Antiviral compounds

Abstract

The present disclosure provides compounds for treating a variety of diseases, such as respiratory syncytial virus (RSV), HRV, hMPV, Ebola, Zika, West Nile, dengue, and HCV.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 978,192, filed on February 18, 2020, and entitled “ANTIVIRAL COMPOUNDS,” which is incorporated herein by reference in its entirety. Background Art

[0003] Pneumoviridae viruses are negative-sense, single-stranded RNA viruses that cause numerous human and animal diseases. The Pneumoviridae family includes human respiratory syncytial virus (HRSV) and human metapneumovirus. Almost all children will be infected with HRSV by the time they are two years old. HRSV is a major cause of lower respiratory tract infections in infancy and childhood, with 0.5% to 2% of infections requiring hospitalization.

[0004] Currently, there is no vaccine available to prevent HRSV infection. The monoclonal antibody palivizumab can be used for immunoprophylaxis, but its use is limited to high-risk infants, such as premature infants or those with congenital heart disease or lung disease, and its general use is often cost-prohibitive. Additionally, the nucleoside analog ribavirin is the only approved antiviral agent for the treatment of HRSV infection, but its efficacy is limited. Therefore, anti-pneumoviral therapeutics are needed.

[0005] Examples of pyrrolo[2,3-d]pyrimidine compounds useful for treating viral infections are described in US 2012 / 0009147 A1 (Cho et al.), US 2012 / 0020921 A1 (Cho et al.), WO 2008 / 089105 A2 (Babu et al.), WO 2008 / 141079 A1 (Babu et al.), WO 2009 / 132135 A1 (Butler et al.), WO 2010 / 002877 A2 (Francom), WO 2011 / 035231 A1 (Cho et al.), WO 2011 / 035250 A1 (Butler et al.), WO 2011 / 150288 A1 (Cho et al.), WO 2012 / 012465 (Cho et al.), WO 2012 / 012776 A1 (Mackman et al.), WO 2012 / 037038 (Clarke et al.), WO 2012 / 087596 A1 (Delaney et al.), and WO 2012 / 142075 A1 (Girijavallabhan et al.).

[0006] Therefore, there is a need for compositions and methods for treating Pneumoviridae infections (such as HRSV infections), Flaviviridae infections (including dengue fever), and EBOV infections that are effective and have an acceptable toxicity profile. The present disclosure addresses these and other needs. Summary of the Invention

[0007] In one embodiment, the present disclosure provides a compound of formula (Ia):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] R 1 and R 2 are each independently H or -C(O)R 1A , where R 1A C 1-6 Alkyl, where R 1 and R 2 At least one of them is H;

[0011] or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-, where each R 2A and R 2B Independently H, C 1-6 Alkyl or C 1-6 alkoxy;

[0012] R 3 -N(H)(R 3A );

[0013] R 3A H or -C(O)R 3A1 , where R 3A1 is C optionally substituted with –NH2 1-18 alkyl;

[0014] R 4A is O or S; and

[0015] R 4B and R 4C Each independently is:

[0016] (A)-OH;

[0017] (B)–OR 4B1 ,in

[0018] R 4B1 is optionally replaced by 1 to 3 R 4B2 C1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-12 aryl or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms each independently selected from N, O or S, wherein

[0019] Each R 4B2 The groups are independently C 1-6 Alkoxy, -SR 4B3 or -S(O)2-R 4B3 ,and

[0020] Each R 4B3 The groups are independently C 1-6 alkyl;

[0021] (C) in

[0022] subscript m is 0, 1, 2, 3, 4, or 5; and

[0023] Each R 4D is independently optionally replaced by 1 to 3 R 4D1 C 1-6 Alkyl, optionally substituted by 1 to 3 R 4D2 C 1-3 Alkoxy, –C(O)OR 4D3 or -C(O)N(R 4D3 )2, where

[0024] Each R 4D1 The groups are independently -NH2 or -C(O)OR 4D3 ,

[0025] Each R 4D2 Independently C 1-3 alkoxy, and

[0026] Each R 4D3 Independently C 1-3 alkyl;

[0027] (D) in

[0028] X 1 and X 2 Each independently is -O- or -N(R 4H )-;

[0029] R 4E1 and R 4E2 are each independently H, optionally substituted by 1 to 3 R 4E3 C 1-6 Alkyl, or C 3-6Cycloalkyl, wherein

[0030] Each R 4E3 The groups are independently -C(O)OR 4E4 、-NH2、–NHC(O)R 4E4 、–NHC(O)OC 1-6 Alkylene-C 6-12 Aryl, C 3-6 Cycloalkyl or C 6-12 aryl, and

[0031] Each R 4E4 The groups are independently C 1-6 alkyl;

[0032] or R 4E1 and R 4E2 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0033] R 4F1 and R 4F2 Each is H or together is oxo;

[0034] R 4G is optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, C 7-18 Alkyl, optionally substituted by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, -C(O)R 4G4 、-C(O)OR 4G5 ,or

[0035]

[0036] Each R 4G1 are independently -OH, C 1-6 Alkyl, C 1-3 Alkoxy, -(CH2OCH2) 1-5 -CH3、C 1-3 Haloalkyl, -N(R 4G8 )2、-C(O)N(R 4G8 ) 2. optionally 1 to 3 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G10 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or C 6-12 aryl;

[0037] Each R4G2 Independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-3 Haloalkyl, -OH, -NH2 or C 6-12 aryl;

[0038] Each R 4G3 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl, oxo, -C(O)R 4G5 or-C(O)OR 4G5 ;

[0039] Each R 4G4 Independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally replaced by OH, NH2 or -NHC(O)OR 4G5 substituted, and wherein the cycloalkyl group is optionally replaced by C 1-6 Alkyl substitution;

[0040] Each R 4G5 Independently C 1-6 alkyl;

[0041] R 4G6 and R 4G7 Each independently is H or –OR 4G11 ,in

[0042] R 4G6 and R 4G7 At least one of -OR 4G11 ;

[0043] Each R 4G8 are independently H or C 1-6 alkyl;

[0044] Each R 4G9 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or -NH2;

[0045] Each R 4G10 Independently C 1-6 Alkyl, C 1-3 a haloalkyl group or an oxo group;

[0046] Each R 4G11 Independently C 10-18 alkyl or benzyl;

[0047] R 4H is H;

[0048] or R 4E1 and R 4H Combined with the atoms to which they are attached, they form a 5- to 6-membered heterocyclyl having 1 to 2 additional heteroatoms selected from N, O, and S; and

[0049] subscript n is 0 or 1; or

[0050] (E)-(OP(O)(OH)) 1-2 -OH; or

[0051] (F) in

[0052] R 4J1 and R 4J2 Each independently represents H, –OR 4J3 or –OC(O)R 4J3 , where R 4J1 and R 4J2 At least one of -OR 4J3 or –OC(O)R 4J3 ,

[0053] Each R 4J3 Independently C 1-18 Alkyl, C 2-6 alkenyl or benzyl, and

[0054] At least one R 4J3 C 10-18 alkyl;

[0055] Alternatively, R 2 and R 4C Combined with the atoms to which they are attached to form a six-membered ring, and R 1 H or -C(O)R 1A , where R 1A C 1-6 alkyl,

[0056] Provided that when the compound of formula (Ia) has the following formula:

[0057]

[0058] And R 4G is ethyl or 2-ethylbutyl, then R 1 and R 2 One of them is -C(O)R 1A , or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-,

[0059] Provided that the compound of formula (Ia) does not have the following structure:

[0060]

[0061] and provided that when the compound of formula (Ia) has the following formula:

[0062]

[0063] Then R 1 and R 2 One of them is -C(O)R 1A , or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-.

[0064] In another embodiment, the present disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0065] In another embodiment, the present disclosure provides a method of treating a Pneumoviridae infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the present disclosure provides a method of treating a Picornaviridae infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0067] In another embodiment, the present disclosure provides a method of treating a Flaviviridae infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the present disclosure provides a method of treating a Filoviridae infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0069] In another embodiment, the present disclosure provides a method for preparing a medicament for treating a Pneumoviridae infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, the present disclosure provides a method for preparing a medicament for treating a Picornaviridae viral infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0071] In another embodiment, the present disclosure provides a method for preparing a medicament for treating a Flaviviridae infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment, the present disclosure provides a method for preparing a medicament for treating a Filoviridae infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0073] In another embodiment, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Pneumoviridae virus infection in a human.

[0074] In another embodiment, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Picornaviridae viral infection in a human.

[0075] In another embodiment, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Flaviviridae infection in a human.

[0076] In another embodiment, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Filoviridae viral infection in humans.

[0077] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Pneumoviridae infection in a human in need thereof.

[0078] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Picornaviridae viral infection in a human in need thereof.

[0079] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Flaviviridae infection in a human in need thereof.

[0080] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Filoviridae infection in a human in need thereof.

[0081] In another embodiment, the present disclosure provides a method for treating or preventing an exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease.

[0082] In another embodiment, the present disclosure provides a method for preparing a medicament for treating or preventing exacerbation of respiratory conditions caused by viral infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease.

[0083] In another embodiment, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing exacerbation of respiratory conditions caused by viral infection in humans, wherein the respiratory condition is chronic obstructive pulmonary disease.

[0084] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. DETAILED DESCRIPTION

[0085] I. Overview

[0086] The present disclosure provides 2',3'-dihydroxy-4'-cyano nucleoside and monoester compounds for use in treating viral infections such as Ebola, Zika, West Nile, yellow fever, dengue, HCV, RSV, and the like.

[0087] II. Definitions

[0088] "Alkyl" is a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group can have 1 to 18 carbon atoms (i.e., C 1-18 Alkyl) or 1 to 8 carbon atoms (ie C 1-8 Alkyl) or 1 to 6 carbon atoms (ie C 1-6 Alkyl) or 1 to 4 carbon atoms (ie C 1-4Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH( CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1- Butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-C )2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0089] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups may include any number of carbon atoms, such as C2, C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 2-7 、C 2-8 、C 2-9 、C 2-10 , C3, C 3-4 、C 3-5 、C 3-6 , C4, C 4-5 、C4-6 , C5, C 5-6 and C6. The alkenyl group may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include but are not limited to vinyl (vinyl / ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatrienyl. The alkenyl group may be substituted or unsubstituted.

[0090] "Alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. As with alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups may be further substituted with various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0091] "Alkoxy-alkoxy" refers to an alkoxy group connected to a second alkoxy group that is connected to the rest of the compound. Alkoxy is as defined above and may include, but is not limited to, methoxy-methoxy (CH3OCH2O-), methoxy-ethoxy (CH3OCH2CH2O-), and the like.

[0092] "Hydroxyl" refers to a -OH group.

[0093] As used herein, the term "halo" or "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0094] As used herein, "haloalkyl" refers to an alkyl group as defined herein wherein one or more of the hydrogen atoms of the alkyl group are independently replaced by a halo substituent, which may be the same or different. For example, C 1-4 A haloalkyl group is one in which C 1-4 A C alkyl group in which one or more hydrogen atoms have been replaced by a halo substituent 1-4 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0095] "Cycloalkyl" refers to all carbocyclic rings (i.e., C ) having from 3 to 20 ring carbon atoms (e.g., from 3 to 12 ring atoms, e.g., from 3 to 10 ring atoms, or from 3 to 8 ring atoms, or from 3 to 6 ring atoms, or from 3 to 5 ring atoms, or from 3 to 4 ring atoms) that are singly saturated or partially unsaturated. 3-20 Cycloalkyl). Term " cycloalkyl " also includes the saturation of multiple condensations and all carbocyclic systems of part unsaturation (for example, the ring system comprising 2, 3 or 4 carbocyclic rings). Therefore, cycloalkyl includes polycyclic carbocycle, such as bicyclic carbocycle (for example, bicyclic carbocycle with about 6 to 12 annular carbon atoms, such as bicyclo [3.1.0] hexane and bicyclo [2.1.1] hexane) and polycyclic carbocycle (for example, tricyclic and tetracyclic carbocycle with up to about 20 annular carbon atoms). When valence requirement allows, the ring of many fused ring systems can be connected to each other by fusion, spirocycle and bridging bond. The non-limiting example of the cycloalkyl of monocycle includes cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0096] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen and sulfur) in the ring. Unless otherwise indicated, the heterocyclyl group has 3 to about 20 cyclic atoms, such as 3 to 12 cyclic atoms, such as 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Therefore, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6 or 7-membered ring) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. When valence requirements allow, the rings of multiple condensed rings (e.g., bicyclic heterocyclyl) systems can be connected to each other by condensation, spirocycles and bridging bonds. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2-thia-6-azaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl and the like.

[0097] As used herein, "aryl" refers to a single all-carbon aromatic ring or a plurality of fused all-carbocyclic ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl group. Aryl also includes a polycondensed ring system (e.g., a ring system comprising 2, 3, or 4 rings) having about 9 to 20 carbon atoms, wherein at least one ring is aromatic, and wherein the other rings may be aromatic or not aromatic (i.e., carbocyclic). Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the polycondensed ring system. When valence requirements permit, the rings of the polycondensed ring systems can be connected to each other by fusion, spirocycles, and bridging bonds. It should also be understood that when referring to a certain atomic range aryl (e.g., 6-10 membered aryl), the atomic range is the total ring atoms of the aryl. For example, a 6-membered aryl group would include phenyl, and a 10-membered aryl group would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0098] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component is connected to the aryl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group connected to the aryl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 0-6 、C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 and C 5-6 In some cases, the alkyl component may not be present. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. Alkyl-aryl groups may be substituted or unsubstituted.

[0099] As used herein, "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes poly-fused ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a heteroaryl as defined above is fused to one or more rings to form a poly-fused ring system, wherein the one or more rings are selected from heteroaryl (to form, for example, 1,8-naphthyridinyl), heterocycle (to form, for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl). Thus, a heteroaryl group (single aromatic ring or poly-fused ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such poly-fused ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portions of the fused rings. When valence requirements permit, the rings of the poly-fused ring systems may be connected to each other by fusion, spirocycle, and bridging bonds. Should be understood that the single ring of many fused ring systems can be connected in any order relative to each other.Should be understood that the attachment point of heteroaryl or heteroaryl many fused ring systems can be positioned at any suitable atom (comprising carbon atom and heteroatom (for example, nitrogen)) of heteroaryl or heteroaryl many fused ring systems.It should also be understood that when with reference to a certain atomic range unit heteroaryl (for example, 5 yuan to 10 yuan heteroaryl), atomic range is the total ring atoms of heteroaryl and comprises carbon atom and heteroatom.For example, 5 yuan heteroaryl will comprise thiazolyl, and 10 yuan heteroaryl will comprise quinolyl. Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.

[0100] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii), including the compounds of the Examples.

[0101] A "pharmaceutically effective amount" refers to that amount of a disclosed compound or combination thereof in a formulation that provides the desired therapeutic or pharmaceutical result.

[0102] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary animals.

[0103] As used herein, "treatment" or "treat" or "treating" refers to an approach for obtaining beneficial or desired results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the extent of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying worsening or progression of the disease or condition); and c) alleviating a disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying progression of the disease, improving quality of life, and / or prolonging survival.

[0104] "Prevention" refers to preventing or delaying the progression of clinical disease in a patient suffering from a viral infection.

[0105] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that effectively causes a desired biological or medical response, including an amount of a compound that is sufficient to achieve such treatment of the disease when administered to a subject to treat a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and if a desired or beneficial result can be achieved or realized in combination with one or more other agents, then a single agent may be considered to be administered in an effective amount. The appropriate dosage of any co-administered compound may optionally be reduced due to the combined action of the compounds (e.g., additive or synergistic effect).

[0106] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents after a few hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure after a few hours (e.g., 1-12 hours). Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially so that a therapeutically effective amount of each agent is present in the patient's body.

[0107] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0108] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. A "pharmaceutically acceptable salt" is a non-toxic salt of the free base form of a compound that has the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyrates, succinate ... Pharmaceutically acceptable salts include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy," 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0109] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium, and NX4. + (wherein X is C1-C4 alkyl). Also included are base addition salts such as sodium or potassium salts.

[0110] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or D, where n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and, therefore, may be used to increase the half-life of a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by employing a starting material in which one or more hydrogen atoms have been replaced by deuterium.

[0111] Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples listed below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0112] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers and therefore may produce enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- or as (D)- or (L)- for amino acids based on absolute stereochemistry. The disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or using, for example, chiral high pressure liquid chromatography (HPLC) to resolve racemates (or racemates of salts or derivatives). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers. Likewise, it is also intended to include all tautomeric forms. Where a compound is represented in its chiral form, it is understood that the embodiments encompass, but are not limited to, the specific diastereomer or enantiomerically enriched form. Where chirality is not specified but present, it is understood that the embodiments relate to the specific diastereomer or enantiomerically enriched form; or a racemic or non-racemic mixture of such a compound. As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0113] "Racemate" refers to a mixture of enantiomers. A mixture may contain equal or unequal amounts of each enantiomer.

[0114] "A stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or has an asymmetrically substituted double bond, the compound can exist as stereoisomers and can therefore be produced as individual stereoisomers or as a mixture. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereoisomers and separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry (4th Edition), J. March, John Wiley and Sons, New York, 1992).

[0115] "Tautomer" refers to alternative forms of a compound that differ in the position of a proton such as enol-keto and imine-enamine tautomers, or tautomeric forms containing heteroaryl groups attached to both the -NH- and the =N- ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0116] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of chemical groups are for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of the group. A dotted line indicates an optional bond. Unless required by chemistry or structure, directionality is not indicated or implied by writing the order of chemical groups or the point at which they are attached to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and the two can be attached in either direction. Similarly, a group, for example, "arylalkyl" can be attached to the rest of the molecule at either the aryl or alkyl portion of the group. Prefixes such as "C u-v " or (C u -C v ) indicates that the following group has u to v carbon atoms. For example, "C 1-6 "C1-C6 alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0117] As used herein, "solvate" refers to the result of the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0118] As used herein, "prodrug" refers to a drug derivative that is converted to the parent drug according to some chemical or enzymatic pathway when administered to the human body.

[0119] III. Compounds

[0120] The present disclosure provides compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii).

