). [00437] Compound 53.2 was prepared from compound 53.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C
18H
23N
5O
6, 405.41, m/z found 406.2 [M+H]
+. Step 3.. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (53). [00438] Compound 53 was prepared according to the procedure of Example 49, Step 2, using 53.2. MS (ESI): mass calcd. for C
18H
26N
5O
15P
3, 645.35, m/z found 644.35 [M-H]-.
1H NMR (400 MHz, D
2O) δ 8.22 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 4.91 (d, J = 4.4 Hz, 1H), 4.44 – 4.38 (m, 2H), 4.10 – 4.03 (m, 1H), 3.98 – 3.93 (m, 1H), 3.50 (q, J = 7.2 Hz, 2H), 3.04 (q, J = 7.2 Hz, 20H), 1.39 (s, 6H), 1.22 – 1.08 (m, 33H).
31P NMR (162 MHz, D
2O) δ -6.34 (d, J = 20.8 Hz, 1H), -11.44 (d, J = 20.0 Hz, 1H), -22.54 (t, J = 20.0 Hz, 1H). Example 54. Synthesis of ((2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (54).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of 2-butoxy-N-(7-((6aR,8R,9R,9aS)-8-cyano-9-hydroxy-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)-2-methylpropanamide (54.1). [00439] Compound 54.1 was prepared according to the procedure of Example 1, Step 3, using 16.2 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C
32H
53N
5O
7Si
2, 675.97, m/z found 676.20 [M+H]
+. Step 2. Synthesis of 2-butoxy-N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylpropanamide (54.2). [00440] Compound 54.2 was prepared from compound 54.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C20H27N5O6, 433.47, m/z found 434.15 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) δ 10.03 (s, 1H), 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.25 (d, J = 6.4 Hz, 1H), 5.25 (d, J = 5.6 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.62 (t, J = 5.6 Hz, 1H), 4.09 – 4.05 (m, 1H), 4.00 – 3.92 (m, 1H), 3.66 – 3.60 (m, 1H), 3.59 – 3.48 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 1.71 – 1.54 (m, 2H), 1.45 (s, 6H), 1.38 – 1.35 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H). Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (54). [00441] Compound 54 was prepared according to the procedure of Example 49, Step 2, using 54.2.- MS (ESI): mass calcd. for C
20H
30N
5O
15P
3, 673.40, m/z found 672.40 [M-H]
- 1H NMR (400 MHz, D
2O) δ 8.29 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 4.98 (d, J = 4.4 Hz, 1H), 4.51 – 4.48 (m, 2H), 4.17 – 4.12 (m, 1H), 4.07 – 4.01 (m, 1H), 3.53 (t, J = 6.8 Hz, 2H), 3.12 (q, J = 7.2 Hz, 19H), 1.64 – 1.57 (m, 2H), 1.47 (s, 6H), 1.38 – 1.32 (m, 2H), 1.20 (t, J = 7.2 Hz, 29H), 0.83 (t, J = 7.6 Hz, 3H).
31P NMR (162 MHz, D
2O) δ -8.44 ~ -10.96 (m, 1H), -11.52 (d, J = 20.0 Hz, 2H), -23.02 (t, J = 20.8 Hz, 1H). EXAMPLE I: Oral Composition of a Compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
WSGR Docket No. 41223-754.601 [00442] To prepare a pharmaceutical composition for oral delivery, 400 mg of compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and the following ingredients are mixed intimately and pressed into single scored tablets. Tablet Formulation Ingredient Quantity per tablet (mg) compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 [00443] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Capsule Formulation Ingredient Quantity per capsule (mg) compound 200 lactose spray dried 148 magnesium stearate 2 EXAMPLE II: Evaluation of cellular permeability in Caco-2 cell monolayers. [00444] The bidirectional permeability of compounds across the Caco-2 cell monolayer was assessed. The Caco-2 model is a widely used in vitro model for small intestinal absorption and potential for efflux. [00445] Cell culture. Caco-2 cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS), 1% Penicillin-Streptomycin and 1% MEM NEAA. The cells were incubated at 37 °C, 5% CO
2/95% air and saturated humidity. After reaching 80-90% confluency, the cells were gently detached with trypsin. Cells at passage 39 were seeded on the 24-well BD insert system at the density of 8×104 cells/cm
2 and cultured for 19 days with medium changed every 2-3 days. Measure the transepithelial electrical resistance (TEER) value of each well. The wells can be used only when their TEER values are greater than 600 Ohms/cm
2. [00446] Transport assay. After removing the cell culture medium from the 24-well insert plate, the cells were rinsed with warm transport buffer. Appropriate dosing and receiving solutions were applied to the donor and receiver chambers to initiate the transport assay in apical to basolateral (A to B) or basolateral to apical (B to A) directions (500 and 1300 µL for apical and basolateral wells, respectively). Duplicate wells in each direction were used for the test compound and control compound. The plate was incubated in CO
2 incubator at 37 °C, with 5% CO
2/95% air and saturated humidity without shaking. The sample after 10-minute incubation was used as the T
0 sample, and the sample after 90-minute incubation was used as the T90 sample. T0 and T90 samples were collected from the donor and receiver side of each well at the designed timepoint, mixed with the transport buffer and acetonitrile/MeOH (1:1, v/v) and the internal standard for LC/MS/MS analysis. All samples were vortexed and centrifuged at 4000 rpm at 4 °C for 15 minutes, diluted with pure water and stored at 4 °C before bioanalysis by LC/MS/MS.
WSGR Docket No. 41223-754.601 [00447] Sample analysis. The concentrations of test compounds and control compounds in Caco-2 cells were quantitatively determined by LC/MS/MS method after protein precipitation. [00448] Calculations. The apparent permeability (P
app, cm/s), efflux ratio (ER) and recovery parameters were calculated for Caco-2 drug transport assay using the following equations:
where V
R is the solution volume in the receiver chamber (0.4 mL on the apical side, 1.2 mL on the basolateral side); Area is the surface area for the insert membrane, i.e., 0.3 cm
2 for the area of the monolayer; Time is incubation time, expressed in seconds, i.e., 5400 s (90 min) for the current experiment; C
0 is the initial concentration of test compound or peak area ratio of control compounds in the donor chamber (µM); V
D is the volume in the donor chambers (0.4 mL on the apical side, 1.2 mL on the basolateral side); C
D and C
R are the final concentrations of test compounds or peak area ratio of control compounds in donor and receiver chambers, respectively. [00449] Data for representative compounds is shown in Table 2. Compounds with P
app < 1.0 are classified as low permeability, P
app between 1-10 are classified as medium permeability, and P
app ≥ 10 are classified as high permeability. An efflux ratio (ER) > 2 indicates the compounds are potential substrates for intestinal cell efflux transporters. Table 2. Bidirectional Caco-2 permeability assay results.
WSGR Docket No. 41223-754.601
EXAMPLE III: Evaluation of oral bioavailability in Sprague-Dawley rats. [00450] The single dose pharmacokinetics of Example Compounds is evaluated in fasted male Sprague-Dawley rats following oral gavage. Compounds are dosed as solutions or acceptable suspensions in vehicles generally-regarded as safe for in vivo studies. Groups of three rats per compound are utilized, and blood samples collected at 0.25, 0.5, 1, 2, 4, 8 and 24 h post-dose, stored on ice prior to plasma preparation by centrifugation at 4 °C at 6000 rpm for 5 min. Plasma samples are stored at -80 °C. Concentrations of Example Compounds and corresponding nucleosides resulting from metabolic processing are determined using ultra-high performance liquid chromatography-triple-quadrupole mass spectrometry, with an internal standard. Pharmacokinetic parameters are derived from the resulting plasma concentration/time graphs, and include the following: plasma half-life (t
1/2), time to maximum plasma concentration (T
max), maximum plasma concentration (C
max), area under the curve of the plasma concentration/time graph (AUC
last, through last timepoint obtained, and AUC
Inf, including the extrapolated area), and mean residence time (MRT
Inf). The resulting AUC
Inf for the resulting nucleosides are compared with that resulting from intravenous bolus administration of the corresponding nucleosides in three rats, and an oral bioavailability (F, %) was be calculated as AUCinf, PO ^^ ^^ ^^ ^^ ( ^^ ^^) ^^ ^^ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^)
× × AUCinf, IV ^^ ^^ ^^ ^^ ( ^^ ^^) ^^ ^^ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^)
WSGR Docket No. 41223-754.601 [00451] Table 3 contains certain pharmacokinetic parameters obtained in rats for compounds of the invention. The compounds were dosed by oral gavage (using 10% ethanol/90% propylene glycol as vehicle). The data obtained for oral dosing of the parent nucleoside, GS-441524, using a solution in 20% Captisol® in water, is included for comparison. Exposures, as reflected by the area under the concentration/time curve (AUCinf), are included, as well as the dose- and prodrug molecular weight- normalized AUCinf values, to enable direct comparisons among the compounds. The compounds of the present invention provided higher plasma exposures of the parent nucleoside than via dosing of the nucleoside itself, demonstrating that the potential to deliver higher concentrations of the nucleoside using the prodrugs of the invention. Table 3. Pharmacokinetic parameters for parent nucleoside following oral dosing of Example Compounds in Sprague-Dawley rat.
*Values normalized to reflect equivalent dose of parent nucleoside (GS-441524). ** Vehicle = 20% Captisol® in water. EXAMPLE IV: Evaluation of stability of example compounds in human fasted-state simulated gastric fluid, and fasted-state simulated intestinal fluid. [00452] The chemical stability of example compounds was determined using human fasted -state simulated gastric fluid, and fasted-state simulated intestinal fluid, prepared as follows. [00453] FaSSGF: • Weigh 1.0 g NaCl and dissolved it in 0.49 L water • Adjust pH value to 1.2, and adjust volume to 0.5 L in water • Filter the NaCl/HCl buffer through a 0.22 µm filter • Weigh 3.0 mg FaSSGF powder (Vendor: Biorelevant, catalog # FFF01), dissolve it in 50 mL NaCl/HCl buffer • Dissolve the FaSSGF powder in NaCl/HCl buffer and make up the volume to 50 mL • Store at 4 °C for future use. [00454] FaSSIF: • Weigh 0.695 g NaOH, 1.115 g maleic acid and 2.005 g NaCl, and dissolve in 0.49 L water
WSGR Docket No. 41223-754.601 • Adjusted the pH value to 6.8 and adjust volume to 0.5 L with water • Filter the maleic acid buffer through a 0.22 µm filter • Weigh 89.5 mg FaSSIF-V2 powder (Vendor: Biorelevant catalog # V2FAS01), dissolve in 50 mL maleic buffer • Dissolve the FaSSIF-V2 powder in maleic buffer and make up the volume to 50 mL • Store at 4 °C for future use. [00455] Briefly, test compounds were prepared as 50 µM working solutions in DMSO, and 2 µL test compound working solution was added to 98 µL of each buffer respectively in six tubes (for six timepoints, 0, 5, 15, 30, 60, and 120 min) and gently mixed. At each corresponding timepoint, the reaction was stopped by addition of 300 µL of quenching solution (methanol solution of 5 ng/mL terfenadine and 10 ng/mL of tolbutamide). Each tube was vortexed for 1 min, centrifuged at 4,000 rpm at 4 °C for 15 min, then 200 µL of supernatant was removed. The half-life of each example compound was determined using LC-MS/MS analysis, using the internal standards present in the quenching solution. [00456] Stability data for selected compounds of the invention is shown in Table 4. Table 4. Stability of example compounds in human fasted-state simulated gastric fluid and fasted- state simulated intestinal fluid. Half-lives in human FaSSGF and FaSSIF determined by LC/MS methods.
EXAMPLE V: Evaluation of SARS-CoV-2 RNA-dependent RNA polymerase inhibitory activity of nucleoside triphosphate derivatives. [00457] The ability of selected amide-derivatized nucleoside triphosphates to inhibit the SARS-CoV-2 RNA-dependent RNA polymerase was assessed in a commercially-available biochemical assay (performed by BPS Bioscience Inc., 6405 Mira Mesa Blvd., Ste. 100, San Diego, CA 92121, USA). Enzymes and Substrates
WSGR Docket No. 41223-754.601
Assay Conditions [00458] The RdRp reactions were conducted in duplicate at 37 °C for 60 min in a 10 µL mixture containing assay buffer, RNA duplex, ATP substrate and enzyme, and the test compound. These 10 µL reactions were carried out in wells of 384-well white plate (Nunc). Dilutions of the test compounds were prepared in assay buffer (5% DMSO concentration) and 2 µL of the dilution was added to a 6 µL of RdRp containing RNAse inhibitor for preincubation (30 minutes at room temperature with slow shaking). Reaction was started by addition of 2 µL of the substrate mix containing RNA duplex and ATP substrate. Final concentration of DMSO was 1% in all of reactions (reference compound 6-Chloropurine-ribose-5'- triphosphate – 0% DMSO). After enzymatic reactions, 10 µL of Eu-labeled anti-Dig antibody (BPS, diluted 1:600 with 1x detection buffer) and Dye-labeled acceptor (diluted 1:200 with 1x detection buffer) added to the reaction mix. After brief shaking, plate was incubated for 20 min. In 20 minutes, the samples were measured in microplate reader (Tecan M1000, Tecan). Data Analysis [00459] Enzyme activity assays were performed in duplicates at each concentration. The TR-FRET data were analyzed and compared. The data were analyzed using the computer software, Graphpad Prism. In the absence of the compound, the intensity (Ce) in each data set was defined as 100 % activity. In the absence of enzyme, the intensity (C
0) in each data set was defined as 0 % activity. The percent activity in the presence of each compound was calculated according to the following equation: % activity = (C-C
0)/(C
e-C
0), where C = the TR-FRET intensity in the presence of the compound. The % activity as a function of compound concentration was then plotted and fitted using non-linear regression analysis of Sigmoidal dose-response curve generated with the equation Y=B+(T-B)/1+10
((LogEC 50 -X)×Hill Slope), where Y = percent activity, B = minimum percent activity, T = maximum percent activity, X = logarithm of compound and Hill Slope = slope factor or Hill coefficient. The IC
50 value was determined as the concentration causing half-maximal percent activity. [00460] Table 5 summarizes the results for select exemplary triphosphate analogs, plus negative control GS-441524 (parent nucleoside analog), and positive control compounds GS-443902 (Mackman, RL, et al, J Med Chem 2023, 66 (17), 11701-11717; DOI: 10.1021/acs.jmedchem.3c00750) and 6-chloropurine- ribose-5'-triphosphate. As may be seen from these results, intermediate amides derived from ester cleavage of the compounds of the invention retain inhibitory activity similar to or better than GS-441524, indicating that these amides have the potential to exert antiviral activity directly, without requiring metabolic conversion to GS-441524 in vivo.
WSGR Docket No. 41223-754.601 Table 5. SARS-CoV-2 RNA-dependent RNA polymerase inhibitory activity of nucleoside-amide triphosphate derivatives.
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
WSGR Docket No. 41223-754.601 R12 is -C(=O)NR22R23; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; each R15a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R15a on the same atom are taken together to form an oxo; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo;
WSGR Docket No. 41223-754.601 or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a; each R16a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R16a on the same atom are taken together to form an oxo; R26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R26a on the same atom are taken together to form an oxo; or two R26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
WSGR Docket No. 41223-754.601 each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [0046] In some aspect, the compound of Formula (I) gets metabolized in vivo. [0047] In some aspect, the compound of Formula (I) gets metabolized in vivo to a compound of Formula (I-M). [0048] Disclosed herein is a compound of Formula (I-M), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (I-M); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is -C(=O)NR22R23;
WSGR Docket No. 41223-754.601 R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R17 is hydrogen,
, , or
R7 is hydrogen or a counterion; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
WSGR Docket No. 41223-754.601 C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [0049] In some embodiments of a compound of Formula
[0050] In some embodiments of a compound of Formula (I) or (I-M), X is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), X is -CN. [0051] In some embodiments of a compound of Formula (I) or (I-M), R13 is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), R13 is C1-C6alkyl. [0052] In some embodiments of a compound of Formula (I) or (I-M), R14 is -OH. In some embodiments of a compound of Formula (I) or (I-M), R14 is fluoro. [0053] In some embodiments of a compound of Formula (I) or (I-M), R11 is hydrogen, -C(=O)R21, or C1-C6alkyl optionally substituted with one or more R11a. In some embodiments of a compound of Formula (I) or (I-M), R11 is hydrogen or -C(=O)R21. In some embodiments of a compound of Formula (I) or (I-M), R11 is hydrogen. In some embodiments of a compound of Formula (I) or (I-M), R11 is - C(=O)R21.
WSGR Docket No. 41223-754.601 [0054] In some embodiments of a compound of Formula (I) or (I-M), each R11a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (I) or (I-M), each R11a is independently halogen. [0055] In some embodiments of a compound of Formula (I) or (I-M), R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. In some embodiments of a compound of Formula (I) or (I-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [0056] In some embodiments of a compound of Formula (I) or (I-M), each R21a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (I-M), each R21a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [0057] In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [0058] In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R22 is C1-C6alkyl. [0059] In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl),
WSGR Docket No. 41223-754.601 C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [0060] In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen, C1-C6alkyl, or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen or C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R23 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (I) or (I-M), R23 is C1-C6alkyl. In some embodiments of a compound of Formula (I) or (I-M), R23 is hydrogen. [0061] In some embodiments of a compound of Formula (I) or (I-M), each R22a is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [0062] In some embodiments of a compound of Formula (I) or (I-M), each R22a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (I-M), each R22a is independently halogen, -OH, - ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (I- M), each R22a is independently halogen, -OC(=O)Ra, or -NRcRd. In some embodiments of a compound of Formula (I) or (I-M), each R22a is independently -OC(=O)Ra or -NRcRd. In some embodiments of a compound of Formula (I) or (I-M), each R22a is independently -OC(=O)Ra. [0063] In some embodiments of a compound of Formula
[0064] In some embodiments of a compound of Formula (I), R15 is hydrogen, -C(=O)R25, or -CH2-O- C(=O)R25. In some embodiments of a compound of Formula (I), R15 is hydrogen or -C(=O)R25. In some embodiments of a compound of Formula (I), R15 is -C(=O)R25. In some embodiments of a compound of Formula (I), R15 is hydrogen. [0065] In some embodiments of a compound of Formula (I), each R15a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (I), each R15a is independently halogen. [0066] In some embodiments of a compound of Formula (I), R25 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is
WSGR Docket No. 41223-754.601 optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (I), R25 is C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (I), R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R25a. [0067] In some embodiments of a compound of Formula (I), each R25a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each R25a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [0068] In some embodiments of a compound of Formula (I), R15 is
, or
. In some embodiments of a compound of Formula (I), R15
. In some embodiments of a compound of Formula (I), R15 is
. In some embodiments of a compound of Formula (I), R15 is
. In some embodiments of a compound of Formula (I), R15 is
. In some embodiments of a compound of Formula (I), R15 is not
. In some embodiments of a compound of Formula (I), R15 is not
. In some embodiments of a compound of Formula (I), R15 is not
. [0069] In some embodiments of a compound of Formula (I), R16 is hydrogen, -C(=O)R26, or -CH2-O- C(=O)R26. In some embodiments of a compound of Formula (I), R16 is hydrogen or -C(=O)R26. In some embodiments of a compound of Formula (I), R16 is -C(=O)R26. In some embodiments of a compound of Formula (I), R16 is hydrogen. In some embodiments of a compound of Formula (I), R16 is -CH2-O- C(=O)R26. [0070] In some embodiments of a compound of Formula (I), each R16a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (I), each R16a is independently halogen.
WSGR Docket No. 41223-754.601 [0071] In some embodiments of a compound of Formula (I), R26 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (I), R26 is C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (I), R26 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R26a. [0072] In some embodiments of a compound of Formula (I), each R26a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), each R26a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [0073] In some embodiments of a compound of Formula (I), R16 is
. In some embodiments of a compound of Formula (I), R16 is
. In some embodiments of a compound of Formula (I), R16 is
. In some embodiments of a compound of Formula (I), R16 is not
. In some embodiments of a compound of Formula (I), R16 is not
. In some embodiments of a compound of Formula (I), R16 is not
. In some embodiments of a compound of Formula
some embodiments of a
WSGR Docket No. 41223-754.601 compound of Formula
some embodiments of a compound of
. ,
[0074] In some embodiments of a compound of Formula (I-M), R7 is hydrogen. In some embodiments of a compound of Formula (I-M), R7 is a counterion. In some embodiments of a compound of Formula (I-M), R7 is Na+. In some embodiments of a compound of Formula (I-M), R7 is Li+. In some embodiments of a compound of Formula (I-M), R7 is Mg2+. [0075] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (II); wherein: X is hydrogen or -CN;
WSGR Docket No. 41223-754.601
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl,
WSGR Docket No. 41223-754.601 C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; each R15a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R15a on the same atom are taken together to form an oxo; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26; R26 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R26a on the same atom are taken together to form an oxo; or two R26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
WSGR Docket No. 41223-754.601 each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [0076] In some aspect, the compound of Formula (II) gets metabolized in vivo. [0077] In some aspect, the compound of Formula (II) gets metabolized in vivo to a compound of Formula (II-M). [0078] Disclosed herein is a compound of Formula (II-M), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (II-M); wherein: X is hydrogen or -CN;
WSGR Docket No. 41223-754.601 R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo;
WSGR Docket No. 41223-754.601 or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro;
R7 is hydrogen or a counterion; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo.