[0121] In some embodiments, the present disclosure provides a compound of Formula (Ia):

[0122]

[0123] or a pharmaceutically acceptable salt thereof, wherein:

[0124] R 1 and R 2 Each independently is H or -C(O)R 1A , where R 1A C 1-6 Alkyl, where R 1 and R 2 At least one of them is H;

[0125] or R 1and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-, where each R 2A and R 2B Independently H, C 1-6 Alkyl or C 1-6 alkoxy;

[0126] R 3 -N(H)(R 3A );

[0127] R 3A H or -C(O)R 3A1 , where R 3A1 is C optionally substituted by -NH2 1-18 alkyl;

[0128] R 4A is O or S; and

[0129] R 4B and R 4C Each independently is:

[0130] (A)-OH;

[0131] (B)–OR 4B1 ,in

[0132] R 4B1 is optionally replaced by 1 to 3 R 4B2 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-12 aryl or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms each independently selected from N, O or S, wherein

[0133] Each R 4B2 The groups are independently C 1-6 Alkoxy, -SR 4B3 or -S(O)2-R 4B3 ,and

[0134] Each R 4B3 The groups are independently C 1-6 alkyl;

[0135] (C) in

[0136] subscript m is 0, 1, 2, 3, 4, or 5; and

[0137] Each R 4D is independently optionally replaced by 1 to 3 R 4D1C 1-6 Alkyl, optionally substituted by 1 to 3 R 4D2 C 1-3 Alkoxy, –C(O)OR 4D3 or -C(O)N(R 4D3 )2, where

[0138] Each R 4D1 The groups are independently -NH2 or -C(O)OR 4D3 ,

[0139] Each R 4D2 Independently C 1-3 alkoxy, and

[0140] Each R 4D3 Independently C 1-3 alkyl;

[0141] (D) in

[0142] X 1 and X 2 Each independently is -O- or -N(R 4H )-;

[0143] R 4E1 and R 4E2 are each independently H, optionally substituted by 1 to 3 R 4E3 C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein

[0144] Each R 4E3 The groups are independently -C(O)OR 4E4 、-NH2、–NHC(O)R 4E4 、–NHC(O)OC 1-6 Alkylene-C 6-12 Aryl, C 3-6 Cycloalkyl or C 6-12 aryl, and

[0145] Each R 4E4 The groups are independently C 1-6 alkyl;

[0146] or R 4E1 and R 4E2 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0147] R 4F1 and R 4F2 Each of them is H or together they are oxo;

[0148] R4G is optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, C 7-18 Alkyl, optionally substituted by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, -C(O)R 4G4 、-C(O)OR 4G5 ,or

[0149]

[0150] Each R 4G1 are independently -OH, C 1-6 Alkyl, C 1-3 Alkoxy, -(CH2OCH2) 1-5 -CH3、C 1-3 Haloalkyl, -N(R 4G8 )2、-C(O)N(R 4G8 ) 2. optionally 1 to 3 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G10 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or C 6-12 aryl;

[0151] Each R 4G2 Independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-3 Haloalkyl, -OH, -NH2 or C 6-12 aryl;

[0152] Each R 4G3 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl, oxo, -C(O)R 4G5 or-C(O)OR 4G5 ;

[0153] Each R 4G4 Independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally replaced by OH, NH2 or -NHC(O)OR 4G5 substituted, and wherein the cycloalkyl group is optionally replaced by C 1-6 Alkyl substitution;

[0154] Each R 4G5 Independently C 1-6 alkyl;

[0155] R 4G6 and R 4G7 Each independently is H or –OR 4G11 ,in

[0156] R 4G6 and R 4G7 At least one of -OR 4G11 ;

[0157] Each R 4G8 are independently H or C 1-6 alkyl;

[0158] Each R 4G9 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or -NH2;

[0159] Each R 4G10 Independently C 1-6 Alkyl, C 1-3 a haloalkyl group or an oxo group;

[0160] Each R 4G11 Independently C 10-18 alkyl or benzyl;

[0161] R 4H is H;

[0162] or R 4E1 and R 4H Combined with the atoms to which they are attached, they form a 5- to 6-membered heterocyclyl having 1 to 2 additional heteroatoms selected from N, O, and S; and

[0163] subscript n is 0 or 1; or

[0164] (E)-(OP(O)(OH)) 1-2 -OH; or

[0165] (F) in

[0166] R 4J1 and R 4J2 Each independently represents H, –OR 4J3 or –OC(O)R 4J3 , where R 4J1 and R 4J2 At least one of -OR 4J3 or –OC(O)R 4J3 ,

[0167] Each R 4J3 Independently C 1-18 Alkyl, C 2-6 alkenyl or benzyl, and

[0168] At least one R 4J3 C 10-18 alkyl;

[0169] Alternatively, R 2 and R 4C Combined with the atoms to which they are attached to form a six-membered ring, and R 1 H or -C(O)R 1A , where R 1A C 1-6 alkyl,

[0170] Provided that when the compound of formula (Ia) has the following formula:

[0171]

[0172] And R 4G is ethyl or 2-ethylbutyl, then R 1 and R 2 One of them is -

[0173] C(O)R 1A , or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-, provided that the compound of formula (Ia) does not have the following structure:

[0174]

[0175] and provided that when the compound of formula (Ia) has the following formula:

[0176]

[0177] Then R 1 and R 2 One of them is -C(O)R 1A , or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-.

[0178] In some embodiments, the compound can be represented by Formula (Ia) or a pharmaceutically acceptable salt thereof, with the proviso that the compound of Formula (Ia) does not have the following structure:

[0179]

[0180] In some embodiments, the compound may be represented by Formula (Ia) or a pharmaceutically acceptable salt thereof, provided that when the compound of Formula (Ia) has the following formula:

[0181]

[0182] And R 4G is ethyl, 2-ethylbutyl or cyclohexyl, then R 1 and R 2 One of them is -C(O)R 1A , or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-.

[0183] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H or -C(O)R 1A , where R 1A C 1-6 Alkyl, where R 1 and R 2 At least one of is H; or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B )-, where each R 2A and R 2B Independently H, C 1-6 Alkyl or C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 Can be H and R 2 Can be -C(O)R 1A , where R 1A C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 Can be -C(O)R 1A , where R 1A C 1-6Alkyl, and R 2 Can be H. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Can combine to form –C(O)- or –C(R 2A )(R 2B )-, where each R 2A and R 2B Independently H, C 1-6 Alkyl or C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Can combine to form –C(O)- or –C(R 2A )(R 2B )-, where each R 2A and R 2B Independently H, C 1-4 Alkyl or C 1-3 Alkoxy.

[0184] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each independently is H or -C(O)R 1A , where R 1A is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, wherein R 1 and R 2 At least one of is H; or R 1 and R 2 Combined to form -C(O)-, -C(Me)2- or -CH(OEt)-. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 Can be H and R 2 Can be -C(O)R 1A , where R 1Ais methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 Can be -C(O)R 1A , where R 1A is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and R 2 Can be H. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Can combine to form –C(O)-, -C(Me)2-, or –CH(OEt)-.

[0185] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 and (I) are each H. In some embodiments, the compound may be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each independently is H or -C(O)R 1A , where R 1A is ethyl, isopropyl or tert-butyl, wherein R 1 and R 2 At least one of is H; or R 1 and R 2 Combined to form -C(O)-, -C(Me)2- or -CH(OEt)-. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 Can be H and R 2 Can be -C(O)R 1A , where R 1A In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1Can be -C(O)R 1A , where R 1A is ethyl, isopropyl or tert-butyl, and R 2 It can be H.

[0186] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 Can be H and R 2 In some embodiments, the compound may be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 Can be H and R 2 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 Can be H and R 2 In some embodiments, the compound may be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 It can be -C(O)-ethyl and R 2 Can be H. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be -C(O)-isopropyl and R 2 Can be H. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be -C(O)-tert-butyl and R 2 Can be H. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Can combine to form -C(Me)2-. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Can combine to form –CH(OEt)-.

[0187] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 3 -N(H)(R 3A );R 3A H or -C(O)R 3A1 , where R 3A1 is C optionally substituted with –NH2 1-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 3 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 3 -NHC(O)R 3A1 , where R 3A1 is C optionally substituted with –NH2 1-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 3 -NHC(O)R 3A1 , where R 3A1 is C optionally substituted with –NH2 1-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 3A1and -NH. In some embodiments, the compound may be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 3A1 Can be n-propyl, isopropyl, isobutyl, heptyl or dodecyl, each optionally substituted with -NH2. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 3A1 Can be n-propyl, isopropyl, heptyl or dodecyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 3A1 It may be 1-aminoisobutyl.

[0188] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4A Can be O or S. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4A It can be S.

[0189] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 can each independently be H or -C(O)R 1A , where R 1A It can be ethyl, isopropyl or tert-butyl, where R 1 and R 2 At least one of them may be H; or R 1 and R 2Combine to form –C(O)-, -C(Me)2- or –CH(OEt)-; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be H; R 2 It can be -C(O)-ethyl; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be H; R 2 It can be -C(O)-isopropyl; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be H; R 2 It can be -C(O)-tert-butyl; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be -C(O)-ethyl; R 2 It can be H; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be -C(O)-isopropyl; R 2 It can be H; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 It can be -C(O)-tert-butyl; R2 It can be H; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 ; R 2 Can combine to form -C(O)-; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 ; R 2 Can combine to form -C(Me)2-; R 3 may be NH2; and R 4A Can be O. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Can combine to form –CH(OEt)-; R 3 may be NH2; and R 4A It can be O.

[0190] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C Can be independently:

[0191] (A)-OH;

[0192] (B)–OR 4B1 ,in

[0193] R 4B1 may be optionally replaced by 1 to 3 R 4B2 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-12 aryl or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms each independently selected from N, O or S, wherein

[0194] Each R 4B2 The groups can be independently C 1-6Alkoxy, -SR 4B3 or -S(O)2-R 4B3 ,and

[0195] Each R 4B3 The groups can be independently C 1-6 alkyl;

[0196] (C) in

[0197] The subscript m can be 0, 1, 2, 3, 4, or 5; and

[0198] Each R 4D may be independently optionally replaced by 1 to 3 R 4D1 C 1-6 Alkyl, optionally substituted by 1 to 3 R 4D2 C 1-3 Alkoxy, –C(O)OR 4D3 or -C(O)N(R 4D3 )2, where

[0199] Each R 4D1 The groups can independently be -NH2 or -C(O)OR 4D3 ,

[0200] Each R 4D2 Can be independently C 1-3 alkoxy, and

[0201] Each R 4D3 Can be independently C 1-3 alkyl;

[0202] (D) in

[0203] X 1 and X 2 can be independently -O- or -N(R 4H )-;

[0204] R 4E1 and R 4E2 may be each independently H, optionally substituted by 1 to 3 R 4E3 C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein

[0205] Each R 4E3 The groups can independently be -C(O)OR 4E4 、-NH2、–NHC(O)R 4E4 、–NHC(O)OC 1-6 Alkylene-C 6-12 Aryl, C3-6 Cycloalkyl or C 6-12 aryl, and

[0206] Each R 4E4 The groups can be independently C 1-6 alkyl;

[0207] or R 4E1 and R 4E2 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0208] R 4F1 and R 4F2 Each is H or together is oxo;

[0209] R 4G may be optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, C 7-18 Alkyl, optionally substituted by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, -C(O)R 4G4 、-C(O)OR 4G5 ,or

[0210]

[0211] Each R 4G1 Can be independently -OH, C 1-6 Alkyl, C 1-3 Alkoxy, -(CH2OCH2) 1-5 -CH3、C 1-3 Haloalkyl, -N(R 4G8 )2、-C(O)N(R 4G8 ) 2. optionally 1 to 3 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G10 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or C 6-12 aryl;

[0212] Each R 4G2 Can be independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-3 Haloalkyl, -OH, -NH2 or C 6-12 aryl;

[0213] Each R 4G3Can be independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl, oxo, -C(O)R 4G5 or-C(O)OR 4G5 ;

[0214] Each R 4G4 Can be independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 The alkyl group may be optionally replaced by OH, NH2 or -NHC(O)OR 4G5 substituted, and wherein the cycloalkyl group may be optionally replaced by C 1-6 Alkyl substitution;

[0215] Each R 4G5 Can be independently C 1-6 alkyl;

[0216] R 4G6 and R 4G7 Can each independently be H or –OR 4G11 ,in

[0217] R 4G6 and R 4G7 At least one of may be –OR 4G11 ;

[0218] Each R 4G8 Can be independently H or C 1-6 alkyl;

[0219] Each R 4G9 Can be independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or -NH2;

[0220] Each R 4G10 Can be independently C 1-6 Alkyl, C 1-3 a haloalkyl group or an oxo group;

[0221] Each R 4G11 Can be independently C 10-18 alkyl or benzyl;

[0222] R 4H It can be H;

[0223] or R 4E1 and R 4H Combined with the atoms to which they are attached, they form a 5- to 6-membered heterocyclyl having 1 to 2 additional heteroatoms selected from N, O, and S; and

[0224] The subscript n can be 0 or 1; or

[0225] (E)-(OP(O)(OH)) 1-2 -OH; or

[0226] (F) in

[0227] R 4J1 and R 4J2 Can be H, –OR 4J3 or –OC(O)R 4J3 , where R 4J1 and R 4J2 At least one of may be –OR 4J3 or –OC(O)R 4J3 ,

[0228] Each R 4J3 Can be independently C 1-18 Alkyl, C 2-6 alkenyl or benzyl, and

[0229] At least one R 4J3 Can be C 10-18 alkyl;

[0230] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4C Can be combined with the atoms to which they are attached to form a six-membered ring. In some embodiments, the compound of Formula (Ia) can have the following structure:

[0231]

[0232] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them may be -OH.

[0234] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them can be -OR 4B1 , where R4B1 is optionally replaced by 1 to 3 R 4B2 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-12 aryl or 5- to 6-membered heteroaryl having 1 to 3 heteroatoms each independently selected from N, O or S, wherein each R 4B2 The groups are independently C 1-6 Alkoxy, -SR 4B3 or -S(O)2-R 4B3 , and each R 4B3 The groups are independently C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4B1 It can be methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(thiomethyl)ethyl, 2-(methylsulfonyl)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl or pyridyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4B1 It may be isopropyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, 2-(thiomethyl)ethyl, 2-(methylsulfonyl)ethyl, cyclopentyl, naphthyl or pyridyl.

[0235] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them can be

[0236]

[0237] where subscript m is 0, 1, 2, 3, 4, or 5; and each R 4D is independently optionally replaced by 1 to 3 R 4D1 C 1-6 Alkyl, optionally substituted by 1 to 3 R 4D2 C 1-3 Alkoxy, –C(O)OR 4D3 or -C(O)N(R 4D3)2, where each R 4D1 The groups are independently -NH2 or -C(O)OR 4D3 , each R 4D2 Independently C 1-3 alkoxy, and each R 4D3 Independently C 1-3 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4D It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, 2-methoxyethoxy, -C(O)OMe, -C(O)OEt, -C(O)NMe2 or

[0238]

[0239] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4D It can be tert-butyl, 2-methoxyethoxy, -C(O)OEt, -C(O)NMe2 or

[0240]

[0241] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them can be

[0242]

[0243] where X 1 and X 2 Each independently is -O- or -N(R 4H )-;

[0244] R 4E1 and R 4E2 are each independently H, optionally substituted by 1 to 3 R 4E3 C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein each R 4E3 The groups are independently -C(O)OR 4E4 、-NH2、–NHC(O)R 4E4 、–NHC(O)OC1-6 Alkylene-C 6-12 Aryl, C 3-6 Cycloalkyl or C 6-12 aryl, and each R 4E4 The groups are independently C 1-6 Alkyl; or R 4E1 and R 4E2 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0245] R 4F1 and R 4F2 Each of them is H or together they are oxo;

[0246] R 4G is optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, C 7-18 Alkyl, optionally substituted by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, -C(O)R 4G4 、-C(O)OR 4G5 ,or

[0247]

[0248] Each R 4G1 are independently -OH, C 1-6 Alkyl, C 1-3 Alkoxy, -(CH2OCH2) 1-5 -CH3、C 1-3 Haloalkyl, -N(R 4G8 )2、-C(O)N(R 4G8 ) 2. optionally 1 to 3 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G10 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or C 6-12 Aryl; each R 4G2 Independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-3 Haloalkyl, -OH, -NH2 or C 6-12 Aryl; each R 4G3 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl, oxo, -C(O)R 4G5 or-C(O)OR4G5 ;

[0249] Each R 4G4 Independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally replaced by OH, NH2 or -NHC(O)OR 4G5 substituted, and wherein the cycloalkyl group is optionally replaced by C 1-6 Alkyl substitution;

[0250] Each R 4G5 Independently C 1-6 alkyl;

[0251] R 4G6 and R 4G7 Each independently is H or –OR 4G11 , where R 4G6 and R 4G7 At least one of -OR 4G11 ;

[0252] Each R 4G8 are independently H or C 1-6 alkyl;

[0253] Each R 4G9 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or -NH2; each R 4G10 Independently C 1-6 Alkyl, C 1-3 haloalkyl or oxo; each R 4G11 Independently C 10-18 alkyl or benzyl;

[0254] R 4H H; or R 4E1 and R 4H Combined with the atoms to which they are attached, they form a 5- to 6-membered heterocyclyl having 1 to 2 additional heteroatoms selected from N, O, and S; and the subscript n is 0 or 1.

[0255] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is independently -O- or -NH-. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein X1 and X 2 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein X 1 Can be -O- and X 2 In some embodiments, the compound may be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein X 1 It can be -NH- and X 2 It can be -O-.

[0256] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4F1 and R 4F2 Each is H. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4F1 and R 4F2 Together they are an oxo group.

[0257] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein the subscript n is 0. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein the subscript n is 1.

[0258] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them can be

[0259]

[0260] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4E1 can be H, optionally 1 to 3 R 4E3 C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein each R 4E3 The groups are independently -C(O)OR 4E4 、-NH2、–NHC(O)R 4E4 、–NHC(O)OC 1-6 Alkylene-C 6-12 Aryl, C 3-6 Cycloalkyl or C 6-12 aryl, and each R 4E4 The groups are independently C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4E1 Can be optionally replaced by 1 R 4E3 C 1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each R 4E3 The groups are independently -C(O)OR 4E4 、-NH2、–NHC(O)R 4E4 , –NHC(O)O-benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, and each R 4E4 The groups are independently methyl, ethyl, isopropyl, n-butyl or isobutyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R E1 It can be methyl, ethyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl or benzyl, wherein the methyl, ethyl and butyl groups are each optionally substituted with -NH2, -NHC(O)Me, -NHC(O)O-benzyl, -C(O)O-butyl, -C(O)O-pentyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4E1 It may be methyl.

[0261] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G may be optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, where each R 4G1 are independently -OH, C 1-6 Alkyl, C 1-3 Alkoxy, -(CH2OCH2) 1-5 -CH3、C 1-3 Haloalkyl, -N(R 4G8 )2、-C(O)N(R 4G8 ) 2. optionally 1 to 3 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G10 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or C 6-12 Aryl; each R 4G8 are independently H or C 1-6 Alkyl; each R 4G9 Independently C 1-6 Alkyl, halogen, C 1-3 haloalkyl or -NH2; and each R 4G10 Independently C 1-6 Alkyl, C 1-3 a haloalkyl group or an oxo group.

[0262] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G Can be

[0263] methyl, cyclopropyl, cyclobutyl, cyclohexyl, piperidine, quinuclidine, oxetane, tetrahydro-2H-pyran or phenyl optionally substituted with -(CH2OCH2)2-CH3, optionally substituted with CF3 or NH2,

[0264] ethyl optionally substituted by NMe2 or N(iPr)2,

[0265] n-propyl optionally substituted by methoxy or morpholine,

[0266] isopropyl optionally substituted by C(O)NH2,

[0267] n-Butyl,

[0268] isobutyl optionally substituted by methoxy, OH or CF3,

[0269] Pentyl, neopentyl, hexyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl or 2-ethyl-butyl.

[0270] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, neopentyl, hexyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl,

[0271]

[0272] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G Can be C 7-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G Can be heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl or octadecyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G It may be octyl, dodecyl, hexadecyl or octadecyl.

[0273] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G may be optionally replaced by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, wherein each R 4G2 Independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-3 Haloalkyl, -OH, -NH2 or C 6-12In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G may be optionally replaced by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, wherein each R 4G2 and independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, F, Cl, -CH2F, -CHF2, -CF3, -CH2CF3, -NH2 or phenyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, each optionally substituted by 1 to 2 R 4G2 Substitute, where each R 4G2 are independently methyl, tert-butyl, methoxy, F, -CF3, -NH2 or phenyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G It can be cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, wherein the cyclohexyl group can be optionally replaced by 1 to 2 R 4G2 Substitute, where each R 4G2 are independently methyl, tert-butyl, methoxy, F, -CF3, -NH2 or phenyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G It can be cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0274]

[0275] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G may be optionally replaced by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, wherein each R 4G3 Independently C 1-6 Alkyl, halogen, C1-3 Haloalkyl, oxo, -C(O)R 4G5 or-C(O)OR 4G5 .