WSGR Docket No. 41223-754.601 [0079] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula
[0080] In some embodiments of a compound of Formula (II) or (II-M), X is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), X is -CN. [0081] In some embodiments of a compound of Formula (II) or (II-M), R13 is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), R13 is C1-C6alkyl. [0082] In some embodiments of a compound of Formula (II) or (II-M), R14 is -OH. In some embodiments of a compound of Formula (II) or (II-M), R14 is fluoro. [0083] In some embodiments of a compound of Formula (II): R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0084] In some embodiments of a compound of Formula (II), R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0085] In some embodiments of a compound of Formula (II),
WSGR Docket No. 41223-754.601 R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, or -C(=O)NR22R23, C1-C6alkyl optionally substituted with one or more R12a; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0086] In some embodiments of a compound of Formula (II), R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0087] In some embodiments of a compound of Formula (II), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0088] In some embodiments of a compound of Formula (II), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0089] In some embodiments of a compound of Formula (II), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, -CH2-O-C(=O)OR25, or C1-C6alkyl optionally substituted with one or more R15a; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26. [0090] In some embodiments of a compound of Formula (II) or (II-M), R11 is hydrogen, -C(=O)R21, or C1-C6alkyl optionally substituted with one or more R11a. In some embodiments of a compound of Formula (II) or (II-M), R11 is hydrogen or -C(=O)R21. In some embodiments of a compound of Formula
WSGR Docket No. 41223-754.601 (II) or (II-M), R11 is hydrogen. In some embodiments of a compound of Formula (II) or (II-M), R11 is - C(=O)R21. [0091] In some embodiments of a compound of Formula (II) or (II-M), each R11a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (II) or (II-M), each R11a is independently halogen. [0092] In some embodiments of a compound of Formula (II) or (II-M), R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. In some embodiments of a compound of Formula (II) or (II-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [0093] In some embodiments of a compound of Formula (II) or (II-M), each R21a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (II-M), each R21a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [0094] In some embodiments of a compound of Formula (II) or (II-M), R12 is hydrogen, -C(=O)R22, - C(=O)OR22, or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R12 is - C(=O)R22, -C(=O)OR22, or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R12 is hydrogen or -C(=O)R22. In some embodiments of a compound of Formula (II) or (II-M), R12 is - C(=O)R22. In some embodiments of a compound of Formula (II) or (II-M), R12 is hydrogen, or - C(=O)OR22. In some embodiments of a compound of Formula (II) or (II-M), R12 is hydrogen or C1- C6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R12 is -C(=O)NR22R23. [0095] In some embodiments of a compound of Formula (II) or (II-M), each R12a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (II) or (II-M), each R12a is independently halogen. [0096] In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. [0097] In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl,
WSGR Docket No. 41223-754.601 C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [0098] In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl optionally substituted with one R22a. In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6alkyl substituted with one R22a. [0099] In some embodiments of a compound of Formula (II) or (II-M), R22 is C1-C6heteroalkyl. [00100] In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00101] In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen, C1-C6alkyl, or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen or C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R23 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (II) or (II-M), R23 is C1-C6alkyl. In some embodiments of a compound of Formula (II) or (II-M), R23 is hydrogen. [00102] In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00103] In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently halogen, -OH,
WSGR Docket No. 41223-754.601 -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently halogen, -OC(=O)Ra, or -NRcRd. In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently -OC(=O)Ra or -NRcRd. In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently -OC(=O)Ra. In some embodiments of a compound of Formula (II) or (II-M), each R22a is independently -ORa. In some embodiments of a compound of Formula (II) or (II-M), R22a is -ORa.
[00105] In some embodiments of a compound of Formula
[00106] In some embodiments of a compound of Formula (II) or (II-M), R12 is
, ,
. , . embodiments of a compound of Formula (II) or (II-M), R12 is
. In some embodiments of a compound of Formula
[00107] In some embodiments of a compound of Formula (II), R15 is hydrogen, -C(=O)R25, or -CH2-O- C(=O)R25. In some embodiments of a compound of Formula (II), R15 is hydrogen or -C(=O)R25. In some embodiments of a compound of Formula (II), R15 is -C(=O)R25. In some embodiments of a compound of Formula (II), R15 is hydrogen. [00108] In some embodiments of a compound of Formula (II), each R15a is independently halogen, - CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (II), each R15a is independently halogen.
WSGR Docket No. 41223-754.601 [00109] In some embodiments of a compound of Formula (II), R25 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (II), R25 is C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (II), R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R25a. [00110] In some embodiments of a compound of Formula (II), each R25a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R25a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00111] In some embodiments of a compound of Formula (II), R15 is
, or
. In some embodiments of a compound of Formula (II), R15 is
. In some embodiments of a compound of Formula (II), R15 is
. In some embodiments of a compound of Formula (II), R15 is
. In some embodiments of a compound of Formula (II), R15 is . In some embodiments of a compound of Formula (II), R15 is
. In some embodiments of a compound of Formula (II), R15 is
. In some embodiments of a compound of Formula (II), R15 is not
. In some embodiments of a compound of Formula (II), R15 is not
. In some embodiments of a compound of Formula (II), R15 is not
. [00112] In some embodiments of a compound of Formula (II), R16 is -C(=O)R26. In some embodiments of a compound of Formula (II), R16 is -C(=O)OR26. In some embodiments of a compound of Formula (II), R16 is -CH2-O-C(=O)R26.
WSGR Docket No. 41223-754.601 [00113] In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1- C6alkylene(cycloalkyl) or C1-C6alkylene(aryl). In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independe ntly substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1- C6alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. [00114] In some embodiments of a compound of Formula (II), R26 is C1alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (II), R26 is C1alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. [00115] In some embodiments of a compound of Formula (II), R26 is C1alkylene(3- to 8-membered cycloalkyl). In some embodiments of a compound of Formula (II), R26 is C1alkylene(4- to 7-membered cycloalkyl). In some embodiments of a compound of Formula (II), R26 is C1alkylene(4- to 6-membered cycloalkyl). In some embodiments of a compound of Formula (II), R26 is C1alkylene(5- to 6-membered cycloalkyl). [00116] In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 26a. In some embodiments of a compound of Formula (II), R26 is C1-C6alkylene(phenyl); wherein the alkylene and phenyl is optionally and independently substituted with one or more R26a. [00117] In some embodiments of a compound of Formula (II), each R26a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), each R26a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
WSGR Docket No. 41223-754.601 [00118] In some embodiments of a compound of Formula (II), R16 is
, ,
. In some embodiments of a compound of Formula (II), R16 is
. In some embodiments of a compound of Formula (II), R16 is
. In some embodiments of a compound
. [00119] In some embodiments of a compound of Formula (II), R15 is
; R12 is -C(=O)R22; and R22 is C1-C6heteroalkyl. [00120] In some embodiments of a compound of Formula (II), R15 is
; R12 is -C(=O)R22; R22 is C1-C6alkyl optionally and independently substituted with one or more R22a; and each R22a is independently -ORa. [00121] In some embodiments of a compound of Formula (II), R15 is
,
WSGR Docket No. 41223-754.601 [00122] In some embodiments of a compound of Formula (II-M), R17 is
,
some embodiments of a compound of Formula
some embodiments of a compound of Formula
. ,
. [00123] In some embodiments of a compound of Formula (II-M), R7 is hydrogen. In some embodiments of a compound of Formula (II-M), R7 is a counterion. In some embodiments of a compound of Formula (II-M), R7 is Na+. In some embodiments of a compound of Formula (II-M), R7 is Li+. In some embodiments of a compound of Formula (II-M), R7 is Mg2+.
WSGR Docket No. 41223-754.601 [00124] In some embodiments, the compound of Formula (II) is of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (IIa); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R32 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl;
WSGR Docket No. 41223-754.601 R14 is -OH or fluoro; R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26; R26 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R26a on the same atom are taken together to form an oxo; or two R26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00125] In some embodiments, the compound of Formula (IIa) gets metabolized in vivo to a compound of Formula (IIa-M):
WSGR Docket No. 41223-754.601
Formula (IIa-M); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R32 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro;
WSGR Docket No. 41223-754.601
R7 is hydrogen or a counterion; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00126] In some embodiments of a compound of Formula (IIa) or (IIa-M), G is
some embodiments of a compound of Formula (IIa) or (IIa-M), G is
WSGR Docket No. 41223-754.601 some embodiments of a compound of Formula (IIa) or (IIa-M), G is
. [00127] In some embodiments of a compound of Formula (IIa) or (IIa-M), X is hydrogen. In some embodiments of a compound of Formula (IIa) or (IIa-M), X is -CN. [00128] In some embodiments of a compound of Formula (IIa) or (IIa-M), R13 is hydrogen. In some embodiments of a compound of Formula (IIa) or (IIa-M), R13 is C1-C6alkyl. [00129] In some embodiments of a compound of Formula (IIa) or (IIa-M), R14 is -OH. In some embodiments of a compound of Formula (IIa) or (IIa-M), R14 is fluoro. [00130] In some embodiments of a compound of Formula (IIa) or (IIa-M), R11 is hydrogen, -C(=O)R21, or C1-C6alkyl optionally substituted with one or more R11a. In some embodiments of a compound of Formula (IIa) or (IIa-M), R11 is hydrogen or -C(=O)R21. In some embodiments of a compound of Formula (IIa) or (IIa-M), R11 is hydrogen. In some embodiments of a compound of Formula (IIa) or (IIa- M), R11 is -C(=O)R21. [00131] In some embodiments of a compound of Formula (IIa) or (IIa-M), each R11a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (IIa) or (IIa-M), each R11a is independently halogen. [00132] In some embodiments of a compound of Formula (IIa) or (IIa-M), R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. In some embodiments of a compound of Formula (IIa) or (IIa-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IIa) or (IIa-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00133] In some embodiments of a compound of Formula (IIa) or (IIa-M), each R21a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IIa) or (IIa-M), each R21a is independently halogen, - OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
WSGR Docket No. 41223-754.601 [00134] In some embodiments of a compound of Formula (IIa) or (IIa-M), R32 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein the alkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IIa) or (IIa-M), R32 is C1-C6alkyl or C1-C6haloalkyl; wherein the alkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IIa) or (IIa-M), R32 is C1-C6alkyl optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IIa), R32 is C1-C6alkyl.