[0276] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G can be pyrrolidine, piperidine, azepane, quinuclidine, oxetane, tetrahydrofuran, tetrahydropyran, piperazine or morpholine, each optionally substituted with 1 to 3 R 4G3 Substitute, where each R 4G3 Independently C 1-6 Alkyl, halogen, C 1-3 Haloalkyl, oxo, -C(O)R 4G5 or-C(O)OR 4G5 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G can be pyrrolidine, piperidine, azepane, quinuclidine, oxetane, tetrahydrofuran, tetrahydropyran, piperazine or morpholine, each optionally substituted with 1 to 3 R 4G3 Substitute, where each R 4G3 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, F, Cl, -CH2F, -CHF2, -CF3, -CH2CF3, oxo, -C(O)Me or -C(O)OC 1-4 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G can be pyrrolidine, piperidine, azepane, quinuclidine, oxetane, tetrahydrofuran, tetrahydropyran or morpholine, each optionally substituted with 1 to 3 R 4G3 Substitute, where each R 4G3 is independently methyl, ethyl, F, -CH2CF3, oxo, -C(O)Me or -C(O)O-tert-butyl.

[0277] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4GIt can be pyrrolidine optionally substituted with methyl, oxo, -C(O)Me or -C(O)O-tert-butyl; piperidine optionally substituted with methyl, ethyl, F or -C(O)Me; azepane; quinuclidine; oxetane; tetrahydrofuran optionally substituted with methyl; tetrahydropyran optionally substituted with methyl; or morpholine. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G It can be:

[0278]

[0279] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G Can be -C(O)R 4G4 , where each R 4G4 Independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally replaced by OH, NH2 or -NHC(O)OR 4G5 substituted, and wherein the cycloalkyl group is optionally replaced by C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G Can be -C(O)R 4G4 , where each R 4G4 is independently methyl, ethyl optionally substituted with NH2, n-propyl, isopropyl, n-butyl, isobutyl optionally substituted with NH2 or -NHC(O)O-tert-butyl, sec-butyl, tert-butyl optionally substituted with OH, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, octadecyl, cyclopropyl optionally substituted with methyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G Can be -C(O)R 4G4 , where each R 4G4is independently ethyl optionally substituted with NH2, isobutyl optionally substituted with NH2 or -NHC(O)O-tert-butyl, tert-butyl optionally substituted with OH, undecyl, cyclopropyl optionally substituted with methyl, or cyclohexyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G Can be

[0280]

[0281] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G Can be -C(O)OR 4G5 , where each R 4G5 Independently C 1-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G5 Can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G5 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G It can be:

[0282]

[0283] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G Can be

[0284]

[0285] where R 4G6 and R 4G7 Each independently is H or –OR 4G11 , where R 4G6and R 4G7 At least one of -OR 4G11 ; and each R 4G11 Independently C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G6 Can be H and R 4G7 Can be –OR 4G11 , where R 4G11 Can be C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G6 and R 4G7 Each independently is –OR 4G11 , where each R 4G11 Independently C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G It can be:

[0286]

[0287] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them can be -(OP(O)(OH)) 1-2 -OH.

[0288] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C One of them can be

[0289]

[0290] where R 4J1 and R 4J2 Each independently represents H, –OR 4J3 or –OC(O)R 4J3 , where R4J1 and R 4J2 At least one of -OR 4J3 or –OC(O)R 4J3 , each R 4J3 Independently C 1-18 Alkyl, C 2-6 alkenyl or benzyl, and at least one R 4J3 C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 Can be H and R 4J2 Can be –OR 4J3 or –OC(O)R 4J3 , where each R 4J3 Independently C 1-18 Alkyl, C 2-6 alkenyl or benzyl, and at least one R 4J3 C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 and R 4J2 Each independently is –OR 4J3 or –OC(O)R 4J3 , where each R 4J3 Independently C 1-18 Alkyl, C 2-6 alkenyl or benzyl, and at least one R 4J3 C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 Can be –OR 4J3 , where R 4J3 Can be C 1-6 Alkyl, C 2-6 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 Can be –OR 4J3 , where R 4J3Can be methyl, ethyl, n-propyl, isopropyl, prop-2-enyl, but-2-enyl, but-3-enyl or benzyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 Can be –OR 4J3 , where R 4J3 Can be methyl, prop-2-enyl or benzyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J2 Can be –OR 4J3 , where R 4J3 Can be C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J2 Can be –OR 4J3 , where R 4J3 Can be dodecyl, undecyl, dodecyl, hexadecyl or octadecyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J2 Can be –OR 4J3 , where R 4J3 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4J1 and R 4J2 Each is –OC(O)R 4J3 , where R 4J3 C 10-18 In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 and R 4J2 Each is –OC(O)R 4J3 , where R 4J3Can be dodecyl, undecyl, dodecyl, pentadecyl, hexadecyl or octadecyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4J1 and R 4J2 Each is –OC(O)R 4J3 , where R 4J3 It may be a pentadecyl group.

[0291] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B and R 4C Each independently is:

[0292] in

[0293] The subscript m is 0, 1, 2, 3, 4, or 5; and each R 4D is independently optionally replaced by 1 to 3 R 4D1 C 1-6 Alkyl, optionally substituted by 1 to 3 R 4D2 C 1-3 Alkoxy, –C(O)OR 4D3 or -C(O)N(R 4D3 )2, where each R 4D1 The groups are independently -NH2 or -C(O)OMe, and each R 4D2 is a methoxy group, and each R 4D3 are independently methyl or ethyl; or

[0294] in

[0295] X 1 and X 2 Each is independently -O- or -NH-;

[0296] R 4E1 is optionally replaced by 1 R 4E3 C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein each R 4E3 The groups are independently -C(O)Me, -C(O)O-n-butyl, -C(O)O-pentyl, -NH2, -NHC(O)Me, -NHC(O)O-benzyl, C 3-6 Cycloalkyl or phenyl;

[0297] R4E2 H; or R 4E1 and R 4E2 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0298] R 4F1 and R 4F2 Each is H or together is oxo;

[0299] R 4G is optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, C 7-18 Alkyl, optionally substituted by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, -C(O)R 4G4 、-C(O)OR 4G5 ,or

[0300]

[0301] Each R 4G1 are independently -OH, hydroxymethyl, methoxy, -(CH2OCH2)2-CH3, -CF3, -N(Me)2, -C(O)NH2, optionally substituted by 1 to 2 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 2 R 4G10 a substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or a phenyl group;

[0302] Each R 4G2 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, F, Cl, Br, CF3, -NH2 or phenyl;

[0303] Each R 4G3 are independently methyl, ethyl, F, Cl, CF3, CH2CF3, oxo, -C(O)Me or -C(O)O-tert-butyl;

[0304] Each R 4G4 Independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with OH, NH2 or -NHC(O)O-tert-butyl, and wherein the cycloalkyl group is optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0305] Each R 4G5 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0306] R 4G6 and R 4G7 Each independently is H or –OR 4G11 , where R 4G6 and R 4G7 At least one of -OR 4G11 ;

[0307] Each R 4G9 are independently methyl, CF3 or -NH2;

[0308] Each R 4G10 are independently methyl, CF3, CH2CF3 or oxo; and

[0309] Each R 4G11 is independently hexadecane, octadecane or benzyl.

[0310] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4C It can be:

[0311] (D) in

[0312] X 1 and X 2 Each is independently -O- or -NH-;

[0313] R 4E1 is optionally replaced by 1 R 4E3 C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein each R 4E3 The groups are independently -C(O)Me, -C(O)O-n-butyl, -C(O)O-pentyl, -NH2, -NHC(O)Me, -NHC(O)O-benzyl, C 3-6 Cycloalkyl or phenyl;

[0314] R 4E2 H; or R 4E1 and R 4E2 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl;

[0315] R 4F1 and R 4F2 Each of them is H or together they are oxo;

[0316] R 4G is optionally replaced by 1 to 3 R 4G1 Substituted C 1-6 Alkyl, C 7-18 Alkyl, optionally substituted by 1 to 3 R 4G2 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 3 R 4G3 substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, -C(O)R 4G4 、-C(O)OR 4G5 ,or

[0317]

[0318] Each R 4G1 are independently -OH, hydroxymethyl, methoxy, -(CH2OCH2)2-CH3, -CF3, -N(Me)2, -C(O)NH2, optionally substituted by 1 to 2 R 4G9 Substituted C 3-8 Cycloalkyl, optionally substituted by 1 to 2 R 4G10 a substituted 3- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, or a phenyl group;

[0319] Each R 4G2 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, F, Cl, Br, CF3, -NH2 or phenyl;

[0320] Each R 4G3 are independently methyl, ethyl, F, Cl, CF3, CH2CF3, oxo, -C(O)Me or -C(O)O-tert-butyl;

[0321] Each R 4G4 Independently C 1-6 Alkyl, C 7-18 Alkyl or C 3-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with OH, NH2 or -NHC(O)O-tert-butyl, and wherein the cycloalkyl group is optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0322] Each R 4G5 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0323] R 4G6 and R 4G7 Each independently is H or –OR 4G11, where R 4G6 and R 4G7 At least one of -OR 4G11 ;

[0324] Each R 4G9 are independently methyl, CF3 or -NH2;

[0325] Each R 4G10 are independently methyl, CF3, CH2CF3 or oxo; and

[0326] Each R 4G11 is independently hexadecane, octadecane or benzyl.

[0327] In some embodiments, the compound has Formula (Ib):

[0328]

[0329] or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments, the compound has Formula Ic:

[0331]

[0332] or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B It can be:

[0334]

[0335] where the subscript m is 1; and

[0336] R 4D is independently methyl, ethyl, n-propyl or tert-butyl, each optionally substituted by 1 to 3 R 4D1 group substituted, where each R 4D1 The groups are independently -NH2 or -C(O)OMe, or

[0337] R 4D is methoxy, ethoxy or propoxy, each optionally substituted by methoxy, or

[0338] R 4D is –C(O)OMe, –C(O)OEt or –C(O)N(Me)2; and

[0339] R 4C It can be:

[0340]

[0341] where R 4E1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentane, neopentane or n-hexane, each optionally substituted by one R 4E3 group substituted, where each R 4E3 The groups are independently -C(O)Me, -C(O)O-n-butyl, -C(O)O-pentyl, -NH2, -NHC(O)Me or -NHC(O)O-benzyl, or

[0342] R 4E1 is cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl or cyclohexylmethyl, or

[0343] R 4E1 It is benzyl.

[0344] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4B Can be

[0345] and

[0346] R 4C Can be

[0347]

[0348] where R E1 may be methyl, ethyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, or benzyl, wherein the methyl, ethyl, and butyl groups are each optionally substituted with —NH , —NHC(O)Me, —NHC(O)O-benzyl, —C(O)O-butyl, or —C(O)O-pentyl; and

[0349] R 4G Methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, neopentyl, hexyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, octyl, dodecyl, hexadecyl, octadecyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0350]

[0351]

[0352] In some embodiments, the compound has Formula (Id):

[0353]

[0354] or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the compound has Formula (Ie):

[0356]

[0357] or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the compound has Formula (If):

[0359]

[0360] or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the compound has Formula (Ig):

[0362]

[0363] or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the compound has Formula (Ih):

[0365]

[0366] or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the compound has Formula (Ii):

[0368]

[0369] or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is the compound, wherein R 4C for:

[0371]

[0372] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is the compound, wherein R4C for:

[0373]

[0374] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentane, neopentane, n-hexane, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, heptane, octane, nonane, decane, undecane, dodecane, pentadecane, hexadecane or octadecane, each optionally substituted with 1 to 2 R 4G1 Substitute, where each R 4G1 are independently -OH, hydroxymethyl, methoxy, -(CH2OCH2)2-CH3, -CF3, -N(Me)2 or -C(O)NH2.

[0375] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, each optionally substituted by 1 to 2 R 4G2 Substitute, where each R 4G2 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, OMe, F, CF3, -NH2 or phenyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl or cyclooctylmethyl, each optionally substituted by 1 to 2 R 4G2 Substitute, where each R 4G2 is independently methyl, CF3 or –NH2.

[0376] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G is pyrrolidine, piperidine, azepane, quinuclidine, oxetane, tetrahydrofuran, tetrahydropyran, morpholine or 1,3-dioxole, each optionally substituted with 1 to 2 R 4G3 Substitute, where each R4G3 are independently methyl, ethyl, F, CH2CF3, oxo, -C(O)Me or -C(O)O-tert-butyl. In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, wherein R 4G is piperidinylmethyl, quinuclidinemethyl, oxetanemethyl, tetrahydrofurylmethyl, tetrahydropyranylmethyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 1,3-dioxolylmethyl, each optionally substituted by 1 to 2 R 4G10 Substitute, where each R 4G10 are independently methyl, CH2CF3 or oxo.

[0377] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G It is benzyl.

[0378] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G -C(O)R 4G4 , where R 4G4 C is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentane, neopentane, n-hexane, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethyl-butyl 1-6 Alkyl; C selected from the group consisting of heptane, octane, nonane, decane, undecane, dodecane, pentadecane, hexadecane and octadecane 7-18 Alkyl; or C selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl 3-8 Cycloalkyl, wherein each C 1-6 The alkyl group is optionally substituted with OH, NH2 or -NHC(O)O-tert-butyl, and wherein each C 3-8 The cycloalkyl group is optionally substituted with methyl.

[0379] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G -C(O)OR 4G5 , where R 4G5is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0380] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G for

[0381] in

[0382] R 4G6 and R 4G7 Each independently is H or –OR 4G11 ,in

[0383] R 4G6 and R 4G7 At least one of -OR 4G11 ,and

[0384] Each R 4G11 is independently hexadecane, octadecane or benzyl.

[0385] In some embodiments, the compound can be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, wherein R 4G Methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, neopentyl, hexyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl, octyl, dodecyl, hexadecyl, octadecyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0386]

[0387]

[0388]

[0389] In some embodiments, the present disclosure provides a compound of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table II, or Table 1J, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1C, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1D, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1E, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1F, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1G, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1H, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table II, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Table 1J, or a pharmaceutically acceptable salt thereof.

[0390] Table 1A.

[0391]

[0392]

[0393]

[0394]

[0395]

[0396] Table 1B.

[0397]

[0398]

[0399]

[0400]

[0401]

[0402] Table 1C.

[0403]

[0404]

[0405]

[0406]

[0407]

[0408] Table 1D.

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416] Table 1E.

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423] Table 1F.

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] Table 1G.

[0430]

[0431]

[0432]

[0433]

[0434]

[0435] Table 1H.

[0436]

[0437]

[0438]

[0439]

[0440]

[0441] Table 1I.

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448] Table 1J.

[0449]

[0450]

[0451]

[0452]

[0453]

[0454] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof has the following structure:

[0455]

[0456]

[0457] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof has the following structure:

[0458]

[0459]

[0460]

[0461] In some embodiments, with the proviso that when the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) has the formula:

[0462]

[0463] And R 4G is ethyl or 2-ethylbutyl, then R 1 and R 2 One of them is -C(O)R 1A , or R 1 and R 2 Combine to form –C(O)- or –C(R 2A )(R 2B In some embodiments, the compound may be represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not:

[0464]

[0465] Also within the scope of this disclosure are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious relative to the prior art. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, novel and unobvious compounds produced by a method comprising contacting a compound with a mammal for a period of time sufficient to produce its metabolic products are included. Such products are typically identified by the following procedures: preparing a radiolabeled (e.g., 14 C or 3H) Compounds are administered parenterally to animals (such as rats, mice, guinea pigs, monkeys) or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), sufficient time is allowed for metabolism (usually about 30 seconds to 30 hours), and their conversion products are isolated from urine, blood, or other biological samples. These products are easily isolated because they are labeled (other products are isolated by using antibodies that can bind to epitopes that survive in the metabolites). The metabolite structures are determined in a conventional manner (e.g., by MS or NMR analysis). In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies. Conversion products can be used for diagnostic determination of therapeutic doses of compounds, even if they do not themselves have HSV antiviral activity, as long as they are not otherwise found in vivo.

[0466] Formulas and methods for determining the stability of compounds in alternative gastrointestinal secretions are known. Compounds are defined herein as being stable in the gastrointestinal tract, wherein less than about 50 mol % of the protecting groups are deprotected in alternative intestinal or gastric fluids after incubation at 37°C for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. Prodrugs are generally stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive cavity, liver, lungs or other metabolic organs or generally speaking in cells. As used herein, prodrugs are understood to be compounds that are chemically designed to effectively release the parent drug after overcoming the oral delivery biological barrier.

[0467] IV. Pharmaceutical Preparations

[0468] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. Also provided herein is a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt, solvate, and / or ester thereof, and a pharmaceutically acceptable carrier or excipient.

[0469] The compounds herein are formulated with conventional carriers and excipients, which are selected according to conventional practice. Tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared in a sterile form and, when intended for delivery by non-oral administration, will generally be isotonic. All formulations will optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrins, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. The pH range of the formulation is from about 3 to about 11, but is typically from about 7 to 10.

[0470] Although the active ingredients can be administered alone, it may be preferable to provide them as pharmaceutical formulations. Formulations for both veterinary and human use comprise at least one active ingredient as defined above, together with one or more acceptable carriers and optionally other therapeutic ingredients, especially those additional therapeutic ingredients as discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not physiologically deleterious to the recipient thereof.

[0471] Preparations include those suitable for the aforementioned routes of administration. Preparations can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical field. Techniques and preparations are generally found in "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally speaking, the preparation is prepared by uniformly and closely associating the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, shaping the product.

[0472] Formulations suitable for oral administration may be provided as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a pill, electuary, or paste.

[0473] Tablet is made by compression or molding, optionally using one or more auxiliary ingredients.Compressed tablets can be prepared by compressing the active ingredient of free-flowing form (such as powdered or granular) in a suitable machine, optionally mixed with binding agent, lubricant, inert diluent, preservative, surfactant or dispersant.Moulded tablets can be prepared by molding the mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine.Tablet can optionally be coated or scored, and is optionally formulated to provide active ingredient therefrom slowly or controlled release.

[0474] For infections of the eye or other external tissues (e.g., mouth and skin), the formulation is preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075% w / w to 20% w / w (including active ingredients in a range between 0.1% and 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2% w / w to 15% w / w, and most preferably 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredient may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base.

[0475] If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0476] The oil phase of the emulsion can be composed of known ingredients in a known manner. Although this phase can include only an emulsifier (or simply an emulsifier), it ideally includes a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. The emulsifier, with or without a stabilizer, together constitutes the so-called emulsifying wax, and the wax, together with the oil and fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0477] Emulsifiers and emulsion stabilizers suitable for use in formulations include 60. 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0478] The present invention provides the present invention and the cosmetics that can be used for the preparation of the present invention.Based on realizing the required cosmetic properties for preparation, select suitable oil or fat.Emulsifiable paste should preferably be non-greasy, non-staining and washable product, has suitable density to avoid leaking from pipe or other containers.Can use straight or branched monoalkyl ester or dialkyl ester, such as propylene glycol diester of diisoadipate, isohexadecanedioate, coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitic acid-2-ethylhexyl ester or the mixture of the branched ester called Crodamol CAP, last three kinds are preferred esters.These esters can be used alone or in combination, specifically depending on required characteristics.Alternatively, use high melting point lipid, such as white soft paraffin and / or liquid paraffin or other mineral oils.