[00136] In some embodiments of a compound of Formula (IIa), R16 is -C(=O)R26. In some embodiments of a compound of Formula (IIa), R16 is -C(=O)OR26. In some embodiments of a compound of Formula (IIa), R16 is -CH2-O-C(=O)R26. [00137] In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1- C6alkylene(cycloalkyl) or C1-C6alkylene(aryl). In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(cycloalkyl). In some embodiments of a compound of Formula (IIa), R26 is C1- C6alkylene(aryl). In some embodiments of a compound of Formula (IIa), R26 is C1- C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(4- to
WSGR Docket No. 41223-754.601 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. [00138] In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(3- to 8-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(4- to 7-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(4- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(5- to 6-membered cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R26a. [00139] In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(3- to 8-membered cycloalkyl). In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(4- to 7-membered cycloalkyl). In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(4- to 6-membered cycloalkyl). In some embodiments of a compound of Formula (IIa), R26 is C1alkylene(5- to 6-membered cycloalkyl). [00140] In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 26a. In some embodiments of a compound of Formula (IIa), R26 is C1-C6alkylene(phenyl); wherein the alkylene and phenyl is optionally and independently substituted with one or more R26a. [00141] In some embodiments of a compound of Formula (IIa), each R26a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IIa), each R26a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00142] In some embodiments of a compound of Formula (IIa), R16 is
, ,
WSGR Docket No. 41223-754.601
. , . embodiments of a compound of Formula (IIa), R16 is
. In some embodiments of a compound
. [00143] In some embodiments of a compound of Formula (IIa-M), R17 is
,
. In some embodiments of a compound of Formula
some embodiments of a compound of Formula
WSGR Docket No. 41223-754.601 . In some embodiments of a compound of Formula (IIa-M), R17 is
[00144] In some embodiments of a compound of Formula (IIa-M), R7 is hydrogen. In some embodiments of a compound of Formula (IIa-M), R7 is a counterion. In some embodiments of a compound of Formula (IIa-M), R7 is Na+. In some embodiments of a compound of Formula (IIa-M), R7 is Li+. In some embodiments of a compound of Formula (IIa-M), R7 is Mg2+. [00145] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (III); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a;
WSGR Docket No. 41223-754.601 each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; each R22 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a;
WSGR Docket No. 41223-754.601 each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a; each R16a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R16a on the same atom are taken together to form an oxo; R26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R26a on the same atom are taken together to form an oxo; or two R26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl,
WSGR Docket No. 41223-754.601 heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00146] In some aspect, the compound of Formula (III) gets metabolized in vivo. [00147] In some aspect, the compound of Formula (III) gets metabolized in vivo to a compound of Formula (II-M). [00148] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a
[00149] In some embodiments of a compound of Formula (III), X is hydrogen. In some embodiments of a compound of Formula (III), X is -CN. [00150] In some embodiments of a compound of Formula (III), R13 is hydrogen. In some embodiments of a compound of Formula (III), R13 is C1-C6alkyl. [00151] In some embodiments of a compound of Formula (III), R14 is -OH. In some embodiments of a compound of Formula (III), R14 is fluoro. [00152] In some embodiments of a compound of Formula (III), R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a;
WSGR Docket No. 41223-754.601 R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00153] In some embodiments of a compound of Formula (III), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00154] In some embodiments of a compound of Formula (III), R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00155] In some embodiments of a compound of Formula (III), R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00156] In some embodiments of a compound of Formula (III), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is hydrogen, -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00157] In some embodiments of a compound of Formula (III), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a;
WSGR Docket No. 41223-754.601 R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is hydrogen, -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00158] In some embodiments of a compound of Formula (III), R11 is -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; and R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a. [00159] In some embodiments of a compound of Formula (III), R11 is hydrogen, -C(=O)R21, or C1- C6alkyl optionally substituted with one or more R11a. In some embodiments of a compound of Formula (III), R11 is hydrogen or -C(=O)R21. In some embodiments of a compound of Formula (III), R11 is hydrogen. In some embodiments of a compound of Formula (III), R11 is -C(=O)R21. [00160] In some embodiments of a compound of Formula (III), each R11a is independently halogen, - CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (III), each R11a is independently halogen. [00161] In some embodiments of a compound of Formula (III), R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. In some embodiments of a compound of Formula (III), R21 is C1-C6alkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R21 is C1-C6alkyl, C1- C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00162] In some embodiments of a compound of Formula (III), each R21a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R21a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00163] In some embodiments of a compound of Formula (III), R12 is hydrogen, -C(=O)R22, - C(=O)OR22, or C1-C6alkyl. In some embodiments of a compound of Formula (III), R12 is -C(=O)R22, - C(=O)OR22, or C1-C6alkyl. In some embodiments of a compound of Formula (III), R12 is hydrogen or - C(=O)R22. In some embodiments of a compound of Formula (III), R12 is hydrogen, or -C(=O)OR22. In some embodiments of a compound of Formula (III), R12 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (III), R12 is -C(=O)OR22. In some embodiments of a compound of Formula (III), R12 is -C(=O)NR22R23.
WSGR Docket No. 41223-754.601 [00164] In some embodiments of a compound of Formula (III), each R12a is independently halogen, - CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (III), each R12a is independently halogen. [00165] In some embodiments of a compound of Formula (III), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (III), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00166] In some embodiments of a compound of Formula (III), R22 is C1-C6alkyl or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (III), R22 is C1-C6alkyl optionally and independently substituted with one or more R22a. [00167] In some embodiments of a compound of Formula (III), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (III), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (III), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00168] In some embodiments of a compound of Formula (III), R23 is hydrogen, C1-C6alkyl, or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (III), R23 is hydrogen or C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (III), R23 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (III), R23 is C1-C6alkyl. In some embodiments of a compound of Formula (III), R23 is hydrogen.
WSGR Docket No. 41223-754.601 [00169] In some embodiments of a compound of Formula (III), each R22a is independently halogen, - CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00170] In some embodiments of a compound of Formula (III), each R22a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R22a is independently halogen, -OH, -ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R22a is independently halogen, -OC(=O)Ra, or -NRcRd. In some embodiments of a compound of Formula (III), each R22a is independently -OC(=O)Ra or -NRcRd. In some embodiments of a compound of Formula (IV), each R22a is independently -OC(=O)Ra. [00171] In some embodiments of a compound of Formula (III), R12 is
, , ,
some embodiments of a compound of Formula
. [00173] In some embodiments of a compound of Formula (III), R15 is -C(=O)R25. In some embodiments of a compound of Formula (III), R15 is -C(=O)OR25. In some embodiments of a compound of Formula (III), R15 is -CH2-O-C(=O)R25. [00174] In some embodiments of a compound of Formula (III), R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (III), R25 is C1- C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (III), R25 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 25a. [00175] In some embodiments of a compound of Formula (III), each R25a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R25a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00176] In some embodiments of a compound of Formula (III), R16 is hydrogen, -C(=O)R26, or -CH2- O-C(=O)R26. In some embodiments of a compound of Formula (III), R16 is hydrogen or -C(=O)R26. In some embodiments of a compound of Formula (III), R16 is -C(=O)R26. In some embodiments of a
WSGR Docket No. 41223-754.601 compound of Formula (III), R16 is hydrogen. In some embodiments of a compound of Formula (III), R16 is -CH2-O-C(=O)R26. [00177] In some embodiments of a compound of Formula (III), each R16a is independently halogen, - CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (III), each R16a is independently halogen. [00178] In some embodiments of a compound of Formula (III), R26 is C1-C6alkyl, C1-C6aminoalkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (III), R26 is C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl); wherein the alkyl, alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R26a. In some embodiments of a compound of Formula (III), R26 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more R26a. [00179] In some embodiments of a compound of Formula (III), each R26a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III), each R26a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
R16 is not . In some embodiments of a compound of Formula (III), R16 is not . In some embodiments of a compound of Formula (III), R16 is not
. [00181] Also disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
WSGR Docket No. 41223-754.601 Formula (IV); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a;
WSGR Docket No. 41223-754.601 or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R15 is -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl,
WSGR Docket No. 41223-754.601 heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00182] In some aspect, the compound of Formula (IV) gets metabolized in vivo. [00183] In some aspect, the compound of Formula (IV) gets metabolized in vivo to a compound of Formula (IV-M). [00184] Also disclosed herein is a compound of Formula (IV-M), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (IV-M); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl,
WSGR Docket No. 41223-754.601 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R17 is hydrogen,
; R7 is hydrogen or a counterion;
WSGR Docket No. 41223-754.601 each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00185] In some embodiments of a compound of Formula
embodiments of a compound of Formula
some embodiments of a compound of Formula
WSGR Docket No. 41223-754.601 [00186] In some embodiments of a compound of Formula (IV) or (IV-M), X is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), X is -CN. In some embodiments of a compound of Formula (IV) or (IV-M), R13 is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), R13 is C1-C6alkyl. [00187] In some embodiments of a compound of Formula (IV) or (IV-M), R14 is -OH. In some embodiments of a compound of Formula (IV) or (IV-M), R14 is fluoro. [00188] In some embodiments of a compound of Formula (IV) or (IV-M), R11 is hydrogen, -C(=O)R21, or C1-C6alkyl optionally substituted with one or more R11a. In some embodiments of a compound of Formula (IV) or (IV-M), R11 is hydrogen or -C(=O)R21. In some embodiments of a compound of Formula (IV) or (IV-M), R11 is hydrogen. In some embodiments of a compound of Formula (IV) or (IV-M), R11 is -C(=O)R21. [00189] In some embodiments of a compound of Formula (IV) or (IV-M), each R11a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (IV) or (IV-M), each R11a is independently halogen. [00190] In some embodiments of a compound of Formula (IV) or (IV-M), R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. In some embodiments of a compound of Formula (IV) or (IV-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R21 is C1-C6alkyl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00191] In some embodiments of a compound of Formula (IV) or (IV-M), each R21a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) or (IV-M), each R21a is independently halogen, - OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00192] In some embodiments of a compound of Formula (IV) or (IV-M), R12 is -C(=O)R22, - C(=O)OR22, or C1-C6alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R12 is - C(=O)R22. In some embodiments of a compound of Formula (IV) or (IV-M), R12 is -C(=O)OR22. In some embodiments of a compound of Formula (IV) or (IV-M), R12 is C1-C6alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R12 is -C(=O)NR22R23. [00193] In some embodiments of a compound of Formula (IV) or (IV-M), each R12a is independently halogen, -CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (IV) or (IV-M), each R12a is independently halogen. [00194] In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-
WSGR Docket No. 41223-754.601 C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. [00195] In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. [00196] In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00197] In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (IV) or (IV-M), R22 is C1-C6alkyl optionally and independently substituted with one or more R22a. [00198] In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00199] In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen, C1-C6alkyl, or C1-C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen or C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (IV) or (IV-M), R23 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (IV) or (IV-M), R23 is C1-C6alkyl. In some embodiments of a compound of Formula (IV) or (IV-M), R23 is hydrogen.
WSGR Docket No. 41223-754.601 [00200] In some embodiments of a compound of Formula (IV) or (IV-M), each R22a is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00201] In some embodiments of a compound of Formula (IV) or (IV-M), each R22a is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) or (IV-M), each R22a is independently halogen, - OH, -ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV) or (IV-M), each R22a is independently halogen, -OC(=O)Ra, or -NRcRd. In some embodiments of a compound of Formula (IV) or (IV-M), each R22a is independently -OC(=O)Ra or -NRcRd. In some embodiments of a compound of Formula (IV) or (IV-M), each R22a is independently -OC(=O)Ra. [00202] In some embodiments of a compound of Formula (IV) or (IV-M), R12 is
, ,
[00203] In some embodiments of a compound of Formula
[00204] In some embodiments of a compound of Formula (IV), R15 is -C(=O)R25. In some embodiments of a compound of Formula (IV), R15 is -C(=O)OR25. In some embodiments of a compound of Formula (IV), R15 is -CH2-O-C(=O)R25. In some embodiments of a compound of Formula (IV), R25 is C1-C6alkylene(cycloalkyl) or C1-C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (IV), R25 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R25a. In some embodiments of a compound of Formula (IV), R25 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R25a. [00205] In some embodiments of a compound of Formula (IV), each R25a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IV), each R25a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl.