[0479] The pharmaceutical formulations herein comprise a combination of one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorants, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients may include, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.

[0480] Formulations for oral use may also be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0481] Aqueous suspensions contain active substances mixed with excipients suitable for making aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and gum arabic; and dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl parahydroxybenzoate or n-propyl parahydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0482] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil), or by suspending it in a mineral oil (such as liquid paraffin). Oral suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners (such as those mentioned above) and flavorings can be added to provide a palatable oral formulation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

[0483] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0484] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth; naturally occurring phospholipids such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavorings. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such preparations can also contain a demulcent, a preservative, a flavoring, or a coloring agent.

[0485] The pharmaceutical composition can be in the form of a sterile injectable or intravenous preparation, such as a sterile injectable aqueous or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injectable or intravenous preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent (such as a solution in 1,3-butanediol), or be prepared as a lyophilized powder. Acceptable solvents and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can generally be used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0486] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a sustained-release formulation intended for oral administration to a human can contain approximately 1 mg to 1000 mg of active material, compounded with an appropriate and convenient amount of carrier material, which can vary between about 5% to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable dosage. For example, an aqueous solution intended for intravenous infusion can contain approximately 3 to 500 μg of active ingredient per milliliter of solution to infuse a suitable volume at a rate of about 30 mL / hr.

[0487] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and especially about 1.5% w / w.

[0488] Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored form, usually sucrose and acacia or tragacanth; lozenges containing an inert active ingredient, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0489] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0490] Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size in the range of 0.1 micron to 500 microns (such as 0.5 micron, 1 micron, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents, such as compounds used to date for the treatment or prevention of Pneumoviridae infections, as described below.

[0491] Another embodiment provides a novel, effective, safe, non-irritating and physiologically compatible inhalable composition comprising a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) or a pharmaceutically acceptable salt thereof, which is suitable for treating Pneumoviridae infections and potentially associated bronchiolitis. Preferred pharmaceutically acceptable salts are inorganic acid salts, including hydrochlorides, hydrobromides, sulfates or phosphates, as they may cause less lung irritation. Preferably, the inhalable formulation is delivered to the endobronchial space in the form of an aerosol comprising particles having a mass median aerodynamic diameter (MMAD) between about 1 μm and 5 μm. Preferably, the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is formulated for aerosol delivery using a nebulizer, a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI).

[0492] Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers, including those utilizing adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Suppl 1, S1-S10). Jet nebulizers utilize air pressure to break up a liquid solution into aerosol droplets. Ultrasonic nebulizers operate by using piezoelectric crystals that shear a liquid into small aerosol droplets. Pressurized nebulization systems force a solution through a small orifice under pressure to produce aerosol droplets. Vibrating porous plate devices utilize rapid vibrations to shear a liquid stream into an appropriate droplet size.

[0493] In a preferred embodiment, the formulation for aerosolization is delivered to the endobronchial space as an aerosol comprising particles having an MMAD predominantly between about 1 μm and 5 μm using a nebulizer capable of aerosolizing a formulation of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) into particles of the desired MMAD. For optimal therapeutic efficacy and to avoid upper respiratory tract and systemic side effects, the majority of the sprayed particles should not have an MMAD greater than about 5 μm. If the aerosol contains a large number of particles having an MMAD greater than 5 μm, the particles are deposited in the upper airways, thereby reducing the amount of drug delivered to sites of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is less than about 1 μm, the particles tend to remain suspended in the inhaled air and are subsequently exhaled during exhalation.

[0494] When formulated and delivered according to the methods herein, aerosol formulations for nebulization deliver a therapeutically effective dose of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) sufficient to treat a Pneumoviridae infection to the site of the Pneumoviridae infection. The amount of drug administered must be adjusted to reflect the delivery efficiency of the therapeutically effective dose of the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii). In a preferred embodiment, the combination of an aqueous aerosol formulation with a nebulizing nebulizer, a jet nebulizer, a pressurized nebulizer, a vibrating porous plate nebulizer, or an ultrasonic nebulizer allows, depending on the nebulizer, about at least 20% to about 90%, typically about 70%, of the administered dose of the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) to be delivered to the airways. In a preferred embodiment, at least about 30% to about 50% of the active compound is delivered. More preferably, about 70% to about 90% of the active compound is delivered.

[0495] In another embodiment, the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii), or a pharmaceutically acceptable salt thereof, is delivered as a dry, inhalable powder. The compound is typically administered intrabronchially as a dry powder formulation to effectively deliver fine particles of the compound to the endobronchial space using a dry powder or metered dose inhaler. For delivery by DPI, the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is processed into particles having an MMAD primarily between about 1 μm and about 5 μm by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling, and spray drying apparatus and procedures capable of producing particle sizes having an MMAD between about 1 μm and about 5 μm are well known in the art. In one embodiment, an excipient is added to the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) prior to processing into particles of the desired size. In another embodiment, an excipient is blended with particles of the desired size to aid in the dispersion of the drug particles, for example, by using lactose as an excipient.

[0496] Particle size determination is performed using apparatus well known in the art, for example, the Anderson multi-stage cascade impactor or other suitable methods (such as those specifically cited in USP Chapter 601) as a characterization apparatus for aerosols in metered doses and dry powder inhalers.

[0497] In another preferred embodiment, the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) is delivered in dry powder form using a device such as a dry powder inhaler or other dry powder dispersion device. Non-limiting examples of dry powder inhalers and devices include those disclosed in US5,458,135; US5,740,794; US5775320; US5,785,049; US3,906,950; US4,013,075; US4,069,819; US4,995,385; US5,522,385; US4,668,218; US4,667,668; US4,805,811 and US5,388,572. There are two main designs of dry powder inhalers. One design is a metering device, in which a reservoir for the drug is placed in the device, and the patient adds the drug dose to the inhalation chamber. The second design is a factory metering device, in which each individual dose is manufactured in a separate container. Both systems depend on the drug being formulated into small particles with an MMAD of 1 μm to about 5 μm, and often involve co-preparation with larger excipient particles (such as, but not limited to, lactose). The drug powder is placed in the inhalation chamber (by device metering or by crushing factory metered doses), and the patient's inhalation flow accelerates the powder out of the device and into the oral cavity. The non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes them to become embedded in the back of the throat, while the smaller drug particles are deeply deposited in the lungs. In a preferred embodiment, a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, is delivered in dry powder form using any type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, excluding any excipients, is primarily in the range of 1 μm to about 5 μm.

[0498] In another embodiment, the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) is delivered in dry powder form using a metered dose inhaler. Non-limiting examples of metered dose inhalers and devices include those disclosed in US Pat. Nos. 5,261,538, 5,544,647, 5,622,163, 4,955,371, 3,565,070, 3,361,306, and 6,116,234. In a preferred embodiment, the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii), or a pharmaceutically acceptable salt thereof, is delivered in dry powder form using a metered dose inhaler, wherein the MMAD of the dry powder, excluding any excipients, is primarily in the range of about 1 μm to 5 μm.

[0499] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0500] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0501] The preparation is present in unit dose or multidose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injections and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned type. Preferred unit dose formulations are formulations containing a daily dose or unit daily subdose of the active ingredient as described above, or an appropriate fraction thereof.

[0502] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0503] There is further provided a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier thereof.

[0504] Veterinary carriers are materials useful for administering the composition and can be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

[0505] The compounds herein are useful in providing controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds as active ingredients, wherein the release of the active ingredient is controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0506] The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (lower doses) or against active viral infection, the method of delivery and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. The dose can be expected to be about 0.0001 to about 100 mg / kg body weight per day; typically, about 0.01 to about 10 mg / kg body weight per day; more typically, about 0.01 to about 5 mg / kg body weight per day; most typically, about 0.05 to about 0.5 mg / kg body weight per day. For example, a candidate daily dose range for an adult weighing approximately 70 kg would be 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can be in the form of a single dose or multiple doses.

[0507] V. Route of Administration

[0508] One or more of the compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) (referred to herein as the active ingredient) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), among others. It will be appreciated that the preferred route may vary depending, for example, on the condition of the recipient.

[0509] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc. It will be understood that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0510] The compounds of the present disclosure can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compounds are administered on a daily or intermittent schedule during the life of the individual.

[0511] The dosage or frequency of administration of the compounds of the present disclosure may be adjusted during the course of treatment according to the judgment of the administering physician.

[0512] The compound can be administered to an individual (eg, a human) in an effective amount. In certain embodiments, the compound is administered once daily.

[0513] Compound can be used by any available approach and means, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of compound can include about 0.00001mg / kg body weight to about 10mg / kg body weight every day, such as about 0.0001mg / kg body weight to about 10mg / kg body weight every day, or such as about 0.001mg / kg body weight to about 1mg / kg body weight every day, or such as about 0.01mg / kg body weight to about 1mg / kg body weight every day, or such as about 0.05mg / kg body weight to about 0.5mg / kg body weight every day, or such as about 0.3mg to about 30mg every day, or such as about 30mg to about 300mg every day.

[0514] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dose of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of compound). A therapeutically effective amount can include from about 1 mg / dose to about 1000 mg / dose, such as from about 50 mg / dose to about 500 mg / dose, or such as from about 100 mg / dose to about 400 mg / dose, or such as from about 150 mg / dose to about 350 mg / dose, or such as from about 200 mg / dose to about 300 mg / dose. Other therapeutically effective amounts of a compound of the present disclosure are about 100 mg / dose, about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 325 mg / dose, about 350 mg / dose, about 375 mg / dose, about 400 mg / dose, about 425 mg / dose, about 450 mg / dose, about 475 mg / dose, or about 500 mg / dose. Other therapeutically effective amounts of compounds of the present disclosure are about 100 mg / dose, or about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 350 mg / dose, about 400 mg / dose, about 450 mg / dose, or about 500 mg / dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once a week. A single dose can also be administered once a month.

[0515] Other therapeutically effective amounts of a compound of the present disclosure are about 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose.

[0516] The frequency of the dosage of the compound of the present disclosure will be determined by the needs of the individual patient, and can be, for example, once a day or twice a day or more. As long as the treatment of viral infection requires, the administration of the compound is continued. For example, the compound can be administered to a person infected by the virus for a period of 20 to 180 days, or for example, a period of 20 to 90 days, or for example, a period of 30 to 60 days.

[0517] Administration can be intermittent, and the patient receives the compound of the present disclosure of daily dose in the time period of a few days or more days, and the patient does not receive the compound of daily dose in the time period of a few days or more days afterwards.For example, the patient can receive a certain dose of compound every other day or three times a week.Again by way of example, the patient can receive a certain dose of compound every day in the time period of 1 to 14 days, then in the time period of 7 to 21 days, the patient does not receive a certain dose of compound, then in the subsequent time period (for example, 1 to 14 days), the patient again receives a certain daily dose of compound.According to clinical needs, the compound can be repeatedly administered, the alternating time period of not administering compound afterwards is treated patient.

[0518] In one embodiment, pharmaceutical compositions are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents and a pharmaceutically acceptable excipient.

[0519] In one embodiment, kits are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0520] In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0521] In certain embodiments, when the compounds of the present disclosure are combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0522] In certain embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid dosage form for oral administration.

[0523] In certain embodiments, compounds of the present disclosure are co-administered with one or more additional therapeutic agents.

[0524] In order to prolong the effect of the compounds of the present invention, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable long-acting forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Long-acting injectable formulations are also prepared by embedding the compound in liposomes or microemulsions compatible with body tissues.

[0525] VI. Combination Therapy

[0526] The compounds and compositions of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) provided herein are also useful in combination with other active therapeutic agents for the treatment of viral infections, such as Pneumoviridae, Picornaviridae, Flaviviridae, or Filoviridae viral infections.

[0527] Combination therapy for the treatment of pneumoviridae

[0528] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In order to treat Pneumoviridae virus infection, preferably, the other active therapeutic agent is active against Pneumoviridae virus infection, particularly respiratory syncytial virus infection and / or metapneumovirus infection. Non-limiting examples of these other active therapeutic agents active against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; viral replication inhibitors such as nitazoxanide.

[0529] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDIδM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0530] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators, such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for treating metapneumovirus infection, such as EV-046113.

[0531] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0532] Combination therapy for the treatment of picornaviruses

[0533] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In order to treat Picornaviridae virus infection, preferably, other active therapeutic agents are active for Picornaviridae virus infection, particularly enterovirus infection. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors, such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins, such as DAS-181; capsid protein VP1 inhibitors, such as VVX-003 and AZN-001; viral protease inhibitors, such as CW-33; phosphatidylinositol 4 kinase beta inhibitors, such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0534] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing infection by a Picornaviridae virus, including but not limited to EV71 vaccine, TAK-021, and EV-D68 adeno-based vaccines.

[0535] Combination therapy for respiratory infections

[0536] Many infections with Pneumoviridae and Picornaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents for treating respiratory symptoms and sequelae of infection can be used in combination with the compounds provided herein. The additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for treating viral respiratory infections in combination with the compounds provided herein include, but are not limited to, bronchodilators and corticosteroids.

[0537] Glucocorticoids

[0538] Glucocorticoids (Carryer, Journal of Allergy, 21, 282-287, 1950), first introduced as asthma therapy in 1950, remain the most effective and persistent therapy for this disease, but their mechanism of action is not yet fully understood (Morris, J.Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects, such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to alleviate the serious adverse effects of oral steroids. Non-limiting examples of corticosteroids that can be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone acetonide, fluocinolone acetonide, flunisolide, fluocortidine-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or pharmaceutically acceptable salts thereof.

[0539] anti-inflammatory agents

[0540] Other anti-inflammatory agents that work by anti-inflammatory cascade mechanisms also can be used as additional therapeutic agents for the treatment of viral respiratory infections in combination with compound provided herein. Application of " anti-inflammatory signal transduction regulators " (referred to herein as AISM) such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5 or PDE-7 specificity), transcription factor inhibitors (e.g., by IKK inhibition blocking NFκB) or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach to cut off inflammation because these small molecules target a limited number of common intracellular pathways (these signal transduction pathways are key points for anti-inflammatory treatment intervention) (see PJBarnes, 2006 review).These non-limiting additional therapeutic agents include: 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)- )amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methylsulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylaminoethyl ester (Cilomilast ( Cilomilast), a 2-diethyl-ethyl ester prodrug of a PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (Gefitinib, an EGFR inhibitor); and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (Imatinib, an EGFR inhibitor).

[0541] β2-adrenergic receptor agonist bronchodilator

[0542] Combinations comprising an inhaled β2-adrenergic receptor agonist bronchodilator such as formoterol, albuterol, or salmeterol and a compound provided herein are also suitable, but non-limiting, combinations useful in treating respiratory viral infections.

[0543] Combinations of inhaled β2-adrenergic agonist bronchodilators (such as formoterol or salmeterol) and ICS are also used to treat bronchoconstriction and inflammation (respectively and Combinations comprising these ICS and β2-adrenergic receptor agonist combinations and the compounds provided herein are also suitable, but non-limiting, combinations useful for treating respiratory viral infections.

[0544] Other examples of β2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abetrol, salmeterol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0545] Anticholinergics

[0546] For the treatment or prevention of pulmonary bronchoconstriction, anticholinergic agents have potential uses and can therefore be used as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergics include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype) that have shown therapeutic efficacy in humans for the control of cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate); 1-cyclohexyl-3, 4-Dihydro-1H-isoquinoline-2-carboxylic acid-1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin); 2-Hydroxymethyl-4-methylsulfinyl-2-phenyl-butyric acid-1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (Darifenacin); 4-Azacycloheptan-1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (octopium bromide-N,N-diethylglycinate); 7-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (tiotropium bromide-N,N-diethylglycinate); dimethylamino-acetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethyl 1-phenyl-3-nitroprop-2-yne-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2] Octane (Aclidinium bromide-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; refenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, bencycloquidium bromide.

[0547] mucolytics

[0548] The compounds provided herein and the compositions provided herein can also be combined with mucolytics to treat symptoms of infection and respiratory tract infection. A non-limiting example of a mucolytic is ambroxol. Similarly, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) can be combined with an expectorant to treat symptoms of infection and respiratory tract infection. A non-limiting example of an expectorant is guaifenesin.

[0549] Nebulized hypertonic saline is used to improve immediate and long-term clearance of the small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein may also be combined with nebulized hypertonic saline, particularly when Pneumoviridae viral infection is complicated by bronchiolitis. The combination of a compound of Formula (I) or Formula (II) with hypertonic saline may also include any of the additional agents described above. In one embodiment, about 3% nebulized hypertonic saline is used.

[0550] Combination therapies for treating COPD

[0551] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In order to treat respiratory exacerbations of COPD, other active therapeutic agents include other active agents for COPD. Non-limiting examples of these other active therapeutic agents include anti-IL5 antibodies, such as benralizumab, mepolizumab; dipeptidyl peptidase I (DPP1) inhibitors, such as AZD-7986 (INS-1007); DNA gyrase inhibitors / topoisomerase IV inhibitors, such as ciprofloxacin hydrochloride; MDR-associated protein 4 / phosphodiesterase (PDE) 3 and 4 inhibitors, such as RPL-554; CFTR stimulants, such as ivacaftor, QBW-251; MMP-9 / MMP-12 inhibitors, such as RBx-10017609; adenosine A1 receptor antagonists, such as PBF-680; GATA 3 transcription factor inhibitors, such as SB-010; muscarinic receptor modulators / nicotinic acetylcholine receptor agonists, such as ASM-024; MARCKS protein inhibitors, such as BIO-11006; kit tyrosine kinase / PDGF inhibitors, such as masitinib; phosphodiesterase (PDE) 4 inhibitors, such as roflumilast, CHF-6001; phosphoinositide-3 kinase delta inhibitors, such as nemiralisib; 5-lipoxygenase inhibitors, such as TA-270; muscarinic receptor antagonists / β2 adrenergic receptor agonists, such as fenbuterol succinate, AZD-887, ipratropium bromide; TRN-157; elastase inhibitors, such as erdosteine; metalloproteinase-12 inhibitors, such as FP-025; interleukin-18 ligand inhibitors, such as tadekinig alfa; skeletal muscle troponin activators, such as CK-2127107; p38 MAP kinase inhibitors, such as acumapimod; IL-17 receptor modulators, such as CNTO-6785; CXCR2 chemokine antagonists, such as danirixin; leukocyte elastase inhibitors, such as POL-6014; epoxide hydrolase inhibitors, such as GSK-2256294; HNE inhibitors, such as CHF-6333; VIP agonists, such as aviptadil; phosphoinositide-3 kinase delta / gamma inhibitors, such as RV-1729; complement C3 inhibitors, such as APL-1; and G protein-coupled receptor-44 antagonists, such as AM-211.

[0552] Other non-limiting examples of active therapeutic agents include budesonide, adipocell, nitric oxide, PUR-1800, YLP-001, LT-4001, azithromycin, gamunex, QBKPN, sodium pyruvate, MUL-1867, mannitol, MV-130, MEDI-3506, BI-443651, VR-096, OPK-0018, TEV-48107, doxofylline, TEV-46017, OligoG-COPD-5 / 20, ZP-051, lysine acetylsalicylate.

[0553] In some embodiments, the other active therapeutic agent may be a vaccine active against COPD, including but not limited to MV-130 and GSK-2838497A.

[0554] Combination therapy for the treatment of dengue fever

[0555] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In order to treat Flaviviridae virus infection, preferably, other active therapeutic agents are active against Flaviviridae virus infection, particularly dengue fever infection. Non-limiting examples of these other active therapeutic agents are host cell factor regulators, such as GBV-006; fenretinide ABX-220, BRM-211; α-glucosidase 1 inhibitors, such as celgosivir; platelet-activating factor receptor (PAFR) antagonists, such as modipafant; cadherin-5 / factor Ia regulators, such as FX-06; NS4B inhibitors, such as JNJ-8359; viral RNA splicing regulators, such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR regulators.

[0556] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing dengue fever, including but not limited to TetraVax-DV, DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2delta30-7169; and DENV-1 PIV.

[0557] Combination therapy for Ebola

[0558] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae infections, preferably, the other active therapeutic agents are active against Filoviridae infections, particularly Marburg virus, Ebola virus, and Cueva virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, palivizumab, motavizumab, RSV-IGIV MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)-3-nitropropene]pyrimidine-7-yl)pyrimidine-3,4-diol)

[00145] In some embodiments, the present invention includes but is not limited to: (i) quinolin-3,9-dimethylquinolin-[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cell factor modulators such as GMV-006; cadherin-5 / factor Ia modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0559] Other non-limiting active therapeutic agents active against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 phagocytic non-integrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cell factor modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope protein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0560] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing Ebola, including but not limited to VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0561] Compound and composition provided herein can also be used in conjunction with phosphoramidate morpholino oligomer (PMO) (being designed to disturb the synthetic antisense oligonucleotide analogue of translation process by forming base pair duplex with specific RNA sequence).The example of PMO includes but is not limited to AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002 and AVI-6003.

[0562] The compounds and compositions provided herein are also intended for use with general care provided to patients with Filoviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common diseases in the patient population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or shigellosis vaccines.

[0563] VII. Methods of Treating Viral Infections

[0564] The present disclosure provides methods of using compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) to treat a variety of diseases, such as respiratory syncytial virus (RSV), Ebola, Zika, West Nile, dengue, and HCV.

[0565] Paramyxoviridae

[0566] In some embodiments, the present disclosure provides a method for treating a Paramyxoviridae infection, the method comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual (e.g., a human) infected with a Paramyxoviridae virus. Paramyxoviridae viruses include but are not limited to respiratory syncytial virus (RSV).

[0567] Pneumoviridae

[0568] In some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is human metapneumovirus infection.

[0569] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a person in need thereof, characterized in that a compound of the present disclosure or a pharmaceutically acceptable salt thereof is used. In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Pneumoviridae virus infection in a person. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0570] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a Pneumoviridae viral infection in a human in need thereof. In some embodiments, the Pneumoviridae viral infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae viral infection is a human metapneumovirus infection.

[0571] In certain embodiments, the present disclosure provides a method for treating RSV infection, the method comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual (e.g., a human) infected with respiratory syncytial virus. Typically, the individual suffers from chronic respiratory syncytial virus infection, but treating people with acute RSV infection is also within the scope of the present disclosure.

[0572] In certain embodiments, a method of inhibiting RSV replication is provided, comprising administering to a subject (eg, a human) a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0573] In certain embodiments, the present disclosure provides a method for reducing viral load associated with RSV infection, wherein the method comprises administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (e.g., a human) infected with RSV, wherein the therapeutically effective amount is sufficient to reduce the RSV viral load in the individual.

[0574] As described more fully herein, the compounds of the present invention can be administered to individuals (e.g., humans) infected with RSV together with one or more additional therapeutic agents. The additional therapeutic agent can be administered to an infected individual (e.g., a human) simultaneously with the compounds of the present invention or before or after the administration of the compounds of the present invention.

[0575] In certain embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is provided for use in treating or preventing RSV infection. In certain embodiments, a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof is provided for use in preparing a medicine for treating or preventing RSV infection.

[0576] As described more fully herein, the compounds of the present disclosure can be administered together with one or more additional therapeutic agents to an individual (e.g., a person) infected with RSV. In addition, in certain embodiments, when used to treat or prevent RSV, the compounds of the present disclosure can be administered together with one or more (e.g., one, two, three, four, or more) additional therapeutic agents selected from the group consisting of the following items: RSV combination drugs, RSV vaccines, RSV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) regulators, interferon alpha receptor ligands, hyaluronidase inhibitors, respiratory syncytial surface antigen inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, RSV virus entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease regulators, ribonucleotide reductase inhibitors, RSV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, RSV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nuclear protein regulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, RSV replication inhibitors, arginase inhibitors and other RSV drugs.

[0577] Picornaviridae

[0578] In some embodiments, the present disclosure provides a method for treating a Picornaviridae viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Picornaviridae viruses are enteroviruses that cause a heterogeneous class of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic myelitis-like syndrome, epidemic chest pain (acute, febrile, infectious disease that typically occurs in epidemics), hand, foot and mouth syndrome, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the Picornaviridae viral infection is a human rhinovirus infection.

[0579] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Picornaviridae viral infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Picornaviridae viral infection in a human. In some embodiments, the Picornaviridae viral infection is a human rhinovirus infection.

[0580] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Picornaviridae viral infection in a human in need thereof. In some embodiments, the Picornaviridae viral infection is a human rhinovirus infection.

[0581] Flaviviridae

[0582] In some embodiments, the present disclosure provides a method for treating a Flaviviridae virus infection in a person in need thereof, the method comprising administering to the person a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Representative Flaviviridae viruses include, but are not limited to, dengue virus, yellow fever virus, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0583] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Flaviviridae infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Flaviviridae infection in a human. In some embodiments, the Flaviviridae infection is a dengue virus infection. In some embodiments, the Flaviviridae infection is a yellow fever virus infection. In some embodiments, the Flaviviridae infection is a West Nile virus infection. In some embodiments, the Flaviviridae infection is a Zika virus infection. In some embodiments, the Flaviviridae infection is a hepatitis C virus infection.

[0584] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Flaviviridae infection in a human in need thereof. In some embodiments, the Flaviviridae infection is a dengue virus infection. In some embodiments, the Flaviviridae infection is a yellow fever virus infection. In some embodiments, the Flaviviridae infection is a West Nile virus infection. In some embodiments, the Flaviviridae infection is a Zika virus infection. In some embodiments, the Flaviviridae infection is a hepatitis C virus infection.

[0585] Filoviridae

[0586] In some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Representative Filoviridae viruses include, but are not limited to, Ebola virus and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection.

[0587] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Filoviridae viral infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Filoviridae viral infection in a human. In some embodiments, the Filoviridae viral infection is an Ebola virus infection.

[0588] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Filoviridae viral infection in a human in need thereof. In some embodiments, the Filoviridae viral infection is an Ebola virus infection.

[0589] VIII. Methods for treating or preventing worsening respiratory symptoms caused by viral infections

[0590] Compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) may also be used to treat or prevent exacerbations of respiratory conditions caused by viral infections in humans in need thereof.

[0591] In some embodiments, the present disclosure provides a method for treating or preventing an exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, or metapneumovirus.

[0592] In some embodiments, the present disclosure provides a method for treating or preventing exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enterovirus, or metapneumovirus.

[0593] In some embodiments, the present disclosure provides a method for preparing a medicament for treating or preventing an exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, or metapneumovirus.

[0594] In some embodiments, the present disclosure provides a method for treating or preventing an exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, characterized in that a compound of the present disclosure or a pharmaceutically acceptable salt thereof is used, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enterovirus, or metapneumovirus.

[0595] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing exacerbation of a respiratory condition caused by a viral infection in a human, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, or metapneumovirus.

[0596] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the manufacture of a method for treating or preventing exacerbation of a respiratory condition caused by a viral infection in a human, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enterovirus, or metapneumovirus.

[0597] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, or metapneumovirus.

[0598] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, wherein the respiratory condition is asthma. In some embodiments, the viral infection is caused by respiratory syncytial virus, rhinovirus, enterovirus, or metapneumovirus.

[0599] IX. Examples

[0600] Abbreviations Certain abbreviations and acronyms are used to describe experimental details. Although most of these will be understood by those skilled in the art, Table 2 contains a listing of many of these abbreviations and acronyms.

[0601] Table 2. List of abbreviations and acronyms

[0602]

[0603]

[0604] Compounds can be subjected to preparative HPLC (Phenomenex Gemini 10u C18 AXIA 250 x 21.2 mm column, gradient 30-70% acetonitrile in water containing 0.1% TFA). Following this preparative HPLC procedure, some compounds were obtained as TFA salts.

[0605] A.Intermediates

[0606] Intermediate 1. (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-diol Hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile

[0607]

[0608] The product can be prepared according to WO2015 / 069939. For example, pages 43-54 of WO2015 / 069939 provide a method for preparing the compound identified as Compound 1 in WO2015 / 069939.

[0609] Intermediate 2. (7-((3aS,4S,6R,6aS)-6-cyano-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3, tert-Butyl 4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0610]

[0611] The compound 14j (21.79 g, 39.93 mmol) from WO2015 / 069939 in THF (400 mL) was cooled in an ice bath. A 1.0 M TBAF solution in THF (50.0 mL, 50.0 mmol) was added once. The mixture was allowed to reach ambient temperature and stirred for about 30 minutes. The reaction was determined to be complete by LCMS. The reaction mixture was quenched with water and the organic matter was removed under reduced pressure. The crude product was distributed between EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAc. The organic matter was combined and dried over sodium sulfate. The solid was filtered off and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography 330 g column 30-100% EtOAc in hexane to obtain the product. MS m / z=431.74[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.25(s,1H),7.21(s,1H),7.03(d,J=4.6Hz,1H),5.77(t,J=6.1Hz,1H),5.59(d,J=4.0H z,1H),5.27(dd,J=6.7,4.1Hz,1H),4.94(d,J=6.7Hz,1H),3.66(dd,J=6.1,2.4Hz,2H),1.62(s,3H),1.50(s,9H),1.33(s,3H).

[0612] Intermediate 3. (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- (((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxolane Olefin-4-carbonitrile

[0613]

[0614] The product can be prepared according to WO2015 / 069939. For example, pages 127-138 of WO2015 / 069939 provide a method for preparing this compound (identified as compound 14k in WO2015 / 069939).

[0615] Intermediate 4. (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(hydroxy methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile

[0616]

[0617] Take intermediate 3 (8.41g, 18.87mmol) and put it into THF (100mL). Add 1.0M THF solution of BAF (28.31mL, 28.31mmol) at ambient temperature in one go. Allow to stir at ambient temperature for 10 minutes. Determine the reaction completion by LCMS. Quench the reaction mixture with water and remove organic matter under reduced pressure. The crude product is distributed between EtOAc and water. Separate the layers and wash the aqueous layer with EtOAc. Combine organic matter and dry over sodium sulfate. Filter out the solid and remove the solvent under reduced pressure. The crude product is purified by silica gel chromatography 120g column 0-10% CH3OH in CH2Cl2 solution to obtain the product. LC / MS: t R = 0.76 min, MS m / z = 332.14 [M+1]; LC system: Thermo Accela 1250 UHPLC. MS system: Thermo LCQ Fleet; Column: 2.6μ XB-C18 100A, 50 x 3.00 mm. Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid. Gradient: 2-100% ACN from 0 min to 2.4 min, 100% ACN from 2.4 min to 2.80 min, 100% to 2% ACN from 2.8 min to 2.85 min, 2% ACN from 2.85 min to 3.0 min, 1.8 mL / min. 1 H NMR (400MHz, DMSO-d6) δ7.87-7.80(m,3H),6.85(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),5.74(t,J=5.8Hz,1H),5.52(d, J=4.2Hz,1H),5.24(dd,J=6.8,4.2Hz,1H),4.92(d,J=6.8Hz,1H),3.65(dd,J=6.1,1.7Hz,2H),1.61(s,3H),1.33(s,3H).

[0618] Intermediate 5. (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(((tert- (butyldimethylsilyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-carbonitrile

[0619]

[0620] Intermediate 1 (2 g, 6.18 mmol) was dissolved in 50 mL of DMF, and tert-butylchlorodimethylsilane (1 g, 7 mmol) and imidazole (1.26 g, 19 mmol) were added to the solution. The resulting mixture was stirred at room temperature for 2 hours, and the reaction was diluted with EtOAc, washed with NH4Cl solution, the organic solvent was evaporated, and the residue was purified by silica gel column chromatography (eluted with 0-100% EtOAc in hexane) to give the product. LCMS: MS m / z=406.36 [M+1], tR =1.45 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =3.25 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0621] Intermediate 6. (2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(((tert- butyldimethylsilyl)oxy)methyl)-2-cyanotetrahydrofuro-3,4-diylbis(2-methylpropionate)

[0622]

[0623] Intermediate 5 (1.8 g, 4.44 mmol) was dissolved in 15 mL of THF, and isobutyric anhydride (1.54 g, 9.8 mmol) and DMAP (179 mg, 1.45 mmol) were added to the solution. The resulting mixture was stirred at room temperature for 5 minutes, and the reaction was quenched with MeOH, then diluted with EtOAc, washed with brine, and the organic solvent was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (eluted with 0-100% EtOAc in hexanes) to give the product. LCMS: MS m / z = 546.16 [M+1], t R =1.92 min; LC system: Thermo Accela 1250 UHPLC; MS system: ThermoLCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R=3.88 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0624] Intermediate 7. (2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano- 2-(Hydroxymethyl)tetrahydrofuran-3,4-diylbis(2-methylpropionate)

[0625]

[0626] In 100mL plastic bottle, intermediate 6 (3.2g, 5.86mmol) is dissolved among the 25mL THF, in this solution, add HF-pyridine (10g, 0.35mmol).Gained mixture was stirred 3 hours at room temperature, and will react NaHCO Cancellous, then use EtOAc dilution, use salt water washing, with organic solvent through Na SO Drying and vaporising under vacuum.Resistates is passed through silica gel column chromatography (with the hexane solution wash-out of 0-100%EtOAc) purifying, obtain product. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.90 (s, 1H), 6.83–6.74 (m, 2H), 6.33 (s, 2H), 5.84–5.74 (m, 2H), 5.62 (d, J = 5.4 Hz, 1H), 4.31 (dd, J = 8.4, 5.2 Hz, 1H), 3.94 (dd, J = 12.2, 5.0 Hz, 1H), 3.87 (dd, J = 12.2, 8.4 Hz, 1H), 2.70 (septet, J = 7.0 Hz, 1H), 2.56 (septet, J = 7.0 Hz, 1H), 1.28–1.17 (m, 6H), 1.12 (dd, J = 15.1, 7.0 Hz, 6H). LCMS: MS m / z = 432.24 [M+1], t R =1.47 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R=2.74 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0627] Intermediate 8. L-Alanine cyclopentyl ester HCl salt

[0628]

[0629] To a mixture of (tert-butoxycarbonyl)-L-alanine (3.95 g, 20.9 mmol), cyclopentanol (1.5 g, 17.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (3.5 g, 22.6 mmol) in acetonitrile (100 mL) was added 4-(dimethylamino)pyridine (DMAP, 3.2 g, 26.1 mmol). The mixture was then stirred at room temperature for 2 hours. The reaction mixture was then diluted with EtOAc, washed with brine, the organic solvent dried over sodium sulfate, and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluted with 0-100% ethyl acetate in hexane) to obtain an intermediate, which was dissolved in 10 mL of DCM. 4N HCl in dioxane (3 mL) was added to the solution. The reaction mixture was stirred at room temperature for 30 minutes, the solvent was then evaporated, and the residue was dried under high vacuum to obtain a crude product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.75–8.42 (m, 2H), 5.20 (tt, J = 5.6, 2.5 Hz, 1H), 4.22–4.07 (m, 1H), 1.87–1.58 (m, 8H), 1.54 (dd, J = 12.6, 7.2 Hz, 3H).

[0630] Intermediate 9. L-Alanine cyclopropyl ester HCl salt

[0631]

[0632] To a mixture of (tert-butoxycarbonyl)-L-alanine (5.86 g, 31 mmol), cyclopropanol (1.5 g, 25.8 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (5.2 g, 33.6 mmol) in acetonitrile (100 mL) was added 4-(dimethylamino)pyridine (DMAP, 4.7 g, 38.7 mmol). The mixture was then stirred at room temperature for 2 hours. The reaction mixture was then diluted with EtOAc, washed with brine, the organic solvent dried over sodium sulfate, and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to obtain an intermediate, which was dissolved in 10 mL of DCM and a 4N HCl solution in dioxane (3 mL) was added to the solution. The reaction mixture was stirred at room temperature for 30 minutes, the solvent was then evaporated, and the residue was dried under high vacuum to obtain a crude product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.68 (s, 2H), 4.22 (tt, J = 6.3, 3.2 Hz, 1H), 1.68 (d, J = 7.3 Hz, 3H), 1.42 (s, 1H), 0.86–0.69 (m, 2H), 0.70 (dd, J = 7.1, 3.6 Hz, 2H).

[0633] Intermediate 10. Methylals 1 and 2: 1,1-dimethoxy-N,N-dimethylmethanamine and 1-(dimethoxymethyl)-4- Methylpiperazine

[0634]

[0635] A mixture of N-methylpiperazine (1.5 mL, 15.93 mmol) and DMF-dimethyl acetal (1 mL, 7.50 mmol) was heated in a sealed tube at 100° C. for 3 days, concentrated under high vacuum at 60° C. to remove excess N-methylpiperazine, and then used in the next reaction. Based on the product composition of the next reaction, the product was a mixture of methylal 1 and methylal 2 in a ratio of approximately 1:2.

[0636] Intermediate 11. (S)-2-aminopropionic acid cyclohexyl ester hydrochloride

[0637]

[0638] To a mixture of L-alanine (5 g, 56.12 mmol) and cyclohexanol (56 g, 561 mmol) was added TMSCl (20 mL). The resulting mixture was stirred at approximately 70° C. for approximately 15 hours and concentrated under vacuum at approximately 80° C., co-evaporated with toluene, dissolved in hexane, and stirred at approximately room temperature during which time a solid precipitated. The solid was collected by filtration, and the filter cake was washed several times with a 5% EtOAc solution in hexane and dried under high vacuum for approximately 15 hours to obtain the product.1 H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (s, 3H), 4.85 (tt, J = 8.7, 3.8 Hz, 1H), 4.17 (p, J = 6.5 Hz, 1H), 1.84 (dd, J = 9.9, 5.5 Hz, 2H), 1.70 (d, J = 7.3 Hz, 5H), 1.57–1.42 (m, 3H), 1.32 (ddddd, J = 20.3, 12.8, 9.9, 6.4, 3.1 Hz, 3H).

[0639] Intermediate 12. (S)-2-ethylbutyl 2-((tert-Butoxycarbonyl)amino)-4-methylpentanoate

[0640]

[0641] Take (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid (1.09 g, 4.71 mmol) and place it in acetonitrile (10 mL). Add 2-ethyl-1-butanol (2.88 mL, 23.56 mmol). Then add EDCI (878 mg, 5.66 mmol) and DMAP (863 mg, 7.07 mmol) in one go. Allow to stir at room temperature overnight. Concentrate and dilute with CH Cl. Purify by silica gel chromatography 0-40% EtOAc / Hex to obtain the product. 1 H NMR (400MHz, DMSO-d6) δ7.19 (d, J = 8.7Hz, 1H), 4.00-3.84 (m, 3H), 1.67-1.22 (m, 17H), 0.91-0.80 (m, 12H).

[0642] Intermediate 13. (S)-2-Ethylbutyl 2-amino-4-methylpentanoate hydrochloride

[0643]

[0644] (S)-2-((tert-Butoxycarbonyl)amino)-4-methylpentanoic acid-2-ethylbutyl ester was placed in CH2Cl2 (10 mL) and a solution of 4N HCl in dioxane (10 mL, 40 mmol). The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and co-evaporated with hexane. The mixture was placed under high vacuum for 1 hour and the product was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.43 (s, 3H), 4.08 (d, J = 5.6Hz, 2H), 3.92 (m, 1H), 1.69 (m, 1H), 1.61 (m, 2H), 1.47 (m, 1H), 1.34 (m, 4H), 0.83 (m, 12H).