WSGR Docket No. 41223-754.601 [00206] In some embodiments of a compound of Formula (IV), R15 is
,
. In some embodiments of a compound of Formula (IV), R15 is
. In some embodiments of a compound of Formula (IV), R15 is
. In some embodiments of a compound of Formula (IV), R15 is
. In some embodiments of a compound of Formula (IV), R15 is
. In some embodiments of a compound of Formula (IV), R15 is not
. In some embodiments of a compound of Formula (IV), R15 is not
. In some embodiments of a compound of Formula (IV), R15 is not
. [00207] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a compound of Formula (IV-M), R17 is
WSGR Docket No. 41223-754.601
. [00208] In some embodiments of a compound of Formula (IV-M), R7 is hydrogen. In some embodiments of a compound of Formula (IV-M), R7 is a counterion. In some embodiments of a compound of Formula (IV-M), R7 is Na+. In some embodiments of a compound of Formula (IV-M), R7 is Li+. In some embodiments of a compound of Formula (IV-M), R7 is Mg2+. [00209] Also disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Formula (V); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo;
WSGR Docket No. 41223-754.601 R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R12 is -C(=O)R22, -C(=O)OR22, -C(=O)NR22R23, or C1-C6alkyl optionally substituted with one or more R12a; each R12a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R12a on the same atom are taken together to form an oxo; R22 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a; or R22 and R23 are taken together to form a heterocycloalkyl optionally substituted with one or more R22a; each R22a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R22a on the same atom are taken together to form an oxo; or two R22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl;
WSGR Docket No. 41223-754.601 R14 is -OH or fluoro; R15 is hydrogen, -C(=O)R25, -C(=O)OR25, -CH2-O-C(=O)R25, or -CH2-O-C(=O)OR25; R25 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R25a; each R25a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R25a on the same atom are taken together to form an oxo; or two R25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, -CH2-O-C(=O)OR26, or C1-C6alkyl optionally substituted with one or more R16a; each R16a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R16a on the same atom are taken together to form an oxo; R26 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R26a on the same atom are taken together to form an oxo; or two R26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
WSGR Docket No. 41223-754.601 each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. [00210] In some aspect, the compound of Formula (V) gets metabolized in vivo. [00211] In some aspect, the compound of Formula (V) gets metabolized in vivo to a compound of Formula (IV-M). [00212] In some embodiments of a compound of Formula
some embodiments of a compound of Formula
some embodiments of a
[00213] In some embodiments of a compound of Formula (V), X is hydrogen. In some embodiments of a compound of Formula (V), X is -CN.
WSGR Docket No. 41223-754.601 [00214] In some embodiments of a compound of Formula (V), R13 is hydrogen. In some embodiments of a compound of Formula (V), R13 is C1-C6alkyl. [00215] In some embodiments of a compound of Formula (V), R14 is -OH. In some embodiments of a compound of Formula (V), R14 is fluoro. [00216] In some embodiments of a compound of Formula (V), R11 is hydrogen, -C(=O)R21, or C1- C6alkyl optionally substituted with one or more R11a. In some embodiments of a compound of Formula (V), R11 is hydrogen or -C(=O)R21. In some embodiments of a compound of Formula (V), R11 is hydrogen. In some embodiments of a compound of Formula (V), R11 is -C(=O)R21. [00217] In some embodiments of a compound of Formula (V), each R11a is independently halogen, - CN, -OH, -ORa, or -NRcRd. In some embodiments of a compound of Formula (V), each R11a is independently halogen. [00218] In some embodiments of a compound of Formula (V), R21 is C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a. In some embodiments of a compound of Formula (V), R21 is C1-C6alkyl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R21 is C1-C6alkyl, C1- C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00219] In some embodiments of a compound of Formula (V), each R21a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (V), each R21a is independently halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00220] In some embodiments of a compound of Formula (V), R12 is -C(=O)R22, -C(=O)OR22, or C1- C6alkyl. In some embodiments of a compound of Formula (V), R12 is -C(=O)R22. In some embodiments of a compound of Formula (V), R12 is -C(=O)OR22. In some embodiments of a compound of Formula (V), R12 is C1-C6alkyl. In some embodiments of a compound of Formula (V), R12 is -C(=O)NR22R23. [00221] In some embodiments of a compound of Formula (V), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. [00222] In some embodiments of a compound of Formula (V), R22 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments
WSGR Docket No. 41223-754.601 of a compound of Formula (V), R22 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). In some embodiments of a compound of Formula (V), R22 is C1-C6alkyl or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (V), R22 is C1-C6alkyl optionally and independently substituted with one or more R22a. [00223] In some embodiments of a compound of Formula (V), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (V), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1- C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). In some embodiments of a compound of Formula (V), R23 is hydrogen, C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00224] In some embodiments of a compound of Formula (V), R23 is hydrogen, C1-C6alkyl, or C1- C6alkylene(aryl); wherein the alkyl, alkylene, and aryl is optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (V), R23 is hydrogen or C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (V), R23 is C1-C6alkyl optionally and independently substituted with one or more R22a. In some embodiments of a compound of Formula (V), R23 is C1-C6alkyl. In some embodiments of a compound of Formula (V), R23 is hydrogen. [00225] In some embodiments of a compound of Formula (V), each R22a is independently halogen, - CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00226] In some embodiments of a compound of Formula (V), each R22a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00227] In some embodiments of a compound of Formula (V), each R22a is independently halogen, - OH, -ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00228] In some embodiments of a compound of Formula (V), each R22a is independently halogen, - OC(=O)Ra, or -NRcRd. In some embodiments of a compound of Formula (V), each R22a is independently -OC(=O)Ra or -NRcRd. In some embodiments of a compound of Formula (V), each R22a is independently -OC(=O)Ra.
WSGR Docket No. 41223-754.601
some embodiments of a compound of Formula (V), R12 is
, or
. [00231] In some embodiments of a compound of Formula (V), R15 is hydrogen. In some embodiments of a compound of Formula (V), R15 is -C(=O)R25. In some embodiments of a compound of Formula (V), R15 is -C(=O)OR25. [00232] In some embodiments of a compound of Formula (V), R25 is C1-C6alkylene(cycloalkyl) or C1- C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R25a. [00233] In some embodiments of a compound of Formula (V), R25 is C1-C6alkylene(cycloalkyl); wherein the alkylene and cycloalkyl is optionally and independently substituted with one or more R25a. [00234] In some embodiments of a compound of Formula (V), R25 is C1-C6alkylene(aryl); wherein the alkylene, and aryl is optionally and independently substituted with one or more R 25a. [00235] In some embodiments of a compound of Formula (V), each R25a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00236] In some embodiments of a compound of Formula (V), each R25a is independently halogen, - OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00237] In some embodiments of a compound of Formula (V), R15 is
, , , or
. In some embodiments of a compound of Formula (V), R15 is
embodiments of a compound of Formula (V), R15 is
. In some embodiments of a compound of Formula (V), R15 is
. In some embodiments of a compound of Formula (V), R15 is
. In
WSGR Docket No. 41223-754.601 some embodiments of a compound of Formula (V), R15 is not . In some embodiments of a compound of Formula (V), R15 is not
. In some embodiments of a compound of Formula (V), R15 is not
. [00238] In some embodiments of a compound of Formula (V), R16 is -C(=O)R26. [00239] In some embodiments of a compound of Formula (V), R16 is -C(=O)OR26. [00240] In some embodiments of a compound of Formula (V), R26 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a. [00241] In some embodiments of a compound of Formula (V), R26 is C1-C6alkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1- C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). [00242] In some embodiments of a compound of Formula (V), R26 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl). [00243] In some embodiments of a compound of Formula (V), R26 is C1-C6alkyl, C1-C6aminoalkyl, aryl, C1-C6alkylene(cycloalkyl), or C1-C6alkylene(aryl). [00244] In some embodiments of a compound of Formula (V), R26 is C1-C6alkyl or C1-C6aminoalkyl. [00245] In some embodiments of a compound of Formula (V), each R26a is independently halogen, - CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00246] In some embodiments of a compound of Formula (V), each R26a is independently halogen, - CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00247] In some embodiments of a compound of Formula (V), each R26a is independently halogen, - OH, -ORa, - NRcRd, C1-C6alkyl, or C1-C6haloalkyl. [00248] In some embodiments of a compound of Formula (V), each R26a is independently -OC(=O)Ra, or -NRcRd.
WSGR Docket No. 41223-754.601
. In some embodiments of a compound of Formula (V), R16 is not . In some embodiments of a compound of Formula (V), R16 is not
. [00249] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently C1-C6alkyl. [00250] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed
WSGR Docket No. 41223-754.601 herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is hydrogen. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rb is independently C1-C6alkyl. [00251] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkyl(heteroaryl). In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are hydrogen. In some embodiments of a
WSGR Docket No. 41223-754.601 compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently C1-C6alkyl. [00252] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. [00253] In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC1-C6alkyl, -NH2, - NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, - C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC1-C6alkyl, -NH2, - C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently halogen, -CN, -OH, -OC1-C6alkyl, -NH2, C1-C6alkyl, or C1-C6haloalkyl. [00254] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00255] Described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound in Table 1. Table 1. Exemplary compounds.
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Step 1: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (4.1). [00342] The title compound was prepared according to the procedure of Example 1, Step 3, using 1.3 and 2-ethoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C36H52N6O10, 728.37, found 729.25 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 8.49 (s, 1H), 7.27 – 7.10 (m, 3H), 6.78 (d, J = 6.4 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 5.12 – 5.03 (m, 1H), 4.47 (d, J = 4.0 Hz, 1H), 4.29 (dd, J = 12.4, 3.6 Hz, 1H), 4.19 (dd, J = 12.4, 4.8 Hz, 1H), 4.07 (dd, J = 7.6, 5.2 Hz, 1H), 3.49 (q, J = 6.8 Hz, 2H), 2.22 (dd, J = 13.2, 6.4 Hz, 1H), 2.12 (t, J = 6.4 Hz, 2H), 1.61 – 1.51 (m, 6H), 1.45 (s, 6H), 1.40 (s, 9H), 1.26 – 1.21 (m, 3H), 1.08 (t, J = 6.8 Hz, 3H), 0.95 – 0.78 (m, 8H). Step 2: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (4). [00343] The title compound was prepared from compound 4.1. according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C31H44N6O8, 628.32, found 629.30 [M+H]+. 1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.82 – 6.65 (m, 1H), 5.18 – 5.13 (m, 1H), 5.10 (d, J = 5.2 Hz, 1H), 4.53 – 4.47 (m, 1H), 4.30 – 4.20 (m, 2H), 3.49 (q, J = 7.2 Hz, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.22 – 2.09 (m, 2H), 2.05 – 1.95 (m, 1H), 1.61 – 1.50 (m, 6H), 1.45 (s, 6H), 1.22 (t, J = 7.2 Hz, 3H), 1.17 – 1.05 (m, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.88 – 0.79 (m, 5H). Example 5. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (5).
Step 1: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L- valinate (9.1). [00352] The title compound was prepared from compound 1.3 according to the procedure of Example 1, Step 3, using (R)-2-methylbutanoic acid. MS (ESI): mass calcd. for C35H50N6O9, 698.36, found 699.25 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.42 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.75 (d, J = 6.4 Hz, 1H), 5.17 – 5.13 (m, 1H), 5.11 – 5.05 (m, 1H), 4.46 (d, J = 4.0 Hz, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.18 (dd, J = 12.4, 4.8 Hz, 1H), 4.11 – 4.06 (m, 1H), 2.94 (dd, J = 13.6, 6.8 Hz, 1H), 2.27 – 2.17 (m, 1H), 2.15 – 2.06 (m, 2H), 1.74 – 1.63 (m, 1H), 1.62 – 1.50 (m, 6H), 1.48 – 1.43 (m, 1H), 1.40 (s, 9H), 1.20 – 1.03 (m, 6H), 0.96 – 0.78 (m, 11H). Step 2: Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4-((R)-2- methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (9). [00353] The title compound was prepared from carbamate 9.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C30H42N6O7, 598.31, m/z found 599.05 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.42 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.82 – 6.65 (m, 1H), 5.19 – 5.12 (m, 1H), 5.11 – 5.05 (m, 1H), 4.50 (dd, J = 8.0, 4.0 Hz, 1H), 4.32 – 4.26 (m, 1H), 4.24 – 4.18 (m, 1H), 3.24 (d, J = 5.2 Hz, 1H), 2.94 (dd, J = 13.6, 6.8 Hz, 1H), 2.20 – 2.08 (m, 2H), 2.06 – 1.95 (m, 1H), 1.73 – 1.64 (m, 1H), 1.62 – 1.50 (m, 6H), 1.48 – 1.39 (m, 1H), 1.17 – 1.03 (m, 6H), 0.99 – 0.79 (m, 11H). Example 10. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (10).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((R)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (11.1). [00356] The title compound 11.1 was prepared according to the procedure of Example 1, Step 3, using 2.1 and (R)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C36H46N6O9, 706.33, m/z found 707.15 [M+H]+.