[0645] Intermediate 14. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-(benzyloxy)-2-methylpropyl ester

[0646]

[0647] To a mixture of Boc-L-alanine (1.26 g, 6.66 mmol), 2-benzyloxy-2-methylpropanol (1.0 g, 5.55 mmol), and EDCI (1.12 g, 7.21 mmol) in acetonitrile (20 mL) was added DMAP (2.04 g, 8.32 mmol). The mixture was then stirred at room temperature for 2 hours, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 to 60% EtOAc in hexanes) to give Boc-L-alanine propyl ester, which was dissolved in DCM (10 mL) and 4N HCl in dioxane (5.5 mL, 22.19 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, concentrated in vacuo, redissolved in ACN (10 mL), and lyophilized overnight to give the product. 1 H NMR (400 MHz, chloroform-d) δ 8.82 (s, 3H), 7.42–7.07 (m, 5H), 4.44 (s, 2H), 4.24 (m, 2H), 4.08 (d, J = 11.2 Hz, 1H), 1.70 (d, J = 7.0 Hz, 3H), 1.28 (d, J = 2.4 Hz, 6H). LCMS m / z = 251.97 (free base M+H), t R =0.85 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0648]

[0649] ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-(benzyloxy)-2-methylpropyl ester. To a solution of L-alanine 2-(benzyloxy)-2-methylpropyl ester HCl salt (832 mg, 2.89 mmol) in DCM (20 mL) was added phenyl dichlorophosphate (0.43 mL, 2.89 mmol) in one portion at -78°C, and triethylamine (0.80 mL, 5.76 mmol) was added dropwise over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and cooled to -78°C, and p-nitrophenol (402 mg, 2.89 mmol) was added in one portion, and triethylamine (0.40 mL, 2.89 mmol) was added at -78°C over 5 minutes. After removing the dry ice bath, the resulting mixture was stirred for 50 minutes, then diluted with DCM, washed with brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 60% EtOAc in hexanes) to give the product. 1 HNMR (400 MHz, CHLOROFORM-d) δ 8.23–8.13 (m, 2H), 7.41–7.27 (m, 3H), 7.28–7.14 (m, 4H), 4.45 (m, 2H), 4.27–4.15 (m, 2H), 4.07 (m, 1H), 3.89 (m, 1H), 1.41 (m, 3H), 1.27 (m, 6H). 31 P NMR (162 MHz, chloroform-d) δ -3.10, -3.18. LCMS m / z = 528.78 (M+H), t R =1.70 min; LC system: ThermoAccela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0650] Intermediate 15. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine cyclobutyl methyl ester

[0651]

[0652] L-Alanine cyclobutyl methyl ester-HCl (1.2g, 7.16mmol) is suspended in methylene chloride (10mL), cooled to-78 ℃, and quickly add phenyl dichlorophosphate (1.07mL, 7.16mmol). At-78 ℃, triethylamine (2.0mL, 14.32mmol) is added in 60 minutes, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is cooled to 0 ℃, and 4-nitrophenol (996mg, 7.16mmol) is added once. Then triethylamine (1.0mL, 7.16mmol) is added in 60 minutes. Then the mixture is stirred at room temperature for 3 hours, filtered, and the filtrate is concentrated to one-third volume, and filtered again. The filtrate is concentrated and the residue is purified by silica gel column chromatography (0 to 35% EtOAc in hexane solution) to obtain the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.28–8.16 (m, 2H), 7.45–7.32 (m, 4H), 7.29–7.16 (m, 3H), 4.23–4.01 (m, 3H), 3.95–3.83 (m, 1H), 2.59 (m, 1H), 2.03 (m, 2H), 1.98–1.80 (m, 2H), 1.73 (m, 2H), 1.42 (d, J = 3.2 Hz, 1.5H), 1.40 (d, J = 3.3 Hz, 1.5H). 31 P NMR (162 MHz, chloroform-d) δ -3.06, -3.11.

[0653] Intermediate 16. ((Benzyloxy)(4-nitrophenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester

[0654]

[0655] 4-Nitrophenyl dichlorophosphate (2.00 g, 7.81 mmol) and triethylamine (2.18 mL, 15.6 mmol) were added sequentially to a suspension of L-alanine 2-ethylbutyl ester hydrochloride (1.091 g, 18.9 mmol) in dichloromethane (23 mL) at 0°C under an argon atmosphere. After 1 hour, benzyl alcohol (0.810 mL, 7.81 mmol) and triethylamine (1.09 mL, 7.81 mmol) were then added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to provide the product. 1H NMR (400 MHz, chloroform-d1) δ 8.30–8.07 (m, 2H), 7.42–7.28 (m, 7H), 5.18–5.09 (m, 2H), 4.70 (s, 1H), 4.08–3.95 (m, 2H), 3.68 (q, J = 9.4 Hz, 1H), 1.55–1.18 (m, 8H), 0.87 (t, J = 7.4 Hz, 6H). 31 P NMR (162 MHz, chloroform-d1) δ 2.32 (s), 2.28 (s). LCMS: MS m / z = 463.00 [M–1], t R =1.56 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18100A, 50×4.6 mm; solvent: acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; gradient: 0 min-2.0 min2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min.

[0656] Intermediate 17. ((S)-(4-nitrophenoxy)(phenoxy)(phosphoryl)-L-alanine 2-ethylbutyl ester

[0657]

[0658] Prepared as described in WO 2016 / 069825.

[0659] Intermediate 18. ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester

[0660]

[0661] Prepared as described in Cho et al., J. Med. Chem. 2014, 57, 1812-1825.

[0662] Intermediate 19. ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ethyl ester

[0663]

[0664] Prepared as described in US20120009147A1.

[0665] Intermediate 20. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine cyclopropyl methyl ester

[0666]

[0667] L-Alanine cyclopropyl methyl ester-HCl (1.0g, 5.57mmol) is suspended in methylene chloride (10mL), cooled to-78 ℃, and quickly add phenyl dichlorophosphate (0.83mL, 5.57mmol).In 30 minutes, add DCM (1.5mL) solution of triethylamine (1.54mL, 11.13mmol) and stir 30 minutes at-78 ℃.Disposable addition 4-nitrophenol (774mg, 5.57mmol) is added at-78 ℃.Then, in 30 minutes, add DCM (2mL) solution of triethylamine (0.77mL, 7.16mmol).Then, in 30 minutes, add DCM (2mL) solution of triethylamine.Then the mixture is stirred 30 minutes at the same temperature, water, saturated Na CO solution and salt water washing, and dried over sodium sulfate, and vacuum concentration.By silica gel column chromatography (0 to 20% EtOAc hexane solution) purification of residue, obtain product. 1 HNMR (400MHz, chloroform-d) δ8.22(m,2H),7.58–7.29(m,4H),7.32–7.14(m,3H),4.25–4.07(m,1H),4.07–3.80(m,3H) ),1.44(d,J=2.9Hz,1.5H),1.42(d,J=2.9Hz,1.5H),1.26–1.01(m,1H),0.66–0.49(m,2H),0.42–0.15(m,2H). 31 P NMR (162 MHz, chloroform-d) δ -3.07, -3.11. MS m / z = 420.97.

[0668] Intermediate 21. 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)ethyl pivalate

[0669]

[0670] Pivaloic acid 2-aminoethyl ester hydrochloride.At room temperature, pivaloyl chloride (3.82mL, 31.0mmoL) is added in the solution of (2-hydroxyethyl) tert-butyl carbamate (4.8mL, 31.0mmoL) and diisopropylethylamine (5.4mL, 31.0mmoL) in methylene dichloride (150mL).After 4 hours, gained mixture is washed with saturated sodium bicarbonate aqueous solution (150mL) and salt solution (150mL), through anhydrous sodium sulfate drying, and concentrating under reduced pressure.Thick colorless oil is dissolved in the solution of hydrochloric acid in dioxane (4M, 50mL), and stirs at room temperature, and white solid is slowly precipitated from solution.After 3 hours, solid is collected by vacuum filtration, obtains product. 1 H NMR (400MHz, CD3OD) δ4.32–4.25 (m, 2H), 3.26 (t, J = 5.4Hz, 2H), 1.23 (s, 9H).

[0671]

[0672] 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)ethyl pivalate. To a solution of 2-aminoethyl pivalate hydrochloride (0.861 g, 4.74 mmol) and phenyl dichlorophosphate (0.705 mL, 4.74 mmol) in dichloromethane (23 mL) at 0° C. under an argon atmosphere was added triethylamine (1.2 mL, 9.4 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 1.5 hours. 4-Nitrophenol (660 mg, 4.74 mmol) and triethylamine (0.66 mL, 4.7 mmol) were then added. After 1 hour, the reaction mixture was diluted with dichloromethane (50 mL), and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified via SiO2 column chromatography (40 g SiO2 Combiflash HP Gold column, 0-100% ethyl acetate / hexanes) to give the product. 1 H NMR (400MHz, CDCl3) δ8.23 (d, J = 9.2Hz, 2H), 7.47–7.31 (m, 4H), 7.29–7.16 (m, 3H), 4.18–4.06 (m, 2H), 3.45–3.31 (m, 2H), 1.17 (s, 9H). 31 P NMR(162MHz,DMSO-d6)δ-1.48(s). MS m / z=422.95[M+1].

[0673] Intermediate 22. (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoic acid tetrahydro-2H-pyran- 4-amino ester

[0674]

[0675] (S)-2-aminopropionic acid tetrahydro-2H-pyrans-4-yl ester hydrochloride.To the mixture of L-Alanine (500mg, 5.61mmol) and tetrahydro-2H-pyrans-4-ol (5g, 49.0mmol), add TMSCl (2mL).Gained mixture was stirred 15 hours and vacuum concentrated at 70 ℃, and the gained solid was ground with the hexane solution of 5%EtOAc, filtered, and washed several times with the hexane solution of 5%EtOAc, and dried under high vacuum for 15 hours to obtain product, which was used for the next reaction without the need for any characterization.

[0676]

[0677] (2S)-Tetrahydro-2H-pyran-4-yl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate. (S)-Tetrahydro-2H-pyran-4-yl 2-aminopropanoate hydrochloride (1.33 g, 6.34 mmol) was dissolved in methylene chloride (15 mL), cooled to -78°C, and phenyl dichlorophosphate (1.137 mL, 7.61 mmol) was quickly added. Triethylamine (2.2 mL, 15.2 mmol) was added at -78°C over 30 minutes, and the resulting mixture was stirred at -78°C for 30 minutes. 4-Nitrophenol (882 mg, 6.34 mmol) was then added in one portion, and triethylamine (1.1 mL, 7.61 mmol) was added at -78°C over 30 minutes. The mixture was stirred at -78°C for 30 minutes, washed twice with water and with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 70% EtOAc in hexanes) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (m, 2H), 7.49–7.06 (m, 7H), 4.95 (m, 1H), 4.14 (m, 1H), 4.07–3.80 (m, 3H), 3.52 (m, 2H), 1.95–1.81 (m, 2H), 1.64 m, 2H), 1.42 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.09, -3.13. MS m / z = 451 (M+H) + .

[0678] Intermediate 23. (S)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-methylpyrrolidin-3-yl ester

[0679]

[0680] (S)-(tert-Butoxycarbonyl)-L-alanine 1-methylpyrrolidin-3-yl ester. Boc-L-alanine (2.1 g, 11 mmol) and (R)-3-hydroxy-1-methylpyrrolidine (1.1 mL, 10 mmol) were dissolved in anhydrous THF (20 mL). Triphenylphosphine (3.4 g, 13 mmol) was added at once. Diisopropyl azodicarboxylate (2.4 mL, 12 mmol) was added dropwise. The reaction was stirred for 2 hours. More diisopropyl azodicarboxylate (240 μL, 1.2 mmol) was added dropwise and the reaction was stirred for 16 hours. The reaction was diluted with EtOAc (10 mL) and washed with saturated sodium bicarbonate aqueous solution (10 mL). The organic matter was then extracted with 5% citric acid aqueous solution (30 mL). The citric acid extract was washed with EtOAc (2×5 mL). The citric acid portion was basified with 1N aqueous NaOH to a pH of 9 and extracted with EtOAc (2 x 10 mL).The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.24 (m, 1H), 5.01 (m, 1H), 4.27 (m, 1H), 2.88–2.69 (m, 2H), 2.64 (m, 1H), 2.37 (s, 3H), 2.29 (m, 1H), 1.96–1.80 (m, 1H), 1.44 (s, 9H), 1.37 (d, J = 7.2 Hz, 3H).

[0681]

[0682] (S)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-methylpyrrolidin-3-yl ester. (S)-(tert-Butoxycarbonyl)-L-alanine 1-methylpyrrolidin-3-yl ester (545 mg, 2 mmol) was mixed with 10 mL of 4N HCl in dioxane and stirred for 1 hour. The reaction was concentrated under reduced pressure to give a foam, which was then mixed with 20 mL of anhydrous DCM and stirred in an ice bath under atmospheric nitrogen. Phenyl dichlorophosphate (298 μL, 2 mmol) was added to the reaction in one go. The reaction was stirred for 15 minutes. Triethylamine (837 μL, 6 mmol) was added dropwise to the reaction. The reaction was stirred for 1 hour. Triethylamine (279 μL, 2 mmol) was added dropwise to the reaction and then stirred for 30 minutes. p-Nitrophenol (250 mg, 1.8 mmol) was added in one go. The reaction mixture was stirred for 16 hours. The reaction was diluted with DCM (20 mL) and washed with water (5 x 20 mL). The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO column chromatography (12 g SiO Combiflash HP Gold column, 0-10% methanol / DCM). The fractions were combined and concentrated under reduced pressure to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.28–8.15 (m, 2H), 7.46–7.28 (m, 4H), 7.28–7.13 (m, 3H), 5.17 (m, 1H), 4.21–4.04 (m, 1H), 4.01–3.85 (m, 1H), 2.81 (m, 1H), 2.70–2.55 (m, 2H), 2.35 (s, 3H), 2.33–2.21 (m, 2H), 1.84–1.70 (m, 1H), 1.39 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.16, -3.21. LCMS: MS m / z = 450.3 [M+1]; 448.1 [M-1], t R =1.15 min; LC system: Thermo Dionex Ultimate 3000 UHPLC; column: Phenomenex Kinetex 2.6μ C18 100A, 50×3 mm; solvent: A: water containing 0.1% acetic acid, B: acetonitrile containing 0.1% acetic acid; gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% B, 2 mL / min. HPLC: t R=2.61 min; HPLC system: Agilent 1100 series; column: Phenomenex Gemini 5μ C18 110A, 50×4.6 mm; solvent: A: water containing 0.1% TFA, B: acetonitrile containing 0.1% TFA; gradient: 2-98% B in 5 min, 2 mL / min.

[0683] Intermediate 24. (R)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-methylpyrrolidin-3-yl ester

[0684]

[0685] (R)-(tert-Butoxycarbonyl)-L-alanine 1-methylpyrrolidin-3-yl ester. Boc-L-alanine (5.2 g, 27.5 mmol) and (R)-3-hydroxy-1-methylpyrrolidine (2.74 mL, 25 mmol) were dissolved in anhydrous THF (25 mL). N,N'-diisopropylcarbodiimide (4.67 mL, 30 mmol) was added dropwise. The reaction was stirred for 2 hours. More N,N'-diisopropylcarbodiimide (467 μL, 3 mmol) was added dropwise, and the reaction was stirred for 2 hours. More N,N'-diisopropylcarbodiimide (467 μL, 3 mmol) was added dropwise, and the reaction was stirred for 16 hours.

[0686] The reaction was diluted with EtOAc (25 mL) and stirred for 10 minutes. The solid was filtered off and washed with a small amount of EtOAc. The filtrate was washed with saturated sodium bicarbonate aqueous solution (3×10 mL). The organic matter was then extracted with 5% citric acid aqueous solution (50 mL). The citric acid extract was washed with EtOAc (5 mL). The citric acid portion was basified with 1N NaOH aqueous solution to obtain a pH of 9, and then extracted with EtOAc (3×15 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the product. 1 HNMR (400 MHz, chloroform-d) δ 5.28–5.18 (m, 1H), 5.02 (m, 1H), 4.28 (m, 1H), 2.84–2.75 (m, 1H), 2.69 (d, J = 4.2 Hz, 2H), 2.36 (s, 3H), 2.34–2.22 (m, 2H), 1.87–1.76 (m, 1H), 1.44 (s, 9H), 1.37 (d, J = 7.2 Hz, 3H).

[0687]

[0688] (R)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-methylpyrrolidin-3-yl ester. (R)-(tert-butoxycarbonyl)-L-alanine 1-methylpyrrolidin-3-yl ester (3.9 g, 14.3 mmol) was mixed with a solution of 30 mL 4N HCl in dioxane and stirred for 3 hours. The reaction was concentrated under reduced pressure to obtain a foam, which was then mixed with 30 mL anhydrous DCM and stirred in an ice bath under atmospheric nitrogen. Phenyl dichlorophosphate (2.34 mL, 15.75 mmol) was added to the reaction in one go. The reaction was stirred for 15 minutes. Triethylamine (4.4 mL, 31.5 mmol) was mixed with anhydrous DCM (5 mL) and added dropwise to the reaction. The reaction was stirred for 1 hour. Triethylamine (2.2 mL, 15.75 mmol) was mixed with anhydrous DCM (3 mL) and added dropwise to the reaction. The reaction was stirred for 15 minutes. p-Nitrophenol (1.8 g, 12.87 mmol) was added in one portion and the reaction mixture was stirred for 2 hours.

[0689] The reaction was diluted with DCM (20 mL) and washed with aqueous sodium bicarbonate (3 x 20 mL). The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO column chromatography (40 g SiO Combiflash HP Gold column, 0-10% methanol / DCM). The fractions were combined and concentrated under reduced pressure to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.29–8.15 (m, 2H), 7.48–7.29 (m, 4H), 7.29–7.13 (m, 3H), 5.20 (m, 1H), 4.21–4.07 (m, 1H), 3.99 (m, 1H), 2.86 (m, 1H), 2.70 (m, 1H), 2.63 (m, 1H), 2.37 (m, 3H), 2.35–2.21 (m, 2H), 1.86–1.73 (m, 1H), 1.40 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.12, -3.14. LCMS: MS m / z = 450.3 [M+1]; 448.1 [M-1], t R=1.24 min; LC system: Thermo Dionex Ultimate 3000 UHPLC; column: Phenomenex Kinetex 2.6μ C18 100A, 50×3 mm; solvent: A: water containing 0.1% acetic acid, B: acetonitrile containing 0.1% acetic acid; gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% B, 2 mL / min. HPLC: t R =2.63 min; HPLC system: Agilent 1100 series; column: Phenomenex Gemini 5μC18 110A, 50×4.6 mm; solvent: A: water containing 0.1% TFA, B: acetonitrile containing 0.1% TFA; gradient: 2-98% B in 5 min, 2 mL / min.