WSGR Docket No. 41223-754.601 Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((R)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (11). [00357] The title compound was prepared from carbamate 11.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C31H38N6O7, 606.28, m/z found 607.0 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.41 (s, 1H), 7.34 – 7.14 (m, 6H), 7.10 (d, J = 4.8 Hz, 1H), 6.80 – 6.68 (m, 1H), 5.18 – 5.10 (m, 1H), 5.05 (d, J = 5.2 Hz, 1H), 4.51 (dd, J = 8.0, 4.0 Hz, 1H), 4.37 – 4.29 (m, 1H), 4.28 – 4.20 (m, 1H), 3.68 – 3.63 (m, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.83 – 2.75 (m, 1H), 2.11 – 1.96 (m, 1H), 1.95 – 1.85 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.97 – 0.89 (m, 9H), 0.85 (d, J = 6.8 Hz, 3H). Example 12. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxy-5-(4- ((S)-2-methylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl L-valinate (12).
[00358] The title compound was prepared from compound 1.3 according to the procedure of Example 1, Steps 3 and 4, using (S)-2-methylbutanoic acid. MS (ESI): mass calcd. for C30H42N6O7, 598.311, m/z found 599.25 [M+H]+. Example 13. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-((R)-2,3- dimethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate
[00359] The title compound 13 was prepared from compound 1.3 according to the procedure of Example 1, Steps 3 and 4, using (R)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C31H44N6O8, 612.327, m/z found 613.20 [M+H]+. Example 14. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-((S)-2,3- dimethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (14).
WSGR Docket No. 41223-754.601
[00360] The title compound was prepared from compound 1.3 according to the procedure of Example 1, Steps 3 and 4, using (S)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C31H44N6O8, 612.327, m/z found 613.20 [M+H]+. Example 15. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-5-(4-(3-isopropylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (15).
[00361] The title compound was prepared from compound 2.1 according to the procedure of Example 6. MS (ESI): mass calcd. for C29H35N7O7, 593.260, m/z found 594.15 [M+H]+. Example 16. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-cyclohexylacetate (16).
Step 1. Synthesis of (6aR,8R,9R,9aS)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-9-hydroxy-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocine-8-carbonitrile (16.2).
WSGR Docket No. 41223-754.601 [00362] To a solution of compound 16.1 (4 g, 0.013 mol) and imidazole (5.6 g, 0.082 mol) in DMF (40 mL) was added chloro[(chlorodiisopropylsilyl)oxy]diisopropylsilane (5.19 g, 0.016 mmol) at 0 °C, the mixture was stirred at 25 °C for 4 h. The reaction was extracted with EtOAc (10 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 30%) to obtain compound 16.2 as a white solid (5.00 g, 65% yield). MS (ESI): mass calcd. for C24H39N5O5Si2, 533.78, m/z found 534.2 [M+H]+. Step 2. Synthesis of (6aR,8R,9R,9aR)-8-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-cyclohexylacetate (16.3). [00363] To a solution of compound 16.2 (800 mg, 1.50 mmol) in THF (25 mL) was added cyclohexylacetic acid (426 mg, 3.00 mmol), EDCI (862 mg, 4.50 mmol) and DMAP (549 mg, 4.50 mmol), the mixture was stirred at 25 °C for 16 h. The reaction was extracted with EA (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/petroleum ether, from 0% to 40%) to obtain compound 16.3 as a white solid (500 mg, 46% yield). MS (ESI): mass calcd. for C32H51N5O6Si2, 657.96, m/z found 658.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 8.01 (d, J = 18.8 Hz, 2H), 7.89 (s, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H), 5.87 (d, J = 5.2 Hz, 1H), 4.54 (dd, J = 8.8, 5.2 Hz, 1H), 4.14 (t, J = 10.4 Hz, 2H), 4.01 – 3.91 (m, 1H), 2.35 (d, J = 6.4 Hz, 2H), 1.88 – 1.72 (m, 3H), 1.62 –1.60 (m, 3H), 1.23 – 1.09 (m, 3H), 1.08 – 0.84 (m, 30H). Step 3. Synthesis of (6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-8-(4-pentanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-cyclohexylacetate (16.4). [00364] To a solution of compound 16.3 (100 mg, 0.152 mmol) in DCM (2 mL) was added pyridine (144 mg, 1.82 mmol), followed by pentanoyl chloride (45.8 mg, 0.380 mmol) at 0 oC and stirred for 2 hours. The reaction was extracted with DCM (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EA/PE from 0% to 30%) to obtain compound 16.4 as a white solid (70.0 mg, 56% yield). MS (ESI): mass calcd. for C37H59N5O7Si2, 741.40, m/z found 742.1 [M+H]+. Step 4. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-cyclohexylacetate (16). [00365] To a solution of compound 16.4 (70 mg, 0.0940 mmol) in THF (1 mL) was added TBAF in THF (0.2 mL, 1 M), the mixture was stirred at 25 °C for 2 h. The reaction was extracted with EtOAc (5 mL×3). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by prep-HPLC to afford compound 16 (5.67 mg, 12% yield) as a white solid MS (ESI): mass calcd. for C25H33N5O6, 499.24, m/z found 500.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.40 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.58 (d, J = 6.4 Hz, 1H),5.18 (dd, J = 5.6, 4.0 Hz, 1H), 5.04 (t, J = 5.6 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.28 (q, J = 3.6 Hz,
WSGR Docket No. 41223-754.601 1H), 3.67 – 3.49 (m, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.27 (d, J = 6.8 Hz, 2H), 1.92 –1.70 (m, 3H), 1.69 – 1.57 (m, 5H), 1.44 – 1.31 (m, 2H), 1.20 – 1.10 (m, 3H), 0.99 – 0.87 (m, 5H). Example 17. Synthesis of (2R,3S,4R,5R)-5-cyano-4-hydroxy-2-(hydroxymethyl)-5-(4- pentanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-3-yl 2-methoxy-2-methylpropanoate (17).
Step 1. Synthesis of (6aR,8R,9R,9aR)-8-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-8-cyano- 2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl 2-ethylbutanoate (21.1). [00376] The title compound 21.1 was prepared from compound 19.1 according to the procedure of Example 20, Step 1, using benzoyl chloride. MS (ESI): mass calcd. for C37H53N5O7 Si2, 735.35, m/z found 736.1 [M+H]+. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4- hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-ethylbutanoate (21).
WSGR Docket No. 41223-754.601 [00377] The title compound 21 was prepared from compound 21.1 according to the procedure of Example 16, Step 3. MS (ESI): mass calcd. for C25H27N5O6, 493.20, m/z found 494.05 [M+H]+. 1H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 8.38 (s, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 5.25 (dd, J = 5.6, 3.2 Hz, 1H), 5.08 (t, J = 5.6 Hz, 1H), 5.00 (t, J = 6.4 Hz, 1H), 4.28 – 4.25 (M, 1H), 3.56 – 3.50 (m, 2H), 2.29 – 2.25 (m, 1H), 1.70 – 1.49 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H). Example 23. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-5-(4-(3,3- diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (23).
Step 1. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((S)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (26.1).
WSGR Docket No. 41223-754.601 [00386] The title compound was prepared from compound 2.1 according to the procedure of Example 1, Step 3, using (S)-2,3-dimethylbutanoic acid. MS (ESI): mass calcd. for C36H46N6O9, 706.80, m/z found 707.20 [M+H] +. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-((S)-2,3-dimethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (26). [00387] The title compound was prepared from compound 26.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C31H38N6O7, 606.68, m/z found 607.05 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.41 (s, 1H), 7.31 – 7.15 (m, 6H), 7.09 (d, J = 4.8 Hz, 1H), 6.71 – 6.65 (m, 1H), 5.14 (t, J = 4.8 Hz, 1H), 5.05 – 5.01 (m, 1H), 4.51 – 4.45 (m, 1H), 4.29 (dd, J = 16.0, 4.0 Hz, 2H), 3.66 (s, 2H), 3.24 (d, J = 5.2 Hz, 1H), 2.77 – 2.75 (m, 1H), 2.11 – 1.97 (m, 1H), 1.92 – 1.89 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H), 0.93 – 0.90 (m, 9H), 0.85 (d, J = 6.8 Hz, 3H). Example 28. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (28).
Step 1. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (28.1). [00388] The title compound was prepared from compound 23.6 according to the procedure of Example 1, Step 1, using 2-phenylacetyl chloride. MS (ESI): mass calcd. for C25H28N6O6, 508.54, m/z found 509.20 [M+H] +. Step 2. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate (28.2). [00389] The title compound was prepared from compound 28.1 according to the procedure of Example 1, Step 2, using (tert-butoxycarbonyl)-L-valine. MS (ESI): mass calcd. for C35H45N7O9, 707.79, m/z found 708.2 [M+H]+. Step 3. Synthesis of (2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L-valinate (28).
WSGR Docket No. 41223-754.601 [00390] The title compound 28 was prepared from compound 28.2 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C30H37N7O7, 607.67, m/z found 608.00 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.21 – 7.16 (m, 5H), 6.92 (d, J = 4.4 Hz, 1H), 6.83 (d, J = 4.4 Hz, 1H), 6.50 – 6.28 (m, 1H), 5.16 (dd, J = 5.6, 4.0 Hz, 1H), 4.98 (d, J = 5.6 Hz, 1H), 4.53 – 4.43 (m, 1H), 4.32 (dd, J = 3.6, 12.4 Hz, 1H), 4.25 (dd, J = 5.2, 12.4 Hz, 1H), 3.67 (s, 2H), 3.35 – 3.30 (m, 4H), 3.27 (d, J = 5.2 Hz, 1H), 2.12 –1.96 (m, 1H), 1.12 (t, J = 7.2 Hz, 6H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H). Example 31. Synthesis of (2R,3S,4R,5R)-5-cyano-2-((2-cycloheptylacetoxy)methyl)-5-(4-(2- ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-hydroxytetrahydrofuran-3-yl L-valinate (31).