[0690] Intermediate 25. Cyclohexyl (2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate

[0691]

[0692] Intermediate 11 (3.4 g, 16.37 mmol) was dissolved in methylene chloride (45 mL), cooled to -78°C, and phenyl dichlorophosphate (2.45 mL, 16.37 mmol) was quickly added. At -78°C, triethylamine (4.54 mL, 32.74 mmol) was added over 60 minutes, followed by the addition of 4-nitrophenol (2277 mg, 16.37 mmol) in one portion. At -78°C, triethylamine (2.27 mL, 16.37 mmol) was added over 60 minutes. The resulting mixture was stirred at -78°C for 2 hours, diluted with methylene chloride (100 mL), washed twice with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 20% EtOAc in hexane) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (m, 2H), 7.46–7.30 (m, 4H), 7.29–7.09 (m, 3H), 4.76 (m, 1H), 4.20–4.02 (m, 1H), 3.92 (m, 1H), 1.87–1.64 (m, 4H), 1.54 (m, 2H), 1.46–1.18 (m, 7H). 31 P NMR (162 MHz, chloroform-d) δ -2.94, -3.00. MS m / z = 449 (M+H) + .

[0693] Intermediate 26. 4-(((2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionyl)oxy) tert-Butyl piperidine-1-carboxylate

[0694]

[0695] 4-((L-alanyl)oxy)piperidine-1-carboxylic acid tert-butyl ester. To a mixture of ((benzyloxy)carbonyl)-L-alanine (1.26 g, 5.65 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.68 g, 28.22 mmol) and EDCI (1.05 g, 6.77 mmol) in acetonitrile (15 mL), DMAP (1.03 g, 8.47 mmol) was added. The mixture was then stirred at room temperature for 15 hours, diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (0 to 100% EtOAc in hexane) to obtain Cbz-L-alanine piperidyl ester, which was dissolved in THF (10 mL) and 20% palladium hydroxide (400 mg) / carbon was added. The resulting mixture was stirred under H2 gas for 2 hours, filtered, and the filtrate was concentrated in vacuo. The obtained residue was dried under high vacuum to give the product. 1 H NMR (400MHz, chloroform-d) δ4.95(tt,J=7.9,3.8Hz,1H),3.79–3.62(m,2H),3.56(q,J=7.0Hz,1H),3.25(ddd,J=13.6,8.5,3.7Hz,2H) ,1.85(ddd,J=13.4,6.4,3.4Hz,2H),1.73(s,2H),1.62(ddq,J=12.7,8.7,4.3,3.9Hz,2H),1.46(s,9H),1.34(d,J=7.0Hz,3H). MS m / z=273[M+H].

[0696]

[0697] Tert-Butyl 4-(((2S)-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propionyl)oxy)piperidine-1-carboxylate. Tert-Butyl 4-((L-alanyl)oxy)piperidine-1-carboxylate (0.9 g, 3.31 mmol) was dissolved in methylene chloride (10 mL), cooled to -78°C, and phenyl dichlorophosphate (0.49 mL, 3.31 mmol) was added quickly. Triethylamine (0.46 mL, 3.31 mmol) was added over 30 minutes at -78°C, and 4-nitrophenol (460 mg, 3.31 mmol) was added in one portion. Triethylamine (0.49 mL, 3.31 mmol) was then added over 30 minutes at -78°C. The resulting mixture was stirred at -78°C for 2 hours, diluted with methylene chloride, washed twice with water and with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 70% EtOAc in hexanes) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.23 ​​(m, 2H), 7.42–7.31 (m, 4H), 7.25–7.16 (m, 3H), 4.93 (m, 1H), 4.26–4.03 (m, 1H), 3.85 (m, 1H), 3.75–3.56 (m, 2H), 3.21 (m, 2H), 1.91–1.75 (m, 2H), 1.66–1.48 (m, 2H), 1.46 (s, 9H), 1.44–1.38 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.07, -3.13. MS m / z = 550 (M+H) + .

[0698] Intermediate 27. trans-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-(trifluoromethyl)cyclohexane ester

[0699]

[0700] Trans-L-alanine 4-(trifluoromethyl)cyclohexyl ester. The product was prepared from Cbz-l-alanine (900 mg, 4.03 mmol) and trans-4-(trifluoromethyl)cyclohexan-1-ol (1.02 g, 6.05 mmol) in a manner similar to that described for Intermediate 26. MS m / z = 240 [M+H].

[0701]

[0702] trans-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-(trifluoromethyl)cyclohexyl ester. The product (840 mg) was prepared as an isomeric mixture from trans-L-alanine 4-(trifluoromethyl)cyclohexyl ester (974 mg, 4.07 mmol) in a manner similar to that described for Intermediate 25. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.27–8.19 (m, 2H), 7.43–7.31 (m, 4H), 7.26–7.16 (m, 3H), 4.68 (m, 1H), 4.11 (m, 1H), 3.84 (m, 1H), 2.02 (m, 4H), 1.50–1.27 (m, 8H). 19 F NMR (377 MHz, chloroform-d) δ -73.91 (d, J = 7.7 Hz). 31 P NMR (162 MHz, chloroform-d) δ -3.08, -3.12. MS m / z = 517 [M+H].

[0703] The products were separated by Chiralpak SFC (Chiralpak IF 20 x 250 mm column, 30% isopropanol) to give Intermediate 28 and Intermediate 29:

[0704]

[0705] Intermediate 28. trans-((R)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-(trifluoromethyl)cyclohexyl ester. First eluting diastereomer of Intermediate 27: 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (d, J = 9.1 Hz, 2H), 7.42–7.31 (m, 4H), 7.29–7.16 (m, 3H), 4.69 (tt, J = 10.7, 4.2 Hz, 1H), 4.19–4.04 (m, 1H), 3.90 (dd, J = 11.9, 9.5 Hz, 1H), 2.12–1.97 (m, 5H), 1.52–1.21 (m, 7H). 19 F NMR (376 MHz, chloroform-d) δ -73.90 (d, J = 7.7 Hz). 31 P NMR (162 MHz, chloroform-d) δ -3.07.

[0706] Intermediate 29. trans-((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-(trifluoromethyl)cyclohexyl ester. Second eluting diastereomer of Intermediate 27: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J = 9.08 Hz, 2H), 7.42–7.31 (m, 4H), 7.26–7.13 (m, 3H), 4.67 (tt, J = 10.8, 4.2 Hz, 1H), 4.11 (ddt, J = 15.8, 8.9, 7.1 Hz, 1H), 3.97 (dd, J = 12.0, 9.4 Hz, 1H), 2.07–1.91 (m, 5H), 1.51–1.19 (m, 7H). 19 FNMR (376 MHz, chloroform-d) δ-73.90 (d, J=7.9 Hz). 31 P NMR (162 MHz, chloroform-d) δ -3.08.

[0707] Intermediate 30. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-methylpiperidin-4-yl ester

[0708]

[0709] L-Alanine 1-methylpiperidin-4-yl ester. To a mixture of N-Cbz-L-alanine (1.047 g, 4.688 mmol), 4-hydroxy-N-methylpiperidine (450 mg, 3.907 mmol), and EDCI (788 mg, 5.079 mmol) in acetonitrile (20 mL) was added DMAP (716 mg, 5.861 mmol). The mixture was then stirred at room temperature for 15 hours before being diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 to 10% MeOH in DCM) to give Cbz-L-alanine 4-piperidin-4-yl ester, which was dissolved in THF (10 mL) and 20% Pd(OH)2 (300 mg, 0.427 mmol) was added at room temperature. The resulting mixture was stirred under H2 gas at room temperature for 2 h, filtered, concentrated in vacuo, co-evaporated with DCM several times, and dried under high vacuum overnight to give the product. 1 H NMR (400MHz, chloroform-d) δ4.81 (td, J=8.3, 7.7, 3.8Hz, 1H), 3.52 (q, J=7.0Hz, 1H), 2.63 (s, 2H), 2.29(s,5H),2.14–1.86(m,4H),1.73(ddt,J=12.9,8.8,4.5Hz,2H),1.32(d,J=7.0Hz,3H). LCMS: MS m / z=187.09[M+1]; t R=0.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0710]

[0711] ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-methylpiperidin-4-yl ester. To a solution of L-alanine 1-methylpiperidin-4-yl ester (360 mg, 1.706 mmol) in DCM (10 mL) was added phenyl dichlorophosphate (0.255 mL, 1.706 mmol) in one portion at -78°C, followed by the addition of a solution of triethylamine (0.24 mL, 1.706 mmol) in DCM (2.76 mL) over 30 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and then recooled to -78°C. p-Nitrophenol (0.237 g, 1.706 mmol) was added in one portion, followed by the addition of triethylamine (0.237 mL, 1.706 mmol) over 30 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes, then diluted with EtOAc, washed with water and brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 10% MeOH in DCM) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.28–8.15 (m, 2H), 7.36 (m, 4H), 7.25–7.17 (m, 3H), 4.80 (s, 1H), 4.19–4.04 (m, 1H), 3.93 (m, 1H), 2.64 (s, 2H), 2.31 (m, 5H), 1.90 (m, 2H), 1.78–1.67 (m, 2H), 1.47–1.33 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.04, -3.07. LCMS: MS m / z = 464.32 [M+1]; t R=0.74 min; LC system: Thermo Accela 1250 UHPLC; MS system: ThermoLCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0712] Intermediate 31. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine (tetrahydro-2H-pyran-4-yl)carboxylic acid ester

[0713]

[0714] ((Benzyloxy)carbonyl)-L-alanine (tetrahydro-2H-pyran-4-yl)methyl ester. Cbz-L-Ala (446 mg, 2 mmol) was dissolved in anhydrous MeCN (10 mL). EDCI (422 mg, 2.2 mmol) was added in one portion and the reaction was stirred for 15 minutes. Tetrahydropyran-4-methanol (279 μL, 2.4 mmol) was added. DMAP (269 mg, 2.2 mmol) was then added in one portion. The reaction was stirred for 16 hours.

[0715] The reaction was diluted with EtOAc (30 mL) and washed with 5% aqueous citric acid (10 mL), then with saturated aqueous sodium bicarbonate (10 mL), and finally with brine (10 mL). The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO2 column chromatography (12 g SiO2 Combiflash HP Gold column, 0-80% ethyl acetate / hexane). The fractions were combined and concentrated under reduced pressure to give the product. 1 H NMR (400 MHz, chloroform-d) δ 7.40–7.28 (m, 5H), 5.28 (d, J = 7.9 Hz, 1H), 5.11 (s, 2H), 4.39 (t, J = 7.4 Hz, 1H), 4.07–3.84 (m, 4H), 3.38 (t, J = 11.7 Hz, 2H), 1.92 (s, 1H), 1.68–1.50 (m, 3H), 1.39 (m, 4H).

[0716]

[0717] ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine (tetrahydro-2H-pyran-4-yl)methyl ester. ((Benzyloxy)carbonyl)-L-alanine (tetrahydro-2H-pyran-4-yl)methyl ester (530 mg, 1.65 mmol) was dissolved in anhydrous THF (12 mL). 10% Pd / C Degussa was added and the reaction mixture was stirred under atmospheric hydrogen for 2 hours. The catalyst was filtered and the filtrate was used without purification.

[0718] Phenyl dichlorophosphate (294 μL, 1.98 mmol) was dissolved in anhydrous DCM (10 mL) and stirred in an ice bath under atmospheric nitrogen. The THF solution was added dropwise to the reaction and then stirred for 10 minutes. Triethylamine (300 μL, 2.15 mmol) was added dropwise and then stirred for 30 minutes. p-Nitrophenol (207 mg, 1.49 mmol) and triethylamine (300 μL, 2.15 mmol) were added. The ice bath was removed and the reaction mixture was stirred at room temperature for 14 hours.

[0719] The reaction was diluted with EtOAc (30 mL) and washed with 0.2 M sodium carbonate solution (2 x 10 mL) followed by brine (10 mL). The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO column chromatography (12 g SiO Combiflash HP Gold column, 0-50% ethyl acetate / hexane). The fractions were combined and concentrated under reduced pressure to give the product. 1 H NMR (400MHz, chloroform-d) δ8.23(d,J=9.0Hz,2H),7.45–7.30(m,4H),7.30–7.16(m,3H),4.23–4.07(m,2H),3.97(m,4H ),3.85(t,J=10.5Hz,1H),3.35(t,J=11.8Hz,2H),1.99–1.79(m,1H),1.56(d,J=8.4Hz,3H),1.48–1.29(m,4H). 31 P NMR (162 MHz, chloroform-d) δ -3.13 (s), -3.16 (s). MS m / z = 464.9 [M+1]; 463.1 [M-1].

[0720] Intermediate 32. trans-((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-(tert-butyl) cyclopentyl Hexyl ester

[0721]

[0722] Trans-L-Alanine 4-(tert-Butyl)cyclohexyl ester The product (845 mg) was prepared in a similar manner to that described for Intermediate 26 from Cbz-1-alanine (960 mg, 4.03 mmol) and trans-4-(tert-butyl)cyclohexanol (1.0 g, 6.45 mmol). 1 H NMR (400MHz, chloroform-d) δ4.65(tt,J=11.2,4.5Hz,1H),3.51(q,J=7.1Hz,1H),2.07–1.93(m ,2H),1.87–1.73(m,4H),1.40–1.23(m,4H),1.19–0.94(m,4H),0.85(d,J=2.6Hz,9H). MSm / z=228[M+H].

[0723]

[0724] trans-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-(tert-butyl)cyclohexyl ester. The product (520 mg) was prepared as an isomeric mixture from trans-L-alanine 4-(tert-butyl)cyclohexyl ester (420 mg, 1.85 mmol) in a manner similar to that described for Intermediate 25. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.27–8.19 (m, 2H), 7.37 (m, 4H), 7.28–7.16 (m, 3H), 4.62 (m, 1H), 4.17–4.00 (m, 1H), 3.88 (m, 1H), 1.95 (m, 2H), 1.80 (m, 2H), 1.39 (m, 3H), 1.35–1.22 (m, 2H), 1.15–0.92 (m, 3H), 0.85 (s, 9H). 31 P NMR (162 MHz, chloroform-d) δ -2.98, -3.04. MS m / z = 505 [M+H].

[0725] Intermediate 33. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ((1r,4S)-4-(trifluoromethyl) cyclohexyl)methyl ester

[0726]

[0727] ((1s,4s)-4-(trifluoromethyl)cyclohexyl)methanol. To an ice-cold solution of (1s,4s)-4-(trifluoromethyl)cyclohexanecarboxylic acid (3 g, 15.29 mmol) in anhydrous tetrahydrofuran (40 mL) was added lithium aluminum hydride (0.871 g, 22.94 mmol) in portions over 30 minutes. The reaction mixture was stirred at room temperature for 3 hours. It was cooled to 0°C and quenched with water (0.8 mL), 5N aqueous sodium hydroxide solution (0.8 mL), and then with water (2.4 mL). The separated solid was filtered and the filtrate was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The ethyl acetate was filtered and concentrated under reduced pressure to give the product. The obtained residue was dried under high vacuum for 1 hour and used as is in the subsequent reaction. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.47 (dd, J = 6.3, 1.9 Hz, 2H), 2.08-1.77 (m, 5H), 1.62-1.18 (m, 4H), 0.99 (qd, J = 13.0, 3.2 Hz, 2H). 19 F NMR (376 MHz, chloroform-d) δ -74.33 (d, J = 8.2 Hz).

[0728]

[0729] (tert-Butoxycarbonyl)-L-alanine ((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl ester. The product (1.48 g) was prepared in a similar manner to that described for Intermediate 12. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.00 (s, 1H), 4.30 (s, 1H), 4.04-3.89 (m, 2H), 2.08-1.79 (m, 5H), 1.74-1.57 (m, 1H), 1.44 (s, 9H), 1.38 (d, J = 7.2 Hz, 3H), 1.30 (m, 2H), 1.12-0.93 (m, 2H). 19 F NMR (376 MHz, chloroform-d) δ -74.38 (d, J = 7.8 Hz).

[0730]

[0731] (S)-1-Oxo-1-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methoxy)propan-2-aminium chloride. The product (1.184 g) was prepared in a similar manner to that described for Intermediate 13. 1H NMR (400MHz, DMSO-d6) δ8.55 (s, 3H), 4.17-3.88 (m, 3H), 2.21 (dtd, J = 12.2, 8.8, 3.3Hz, 1H), 1.83 (ddd, J=29.5,13.4,3.4Hz,4H),1.63(tdd,J=11.9,6.0,3.3Hz,1H),1.41(d,J=7.2Hz,3H),1.32-0.93(m,4H). 19 F NMR (377MHz, DMSO-d6) δ-72.84 (d, J=8.8Hz).

[0732]

[0733] ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl ester. The product (1.4 g) was prepared in a similar manner to that described for Intermediate 35. 1 H NMR (400MHz, DMSO-d6) δ8.37-8.22(m,2H),7.56-7.31(m,4H),7.30-7.14(m,2H),6.72(ddd,J=13.7,10.1,8.6Hz,1H),4.10-3.91(m ,1H),3.88-3.75(m,2H),2.20-1.99(m,1H),1.86-1.63(m,4H),1.54-1.41(m,1H),1.29-1.06(m,5H),0.98(td,J=12.7,3.2Hz,2H). MS m / z=531.02[M+1].

[0734] Intermediate 34. ((S)-(Perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine ethyl ester

[0735]

[0736] To a solution of L-alanine ethyl ester-HCl (631 mg, 2.465 mmol) in DCM (15 mL) was added phenyl dichlorophosphate (0.368 mL, 2.465 mmol) in one portion at -78 ° C., and triethylamine (0.68 mL, 4.93 mmol) was added dropwise at -78 ° C. within 5 minutes. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and then cooled to -78 ° C. Pentafluorophenol (454 mg, 2.465 mmol) was added in one portion, and triethylamine (0.34 mL, 2.465 mmol) was added at -78 ° C. within 5 minutes. After removing the dry ice bath, the resulting mixture was stirred for 1 hour, then diluted with DCM, washed with brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 60% EtOAc in hexane) to give a mixture of diastereomers, to which diisopropyl ether (4 mL) was added. The suspension was sonicated and filtered. The filter cake was purified by column chromatography (0 to 60% EtOAc in hexane) to give a mixture of diastereomers, to which diisopropyl ether (4 mL) was added. The suspension was sonicated and filtered. 1 H NMR showed that it was a mixture in a 3:1 ratio. Diisopropyl ether (5 mL) was added to the filter cake and the suspension was heated at 70° C. to a clear solution. After removing the heating bath, needle-like crystals began to form and after 10 minutes, the mixture was filtered and the filter cake was dried under high vacuum for 30 minutes to give the Sp isomer.

[0737] Diastereomeric mixture: 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.43–7.30 (m, 2H), 7.32–7.17 (m, 3H), 4.29–4.11 (m, 3H), 3.94 (m, 1H), 1.52–1.42 (m, 3H), 1.28 (q, J = 7.0 Hz, 3H).

[0738] Sp isomers: 1 H NMR (400 MHz, acetonitrile-d3) δ 7.50–7.36 (m, 2H), 7.32–7.21 (m, 3H), 4.75 (t, J = 11.5 Hz, 1H), 4.17–3.98 (m, 3H), 1.37 (dd, J = 7.1, 1.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H). 31 P NMR (162 MHz, acetonitrile-d3) δ -0.51. 19 F NMR (376 MHz, acetonitrile-d3) δ -155.48–-155.76 (m), -162.73 (td, J=21.3, 3.7 Hz), -165.02–-165.84 (m). LCMS m / z=440.5 (M-ethyl+H), t R=1.57 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0739] Intermediate 35. 2-Ethyl (2S)-2-cyclohexyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)acetate Butyl ester

[0740]

[0741] (S)-2-Ethylbutyl 2-amino-2-cyclohexyl acetate hydrochloride. Take L-cyclohexylglycine (0.90 g, 5.75 mmol) and place it in 2-ethyl-1-butanol (20 mL), and add trimethylchlorosilane (1.31 mL, 10.30 mmol) at one time. Place it in a preheated 60°C oil bath for 16 hours. Concentrate and co-evaporate with toluene 5 times in a 60°C rotary evaporator bath. Place it under high vacuum overnight to obtain the product. The material is used as is in the next step. 1 H NMR (400MHz, DMSO-d6) δ8.38 (s, 3H), 4.17–3.96 (m, 2H), 3.84 (d, J = 4.5Hz, 1H), 1.90–1.40 (m, 5H), 1.41–0.88 (m, 11H), 0.83 (t, J = 7.3Hz, 6H).