728.84, m/z found 729.30 [M+H]+ Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclobutylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (43). [00416] The title compound was prepared from compound 43.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C31H44N6O8, 628.73, m/z found 629.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.82 – 6.66 (m, 1H), 5.29 – 5.18 (m, 1H), 5.16 – 5.05 (m, 1H), 4.60 – 4.46 (m, 1H) 4.28 (dd, J = 12.4, 3.6 Hz, 1H), 4.20 (dd, J = 12.0, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.24 (d, J = 4.8 Hz, 1H), 2.40 – 2.30 (m, 3H), 2.13 – 2.04 (m, 1H), 2.02 – 1.92 (m, 2H), 1.80 – 1.69 (m, 2H), 1.63 – 1.55 (m, 4H), 1.45 (s, 6H), 1.41 – 1.36 (m, 2H), 0.95 – 0.86 (m, 9H). Example 44. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclopentylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl L- valinate (44).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-L-valinate (46.1). [00421] Compound 46.1 was prepared according to the procedure of Example 1, Step 3, using 2.1 and 2-butoxy-2-methylpropanoic acid- MS (ESI): mass calcd. for C38H50N6O10, 750.85, m/z found 751.30 [M+H]+ Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl L- valinate (46). [00422] The title compound was prepared from compound 46.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C33H42N6O8, 650.73, m/z found 651.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.38 – 7.17 (m, 6H), 7.14 (d, J = 4.8 Hz, 1H), 6.80 – 6.60 (m, 1H), 5.24 – 5.13 (m, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.65 – 4.48 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.66 (s, 2H), 3.45 (t, J = 6.4 Hz, 2H), 3.26 (d, J = 5.2 Hz, 1H ), 2.10 – 1.97 (m, 1H), 1.63 – 1.56 (m, 2H), 1.45 (s, 6H), 1.41 – 1.35 (m, 2H), 0.94 – 0.85 (m, 9H). Example 47. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl D- valinate (47).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (47.1). [00423] Title compound 47.1 was prepared according to the procedure of Example 1, Step 3, using compound 37.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C38H50N6O10, 750.36, m/z found 751.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.48 (s, 1H), 7.32 – 7.05 (m, 8H), 7.14 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 6.8 Hz, 1H), 5.26 – 5.20 (m, 1H), 5.14 – 4.98 (m, 1H), 4.60 – 4.52 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.27 (dd, J = 12.4, 4.8 Hz, 1H), 3.70 – 3.62 (m, 2H), 3.45 (t, J = 6.4 Hz, 2H), 3.32 (s, 1H), 2.35 – 2.21 (m, 1H), 1.65 – 1.53 (m, 2H), 1.46 (s, 6H), 1.42 – 1.31 (m, 11H), 0.96 – 0.82 (m, 9H). Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl D- valinate (47). [00424] The title compound was prepared from carbamate 47.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C33H42N6O8, 650.31, m/z found 651.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.30 – 7.17 (m, 6H), 7.14 (d, J = 4.8 Hz, 1H), 6.80 – 6.62 (m, 1H), 5.26 – 5.20 (m, 1H), 5.10 – 5.02 (m, 1H), 4.60 – 4.50 (m, 1H), 4.33 (dd, J = 12.4, 3.6 Hz, 1H), 4.26 (dd, J = 12.4, 4.8 Hz, 1H), 3.71 – 3.61 (m, 2H), 3.47 – 3.41 (m, 2H), 3.26 (d, J = 5.2 Hz, 1H), 2.16 – 2.03 (m, 1H), 1.68 – 1.54 (m, 2H), 1.45 (s, 6H), 1.43 – 1.36 (m, 2H), 0.94 – 0.81 (m, 9H). Example 48. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (48).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl (tert- butoxycarbonyl)-D-valinate (48.1). [00425] Title compound 48.1 was prepared according to the procedure of Example 1, Step 3, using compound 38.1 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C38H56N6O10, 756.41, m/z found 757.25 [M+H]+. Step 2. Synthesis of (2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((2-cyclohexylacetoxy)methyl)-4-hydroxytetrahydrofuran-3-yl D- valinate (48). [00426] The title compound was prepared from carbamate 48.1 according to the procedure of Example 1, Step 4. MS (ESI): mass calcd. for C33H48N6O8, 656.35, m/z found 657.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.90 – 6.56 (m, 1H), 5.28 – 5.20 (m, 1H), 5.14 – 5.05 (m, 1H), 4.60 – 4.48 (m, 1H), 4.29 (dd, J = 12.4, 3.2 Hz, 1H), 4.22 (dd, J = 12.4, 4.8 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.30 – 3.26 (m, 1H), 2.20 – 2.05 (m, 3H), 1.62 – 1.50 (m, 8H), 1.45 (s, 6H), 1.42 – 1.34 (m, 2H), 1.21 – 1.02 (m, 3H), 0.78 – 0.95 (m, 11H). Example 49. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(3- isopropylureido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (49).
WSGR Docket No. 41223-754.601 Step 1. Synthesis of 1-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-isopropylurea (49.1). [00427] Compound 49.1 was prepared according to the procedure of Example 6, Step 1, using 1.1 and 2-isocyanatopropane- MS (ESI): mass calcd. for C16H20N6O5, 376.37, m/z found 377.20 [M+H]+. Step 2. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(3-isopropylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (51). [00428] A solution of 49.1 (45.0 mg, 0.119 mmol) in trimethyl phosphate (0.6 mL) was stirred at 0 °C for 10 min. To the above solution was added phosphorus oxychloride (36.7 mg, 0.239 mmol, fresh distilled) dropwise and the mixture was stirring for 2 h under N2 atmosphere. A mixture of DIEA (61.8 mg, 0.478 mmol) and bis(tributylammonium) pyrophosphate (197 mg, 0.358 mmol) in acetonitrile (1 mL) was added at once. After 25 minutes, the reaction was quenched with water (10 mL), and the clear solution was stirred vigorously for about an h at room temperature. The pH of the solution was adjusted to ~6.53 with tetraethylammonium bromide (TEAB) buffer (2 mL, 1M) and the mixture was vigorous stirred for 3 h. LCMS analysis indicated the formation of the corresponding triphosphate. The reaction mixture was then lyophilized overnight to afford a residue which was purif ied by prep-HPLC (column: Gemini - C18150×21.2 mm, 5um; mobile phase: ACN in 20 mM TEAB; gradient: 0-15%) twice, and subsequently purified via ion column (column: HiPrepTM Q FF 16/10; mobile phase: water in 1M TEAB; gradient: 0-70%) to obtain the total compound 51 (13.81 mg, 0.0224 mmol, 18.7% yield, tris- triethylaminmonium salt) as a white solid. MS (ESI): mass calcd. for C16H23N6O14P3, 616.31, m/z found 615.20 [M-H]-. 1H NMR (400 MHz, D2O) δ 8.16 (s, 1H), 7.12 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 4.98 (d, J = 4.8 Hz, 1H), 4.48 (d, J = 4.0 Hz, 2H), 4.18 – 4.11 (m, 1H), 4.05 – 3.99 (m, 1H), 3.96 – 3.88 (m, 1H), 3.13 (q, J = 7.2 Hz, 19H), 1.24 – 1.17 (m, 34H). 31P NMR (162 MHz, D2O) δ -10.27 (d, J = 15.2 Hz, 1P), -11.49 (d, J = 20.0 Hz, 1P), -23.07 (t, J = 19.6 Hz, 1P). Example 50. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (50).
WSGR Docket No. 41223-754.601 Step 1. Synthesis of N-(7-((6aR,8R,9R,9aR)-8-cyano-2,2,4,4-tetraisopropyl-9- ((trimethylsilyl)oxy)tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)-2-ethylbutanamide (50.1). [00429] Compound 50.1 was prepared according to the procedure of Example 3, Step 1, using 16.2 and 2-ethylbutanoyl chloride. MS (ESI): mass calcd. for C33H57N5O6Si3, 704.10, m/z found 704.30 [M+H]+. Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-ethylbutanamide (50.2). [00430] Compound 50.2 was prepared according to the procedure of Example 16, Step 4, using 52.1.- MS (ESI): mass calcd. for C18H23N5O5, 389.41, m/z found 390.2 [M+H] +. Step 3. Synthesis of Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (50). [00431] Compound 50 was prepared according to the procedure of Example 49, Step 2, using 50.2. MS (ESI): mass calcd. for C18H26N5O14P3, 629.35, m/z found 628.05 [M-H]-. 1H NMR (400 MHz, D2O) δ 8.19 (s, 1H), 7.16 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 4.90 (d, J = 4.4 Hz, 1H), 4.41 – 4.39 (m, 2H), 4.08 – 4.03 (m, 1H), 3.98 – 3.93 (m, 1H), 3.04 (q, J = 7.2 Hz, 18H), 2.48 – 2.38 (m, 1H), 1.58 – 1.46 (m, 4H), 1.12 (t, J = 7.2 Hz, 27H), 0.80 (t, J = 7.6 Hz, 6H). 31P NMR (162 MHz, D2O) δ -8.24 ~ - 10.64 (m, 1H), -11.51 (d, J = 20.0 Hz, 1H), -23.01 (t, J = 18.0 Hz, 1H). Example 51. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (51).
Step 1. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(3,3-diethylureido)pyrrolo[2,1-f][1,2,4]triazin-7- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (51). [00432] Compound 51 was prepared according to the procedure of Example 49, Step 2, using 23.6. MS (ESI): mass calcd. for C17H25N6O14P3, 630.34, m/z found 629.35 [M-H]-. 1H NMR (400 MHz, D2O) δ 7.75 (s, 1H), 7.05 – 6.82 (m, 2H), 4.86 (d, J = 4.8 Hz, 1H), 4.41 – 4.38 (m, 2H), 4.09 – 4.03 (m, 1H), 3.99 – 3.92 (m, 1H), 3.39 – 3.26 (m, 4H), 3.04 (q, J = 7.2 Hz, 19H), 1.11 (t, J = 7.2 Hz, 28H), 1.05 – 0.96 (m, 6H). 31P NMR (162 MHz, D2O) δ -10.39 ~ -8.68 (m, 1P), -11.50 (d, J = 20.0 Hz, 1P), -22.91 (t, J = 19.6 Hz, 1P). Example 52. Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (52).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of N-(7-((6aR,8R,9R,9aS)-8-cyano-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro- 6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxy-2- methylpropanamide (52.1). [00433] Compound 52.1 was prepared according to the procedure of Example 1, Step 3, using 16.2 and 2-methoxy-2-methylpropanoic acid- MS (ESI): mass calcd. for C29H47N5O7Si2, 633.89, m/z found 634.2 [M+H]+ Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxy-2- methylpropanamide (52.2). [00434] Compound 52.2 was prepared from compound 52.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C17H21N5O6, 391.38, m/z found 392.2 [M+H]+. Step 3. . Synthesis of ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-(2-methoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (52). [00435] Compound 52 was prepared according to the procedure of Example 49, Step 2, using 52.2.- MS (ESI): mass calcd. for C17H24N5O15P3, 631.32, m/z found 630.25 [M-H]-. 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 4.91 (d, J = 4.4 Hz, 1H), 4.45 – 4.40 (m, 2H), 4.10 – 4.03 (m, 1H), 3.99 – 3.92 (m, 1H), 3.28 (s, 3H), 3.04 (q, J = 7.2 Hz, 19H), 1.39 (s, 6H), 1.12 (t, J = 7.2 Hz, 6H), 1.12 (t, J = 7.2 Hz, 29H).31P NMR (162 MHz, D2O) δ -7.90 ~ -10.20 (m, 1H), -11.55 (d, J = 20.0 Hz, 1H), -23.06 (t, J = 20.0 Hz, 1H). Example 53. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2- methylpropanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (53).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of N-(7-((6aR,8R,9R,9aS)-8-cyano-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro- 6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-ethoxy-2- methylpropanamide (53.1). [00436] Compound 53.1 was prepared according to the procedure of Example 1, Step 3, using 16.2 and 2-ethoxy-2-methylpropanoic acid. - MS (ESI): mass calcd. for C30H49N5O7Si2, 647.92, m/z found 648.20 [M+H]+. Step 2. Synthesis of N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-ethoxy-2- methylpropanamide (53.2). [00437] Compound 53.2 was prepared from compound 53.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C18H23N5O6, 405.41, m/z found 406.2 [M+H]+. Step 3.. Synthesis of ((2R,3S,4R,5R)-5-cyano-5-(4-(2-ethoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (53). [00438] Compound 53 was prepared according to the procedure of Example 49, Step 2, using 53.2. MS (ESI): mass calcd. for C18H26N5O15P3, 645.35, m/z found 644.35 [M-H]-. 1H NMR (400 MHz, D2O) δ 8.22 (s, 1H), 7.18 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 4.91 (d, J = 4.4 Hz, 1H), 4.44 – 4.38 (m, 2H), 4.10 – 4.03 (m, 1H), 3.98 – 3.93 (m, 1H), 3.50 (q, J = 7.2 Hz, 2H), 3.04 (q, J = 7.2 Hz, 20H), 1.39 (s, 6H), 1.22 – 1.08 (m, 33H). 31P NMR (162 MHz, D2O) δ -6.34 (d, J = 20.8 Hz, 1H), -11.44 (d, J = 20.0 Hz, 1H), -22.54 (t, J = 20.0 Hz, 1H). Example 54. Synthesis of ((2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (54).
WSGR Docket No. 41223-754.601
Step 1. Synthesis of 2-butoxy-N-(7-((6aR,8R,9R,9aS)-8-cyano-9-hydroxy-2,2,4,4- tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)-2-methylpropanamide (54.1). [00439] Compound 54.1 was prepared according to the procedure of Example 1, Step 3, using 16.2 and 2-butoxy-2-methylpropanoic acid. MS (ESI): mass calcd. for C32H53N5O7Si2, 675.97, m/z found 676.20 [M+H]+. Step 2. Synthesis of 2-butoxy-N-(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylpropanamide (54.2). [00440] Compound 54.2 was prepared from compound 54.1 according to the procedure of Example 16, Step 4. MS (ESI): mass calcd. for C20H27N5O6, 433.47, m/z found 434.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.47 (s, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.25 (d, J = 6.4 Hz, 1H), 5.25 (d, J = 5.6 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.62 (t, J = 5.6 Hz, 1H), 4.09 – 4.05 (m, 1H), 4.00 – 3.92 (m, 1H), 3.66 – 3.60 (m, 1H), 3.59 – 3.48 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 1.71 – 1.54 (m, 2H), 1.45 (s, 6H), 1.38 – 1.35 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H). Step 3. Synthesis of ((2R,3S,4R,5R)-5-(4-(2-butoxy-2-methylpropanamido)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (54). [00441] Compound 54 was prepared according to the procedure of Example 49, Step 2, using 54.2.- MS (ESI): mass calcd. for C20H30N5O15P3, 673.40, m/z found 672.40 [M-H]- 1H NMR (400 MHz, D2O) δ 8.29 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 4.98 (d, J = 4.4 Hz, 1H), 4.51 – 4.48 (m, 2H), 4.17 – 4.12 (m, 1H), 4.07 – 4.01 (m, 1H), 3.53 (t, J = 6.8 Hz, 2H), 3.12 (q, J = 7.2 Hz, 19H), 1.64 – 1.57 (m, 2H), 1.47 (s, 6H), 1.38 – 1.32 (m, 2H), 1.20 (t, J = 7.2 Hz, 29H), 0.83 (t, J = 7.6 Hz, 3H). 31P NMR (162 MHz, D2O) δ -8.44 ~ -10.96 (m, 1H), -11.52 (d, J = 20.0 Hz, 2H), -23.02 (t, J = 20.8 Hz, 1H). EXAMPLE I: Oral Composition of a Compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
WSGR Docket No. 41223-754.601 [00442] To prepare a pharmaceutical composition for oral delivery, 400 mg of compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and the following ingredients are mixed intimately and pressed into single scored tablets. Tablet Formulation Ingredient Quantity per tablet (mg) compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 [00443] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Capsule Formulation Ingredient Quantity per capsule (mg) compound 200 lactose spray dried 148 magnesium stearate 2 EXAMPLE II: Evaluation of cellular permeability in Caco-2 cell monolayers. [00444] The bidirectional permeability of compounds across the Caco-2 cell monolayer was assessed. The Caco-2 model is a widely used in vitro model for small intestinal absorption and potential for efflux. [00445] Cell culture. Caco-2 cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS), 1% Penicillin-Streptomycin and 1% MEM NEAA. The cells were incubated at 37 °C, 5% CO2/95% air and saturated humidity. After reaching 80-90% confluency, the cells were gently detached with trypsin. Cells at passage 39 were seeded on the 24-well BD insert system at the density of 8×104 cells/cm2 and cultured for 19 days with medium changed every 2-3 days. Measure the transepithelial electrical resistance (TEER) value of each well. The wells can be used only when their TEER values are greater than 600 Ohms/cm2. [00446] Transport assay. After removing the cell culture medium from the 24-well insert plate, the cells were rinsed with warm transport buffer. Appropriate dosing and receiving solutions were applied to the donor and receiver chambers to initiate the transport assay in apical to basolateral (A to B) or basolateral to apical (B to A) directions (500 and 1300 µL for apical and basolateral wells, respectively). Duplicate wells in each direction were used for the test compound and control compound. The plate was incubated in CO2 incubator at 37 °C, with 5% CO2/95% air and saturated humidity without shaking. The sample after 10-minute incubation was used as the T0 sample, and the sample after 90-minute incubation was used as the T90 sample. T0 and T90 samples were collected from the donor and receiver side of each well at the designed timepoint, mixed with the transport buffer and acetonitrile/MeOH (1:1, v/v) and the internal standard for LC/MS/MS analysis. All samples were vortexed and centrifuged at 4000 rpm at 4 °C for 15 minutes, diluted with pure water and stored at 4 °C before bioanalysis by LC/MS/MS.
WSGR Docket No. 41223-754.601 [00447] Sample analysis. The concentrations of test compounds and control compounds in Caco-2 cells were quantitatively determined by LC/MS/MS method after protein precipitation. [00448] Calculations. The apparent permeability (Papp, cm/s), efflux ratio (ER) and recovery parameters were calculated for Caco-2 drug transport assay using the following equations:
where VR is the solution volume in the receiver chamber (0.4 mL on the apical side, 1.2 mL on the basolateral side); Area is the surface area for the insert membrane, i.e., 0.3 cm2 for the area of the monolayer; Time is incubation time, expressed in seconds, i.e., 5400 s (90 min) for the current experiment; C0 is the initial concentration of test compound or peak area ratio of control compounds in the donor chamber (µM); VD is the volume in the donor chambers (0.4 mL on the apical side, 1.2 mL on the basolateral side); CD and CR are the final concentrations of test compounds or peak area ratio of control compounds in donor and receiver chambers, respectively. [00449] Data for representative compounds is shown in Table 2. Compounds with Papp < 1.0 are classified as low permeability, Papp between 1-10 are classified as medium permeability, and Papp ≥ 10 are classified as high permeability. An efflux ratio (ER) > 2 indicates the compounds are potential substrates for intestinal cell efflux transporters. Table 2. Bidirectional Caco-2 permeability assay results.
WSGR Docket No. 41223-754.601
EXAMPLE III: Evaluation of oral bioavailability in Sprague-Dawley rats. [00450] The single dose pharmacokinetics of Example Compounds is evaluated in fasted male Sprague-Dawley rats following oral gavage. Compounds are dosed as solutions or acceptable suspensions in vehicles generally-regarded as safe for in vivo studies. Groups of three rats per compound are utilized, and blood samples collected at 0.25, 0.5, 1, 2, 4, 8 and 24 h post-dose, stored on ice prior to plasma preparation by centrifugation at 4 °C at 6000 rpm for 5 min. Plasma samples are stored at -80 °C. Concentrations of Example Compounds and corresponding nucleosides resulting from metabolic processing are determined using ultra-high performance liquid chromatography-triple-quadrupole mass spectrometry, with an internal standard. Pharmacokinetic parameters are derived from the resulting plasma concentration/time graphs, and include the following: plasma half-life (t1/2), time to maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), area under the curve of the plasma concentration/time graph (AUClast, through last timepoint obtained, and AUCInf, including the extrapolated area), and mean residence time (MRTInf). The resulting AUCInf for the resulting nucleosides are compared with that resulting from intravenous bolus administration of the corresponding nucleosides in three rats, and an oral bioavailability (F, %) was be calculated as AUCinf, PO ^^ ^^ ^^ ^^ ( ^^ ^^) ^^ ^^ ( ^^ ^^ ^^ ^^ ^^ ^^ ^^)
Formula (IIa); wherein: X is hydrogen or -CN;
R11 is hydrogen, -C(=O)R21, -C(=O)OR21, or C1-C6alkyl optionally substituted with one or more R11a; each R11a is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl; or two R11a on the same atom are taken together to form an oxo; R21 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R21a; each R21a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R21a on the same atom are taken together to form an oxo; or two R21a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;
WSGR Docket No. 41223-754.601 R32 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1- C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; R13 is hydrogen or C1-C6alkyl; R14 is -OH or fluoro; R16 is -C(=O)R26, -C(=O)OR26, -CH2-O-C(=O)R26, or -CH2-O-C(=O)OR26; R26 is C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1- C6alkylene(heteroaryl); wherein the alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R26a; each R26a is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R26a on the same atom are taken together to form an oxo; or two R26a on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
WSGR Docket No. 41223-754.601 each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom are taken together to form an oxo. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is hydrogen. 6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -CN. 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13 is hydrogen. 8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R13 is C1-C6alkyl. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R14 is -OH. 10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R14 is fluoro.
WSGR Docket No. 41223-754.601 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R32 is C1-C6alkyl optionally and independently substituted with one or more R. 12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R32 is C1-C6alkyl. 13. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or
14. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
. 15. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
. 16. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
. 17. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
. 18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R16 is hydrogen or -C(=O)R26. 19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R16 is -C(=O)R26. 20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R26 is C1-C6alkylene(cycloalkyl) or C1-C6alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl, is optionally and independently substituted with one or more 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R26 is C1-C6alkylene(cycloalkyl) or C1-C6alkylene(aryl).
WSGR Docket No. 41223-754.601 22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R26 is C1-C6alkylene(cycloalkyl). 23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R26 is C1-C6alkylene(aryl). 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or 25.
, ,
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pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 26. A pharmaceutical composition comprising the compound of any one of claims 1 -25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier. 27. A method of treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 26. 28. The method of claim 27, wherein the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-CoV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papillomavirus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Poxviridae, Potyviridae, Reoviridae, Retroviridae, Rhabdoviridae, Tectiviridae, Togaviridae, orthopoxvirus, coronavirus, influenza virus, sendai virus (SeV), sindbis virus (SINV), vaccinia viruses, West Nile virus, Hantavirus, viruses which cause the common cold, and any combination thereof. 29. The method of claim 27, wherein the viral infection is caused by coronavirus disease 2019 (SARS-CoV-2). 30. The method of claim 27, wherein the viral infection is caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). 31. The method of claim 27, wherein the viral infection is caused by one Ebolavirus. 32. The method of any one of claims 27-31, further comprising administering at least one antiviral agent. 33. The method of claim 32, wherein the at least one antiviral agent is nirmatrelvir/ritonavir.