[0742]

[0743] 2-Ethylbutyl (2S)-2-cyclohexyl-2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)acetate. To a solution of 2-ethylbutyl (S)-2-amino-2-cyclohexylacetate hydrochloride (1.50 g, 5.39 mmol) and phenyl dichlorophosphate (0.803 mL, 5.39 mmol) in dichloromethane (50 mL) at 0°C under an argon atmosphere was added triethylamine (1.56 mL, 11.16 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 1 hour. 4-Nitrophenol (713 mg, 5.13 mmol) and triethylamine (0.81 mL, 5.63 mmol) were then added. After 2 hours, the reaction mixture was diluted with EtO (100 mL) and the solid was filtered off. The crude product was concentrated under reduced pressure and purified by silica gel chromatography (120 g SiO2 Combiflash HP Gold column, 0-50% ethyl acetate / hexanes) followed by reverse phase HPLC without the modifier 20%-100% ACN in water to give the product. 1 H NMR(400MHz,DMSO-d6)δ8.28(br d,J=9.3Hz,2H),7.55–7.28(m,4H),7.28–7.01(m,3H),6.61–6.52(m,1H),3.85(d, J=4.0Hz,2H)3.75–3.53(m,1H),1.67–1.31(m,7H),1.25(m,6H),1.16–0.67(m,9H). LC / MS:t R = 1.48 min, MS m / z = 519.03 [M+1]; LC system: Thermo Accela 1250 UHPLC. MS system: Thermo LCQ Fleet; Column: 2.6μ XB-C18 100A, 50 × 3.00 mm. Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid. Gradient: 2-100% ACN from 0 min to 2.4 min, 100% ACN from 2.4 min to 2.80 min, 100% ACN from 2.8 min to 2.85 min, 2% ACN from 2.85 min to 3.0 min, 1.8 mL / min.

[0744] Intermediate 36. ((4-nitrophenoxy)(phenoxy)phosphoryl)alanine (1-(2,2,2-trifluoroethyl)piperidin- 4-aminobenzoic acid methyl ester

[0745]

[0746] (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl (tert-butoxycarbonyl)alaninate The product (3.8 g) was prepared in a similar manner to that described for Intermediate 12. 1H NMR(400MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),4.08-3.72(m,3H),3.10(q,J=10.3Hz,2H),2.8 8(d,J=11.0Hz,2H),2.37-2.18(m,2H),1.66-1.47(m,3H),1.36(s,9H),1.21(d,J=7.5Hz,5H). 19 F NMR (376MHz, DMSO-d6) δ-68.52 (t, J=10.3Hz).

[0747]

[0748] Alanine (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl ester hydrochloride The product (3.52 g) was prepared in a similar manner to that described for Intermediate 13. 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 3H), 4.44–3.75 (m, 5H), 3.49–2.81 (m, 4H), 2.00–1.61 (m, 5H), 1.43 (d, J = 7.2Hz, 3H). 19 F NMR (376MHz, DMSO-d6) δ-63.30 (d, J = 443.2Hz).

[0749]

[0750] ((4-Nitrophenoxy)(phenoxy)phosphoryl)alanine (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl ester. The product (4.25 g) was prepared in a similar manner to that described for Intermediate 35. 1 H NMR (400MHz, DMSO-d6) δ8.32–8.24(m,2H),7.53–7.40(m,2H),7.39(ddd,J=8. 1,6.8,3.1Hz,2H),7.24(ddd,J=17.4,6.5,1.6Hz,3H),6.69(ddd,J=13.7,10.0 ,8.4Hz,1H),4.07–3.92(m,1H),3.88–3.77(m,2H),3.08(qd,J=10.3,1.6Hz,2H ),2.87–2.79(m,2H),2.25–2.14(m,2H),1.56–1.39(m,3H),1.26–1.08(m,5H). 31 P NMR (162MHz, DMSO-d6) δ-1.26,-1.49. 19F NMR (376MHz, DMSO-d6) δ-68.45 (td, J=10.2, 2.4Hz). LCMS: MS m / z=546.27[M+1];];t R =1.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0751] Intermediate 37. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine (1-ethyl-3,3-difluoropiperidin- 4-amino ester

[0752]

[0753] tert-Butyl 4-((((Benzyloxy)carbonyl)-L-alanyl)oxy)-3,3-difluoropiperidine-1-carboxylate. To a mixture of N-Cbz-L-alanine (2.0 g, 8.96 mmol), tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (2.12 g, 8.96 mmol), and EDCI (1.67 g, 10.75 mmol) in acetonitrile (20 mL) was added DMAP (1.64 g, 13.44 mmol). The mixture was then stirred at room temperature for 15 hours before being diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (50 to 100% EtOAc in hexanes) to provide the product. 19 F NMR (377MHz, chloroform-d)δ-114.32(m),-117.73–-121.11(m). LCMS: MS m / z=343.14[M+1-Boc],386.82(M+1-t-Bu); t R=1.23 min; LC system: Thermo Accela 1250 UHPLC; MS system: ThermoLCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0754]

[0755] ((Benzyloxy)carbonyl)-L-alanine 3,3-difluoropiperidin-4-yl ester. To a mixture of tert-butyl 4-((((benzyloxy)carbonyl)-L-alanyl)oxy)-3,3-difluoropiperidine 1-carboxylate (330 mg, 0.746 mmol) in DCM (5 mL) was slowly added 4M HCl in dioxane (0.9 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, concentrated in vacuo, co-evaporated with DCM several times, and dried under high vacuum for 15 hours to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (m, 5H), 5.59 (m, 1H), 5.27–5.01 (m, 3H), 4.53–4.25 (m, 1H), 3.12 (m, 1H), 3.03–2.76 (m, 2H), 2.73 (s, 1H), 1.94 (s, 1H), 1.80 (s, 1H), 1.41 (d, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, chloroform-d) δ -114.66 (dd, J = 245.9, 61.8 Hz), -119.63.

[0756]

[0757] A mixture of ((benzyloxy)carbonyl)-L-alanine 3,3-difluoropiperidin-4-yl ester (450 mg, 1.190 mmol), acetaldehyde (0.194 mL, 2.629 mmol) and acetic acid (0.15 mL, 2.629 mmol) in DCM (9 mL) was stirred at room temperature for 20 minutes, and sodium cyanoborohydride (330 mg, 5.258 mmol) was added. The resulting mixture was stirred for 1 hour and the product was analyzed by preparative HPLC (Phenominex Gemini 10u C18 Purification using a 250 x 21.2 mm column, 20-80% acetonitrile (0.1% TFA) / water (0.1% TFA) gradient) gave the product. 1 H NMR (400MHz, acetonitrile-d3) δ10.18(bs,2H),7.38(m,5H),6.19(m,1H),5.47–5.26(m,1H),4.33(m, 1H), 3.82–2.98 (m, 6H), 2.30 (s, 1H), 2.16 (s, 1H), 1.42 (m, 3H), 1.31 (td, J = 7.3, 1.5Hz, 3H). LCMS: MS m / z=371.27[M+1]; t R =0.66 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0758]

[0759] A mixture of ((benzyloxy)carbonyl)-L-alanine 1-ethyl-3,3-difluoropiperidin-4-yl ester (450 mg, 0.929 mmol) and 20% Pd(OH)2 / C in THF (10 mL) was stirred at room temperature under H2 for 1 hour, filtered, concentrated in vacuo, co-evaporated with DCM several times, and dried under high vacuum for 1 hour to give the product. LCMS: MS m / z = 237.09 [M+1]; t R =0.15 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0760]

[0761] ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 1-ethyl-3,3-difluoropiperidin-4-yl ester. Methylene chloride (10 mL) was added to a slurry of L-alanine 1-ethyl-3,3-difluoropiperidin-4-yl ester (480 mg, 1.37 mmol) and TEA (0.190 mL, 0.370 mmol) was added to obtain a solution which was cooled to -78°C and phenyl dichlorophosphate (0.205 mL, 1.370 mmol) was added rapidly. At -78°C, the mixture was stirred for 30 minutes. Triethylamine (0.190 mL, 1.37 mmol) was added. The resulting mixture was stirred at the same temperature for 30 minutes, and 4-nitrophenol (191 mg, 1.370 mmol) was added all at once. Triethylamine (0.190 mL, 1.370 mmol) was then added at -78°C over 30 minutes. The mixture was then stirred at room temperature for 2 hours, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (0 to 100% EtOAc in hexane) to give the product. 1 H NMR (400MHz, chloroform-d) δ8.29–8.15(m,2H),7.44–7.28(m,4H),7.27–7.11(m,3H),5.03(m,1H),4.34–4.14(m,1H),3.94–3.75(m,1H) ),2.88(s,1H),2.63-2.49(m,4H),2.39(m,1H),2.03–1.93(m,1H),1.93–1.77(m,1H),1.44(m,3H),1.09(td,J=7.2,1.0Hz,3H). 31 P NMR (162 MHz, chloroform-d) δ -3.21, -3.26, -3.32, -3.46. 19 FNMR (377MHz, chloroform-d) δ -110.50 (d, J = 244.0Hz), -116.76 (m). LCMS: MS m / z=514.29[M+1]; t R =0.80 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0762] Intermediate 38. 4-Nitrophenyl-N,N'-ethyl L-alaninate phosphorodiamidate

[0763]

[0764] To a solution of L-alanine ethyl ester HCl salt (1.8 g, 11.72 mmol) in DCM (20 mL) was added 4-nitrophenyl dichlorophosphate (1.5 g, 5.86 mmol) in one portion. The resulting mixture was cooled to 0 ° C. and triethylamine (2.37 g, 23.44 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 30 minutes and stirred overnight. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluted with 0-100% ethyl acetate in hexane) to give the product. LCMS: MS m / z = 417.93 [M + 1], t R =1.23 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =3.02 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0765] Intermediate 39. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine benzyl ester

[0766]

[0767] Phenyl dichlorophosphate (1.49 mL, 10 mmol) was dissolved in 20 mL of anhydrous dichloromethane and stirred in an ice bath under atmospheric nitrogen. L-alanine benzyl ester HCl (2.2 g, 10 mmol) was added to the reaction solution in a single step and stirred for 10 minutes. Triethylamine (3 mL, 22 mmol) was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the reaction. The reaction mixture was stirred for 2 hours. p-Nitrophenol (1.25 g, 9 mmol) was added in a single step. Triethylamine (1.5 mL, 11 mmol) was dissolved in 3 mL of anhydrous dichloromethane and added dropwise to the reaction. The reaction mixture was stirred for 1 hour and diluted with dichloromethane (10 mL) and washed with water (3 × 10 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO column chromatography (4 g SiO Combiflash HP Gold column, 0-30% ethyl acetate / hexane). Fractions containing the desired product were combined and concentrated under reduced pressure to afford the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.24–8.10 (m, 2H), 7.40–7.10 (m, 12H), 5.14 (m, 2H), 4.19 (m, 1H), 3.87 (m, 1H), 1.47–1.36 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.15, -3.29. LCMS: MS m / z = 457.1 [M+1]; 455.1 [M-1], t R =1.45 min; LC system: ThermoDionex ultimate 3000 UHPLC; column: Phenomenex Kinetex 2.6μ C18 100A, 50×3 mm; solvent: A: water containing 0.1% acetic acid, B: acetonitrile containing 0.1% acetic acid; gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% B, 2 mL / min. HPLC: t R =4.03 min; HPLC system: Agilent 1100 series; column: Phenomenex Gemini 5μC18 110A, 50×4.6 mm; solvent: A: water containing 0.1% TFA, B: acetonitrile containing 0.1% TFA; gradient: 2-98% B in 5 min, 2 mL / min.

[0768] Intermediate 40. 4-Nitrophenyl-N,N'-methyl L-alanine ester phosphorodiamidate

[0769]

[0770] Triethylamine (3.68 mL, 26.4 mmol) was added to a solution of L-alanine methyl ester hydrochloride (1.63 g, 12.0 mmol) and 4-nitrophenyl dichlorophosphate (1.5 g, 5.9 mmol) in dichloromethane (23 mL) at 0° C. under an argon atmosphere. After 3 hours, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to provide the product. 1 H NMR (400 MHz, chloroform-d1) 8.25–8.16 (m, 2H), 7.38 (dd, J = 9.3, 1.0 Hz, 2H), 4.17–3.95 (m, 2H), 3.73 (br s, 6H), 3.61 (br t, J = 10.0 Hz, 2H), 1.42 (s, 3H), 1.40 (s, 1H). 31 P NMR (162 MHz, chloroform-d1) δ 7.82 (s). LCMS: MS m / z = 389.98 [M+1], t R =1.11 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =2.81 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN, 2 mL / min.

[0771] Intermediate 41. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine methyl ester

[0772]

[0773] Phenyl dichlorophosphate (2.81 mL, 18.9 mmol) and triethylamine (5.38 mL, 37.9 mmol) were added sequentially to a suspension of L-alanine methyl ester hydrochloride (2.64 g, 18.9 mmol) in dichloromethane (100 mL) at 0°C. After 1 hour, 4-nitrophenol (2.64 g, 18.9 mmol) and triethylamine (2.64 mL, 18.9 mmol) were then added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 2.5 hours, the reaction mixture was diluted with dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to provide the product. 1 H NMR (400 MHz, chloroform-d1) δ 8.25–8.18 (m, 2H), 7.43–7.29 (m, 4H), 7.29–7.15 (m, 3H), 4.24–4.07 (m, 1H), 3.97 (br q, J = 9.8 Hz, 1H), 3.70 (s, 3H), 1.45–1.35 (m, 3H). 31 P NMR (162 MHz, chloroform-d1) δ -3.12 (s), -3.17 (s). LCMS: MS m / z = 380.98 [M+1], t R =1.59 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =3.49 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN, 2 mL / min.

[0774] Intermediate 42. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine methyl ester

[0775]

[0776] 4-Nitrophenyl dichlorophosphate (2.00 g, 7.81 mmol) and triethylamine (2.18 mL, 15.6 mmol) were added sequentially to a suspension of L-alanine methyl ester hydrochloride (1.091 g, 18.9 mmol) in dichloromethane (23 mL) at 0°C under an argon atmosphere. After 1 hour, benzyl alcohol (0.810 mL, 7.81 mmol) and triethylamine (1.09 mL, 7.81 mmol) were then added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to provide the product. 1 H NMR (400 MHz, chloroform-d1) δ 8.32–8.09 (m, 2H), 8.32–8.09 (m, 7H), 5.15 (app t, J = 8.4 Hz, 2H), 4.70 (s, 1H), 4.07–3.93 (m, 1H), 3.73–3.65 (m, 3H), 1.42–1.31 (m, 3H). 31 P NMR (162 MHz, chloroform-d1) δ 2.23 (s), 2.15 (s). LCMS: MS m / z = 394.9 [M+1], t R =1.34 min; LC system: Thermo Accela1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; solvent: acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min.

[0777] Intermediate 43. ((4-(dimethylcarbamoyl)phenoxy)(4-nitrophenoxy)phosphoryl)-L-alanine Isopropyl ester

[0778]

[0779] To a solution of 4-nitrophenyl dichlorophosphate (620 mg, 2.422 mmol) and L-alanine isopropyl ester-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added a solution of TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 minutes at -78° C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and cooled to -78° C. and N,N-dimethyl-4-hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and a solution of TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) was added over 30 minutes at -78° C. After removing the dry ice bath, the resulting mixture was stirred for 1 hour, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.26–8.18 (m, 2H), 7.45–7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17–3.94 (m, 2H), 3.19–2.84 (m, 6H), 1.39 (m, 3H), 1.27–1.16 (m, 6H). 31 P NMR (162MHz, chloroform-d) delta -3.13, -3.21. MS m / z=480(M+H). LCMS: MS m / z=480.26[M+1]; t R =1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: ThermoLCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0780] Intermediate 44. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine oxetan-3-yl ester

[0781]

[0782] ((Benzyloxy)carbonyl)-L-alanine oxetan-3-yl ester. To a mixture of ((benzyloxy)carbonyl)-L-alanine (1.8 g, 8.1 mmol), 3-hydroxyoxetane (0.5 g, 6.75 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (1.68 g, 8.77 mmol) in acetonitrile (100 mL) was added 4-(dimethylamino)pyridine (DMAP, 1.24 g, 10.12 mmol). The mixture was then stirred at room temperature for 2 hours, after which the reaction mixture was diluted with EtOAc, washed with brine, and the organic solvent dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to provide the product. 1 H NMR (400MHz, chloroform-d) δ7.40–7.28(m,5H),5.47(p,J=5.9Hz,1H),5.30(d,J=8.0Hz,1H),5.10(s,2H),4. 88(t,J=7.1Hz,2H), 4.62(ddd,J=17.5,7.7,5.3Hz,2H), 4.41(p,J=7.3Hz,1H), 1.44(d,J=7.3Hz,3H). LCMS: MS m / z=280.04[M+1],t R =1.11 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =2.82 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0783]

[0784] L-Alanine oxetan-3-yl ester. ((Benzyloxy)carbonyl)-L-alanine oxetan-3-yl ester (0.1 g, 0.36 mmol) was dissolved in DCM (5 mL), 15 mg of Pd-C (10%, wet) was added to the solution, the reaction flask was degassed and then inflated with H2 balloon, stirred at room temperature for 2 hours, then the reaction mixture was filtered, the solvent was evaporated under vacuum, and the residue was dried under high vacuum for 5 minutes to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.42 (p, J = 5.7 Hz, 1H), 4.87 (t, J = 6.9 Hz, 2H), 4.65–4.54 (m, 2H), 3.58 (qd, J = 7.0, 2.1 Hz, 1H), 1.49 (d, J = 7.1 Hz, 2H), 1.34 (dd, J = 7.2, 2.1 Hz, 3H).

[0785]

[0786] ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine oxetan-3-yl ester. To a solution of L-alanine oxetan-3-yl ester (120 mg, 0.83 mmol) in DCM (10 mL) was added phenyl dichlorophosphate (175 mg, 0.83 mmol) in one portion. The resulting mixture was cooled to 0° C., and triethylamine (252 mg, 2.49 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 30 minutes and cooled to 0° C., and p-nitrophenol (115 mg, 0.83 mmol) was added in one portion, and triethylamine (252 mg, 2.49 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 30 minutes, diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluting with 0-100% ethyl acetate in hexanes) to give the product. LCMS: MS m / z=423.06[M+1],t R =1.25 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R=3.15 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0787] Intermediate 45. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine propyl ester

[0788]

[0789] (tert-Butoxycarbonyl)-L-alanine propyl ester. At room temperature, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.08 g, 31.71 mmol) was added to a solution of Boc-Ala-OH (5 g, 26.43 mmol) and n-propanol (6.02 mL, 80.6 mmol) in acetonitrile (125 mL). After 15 minutes, 4-(dimethylamino)pyridine (3.23 g, 26.43 mmol) was added. After 16 hours, the reaction mixture was concentrated to half its volume, and the mixture was diluted with ethyl acetate (250 mL), and the resulting mixture was washed with saturated aqueous sodium carbonate solution (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography, eluting with 0-20% EtOAc in hexane to obtain the product. 1 H NMR (400 MHz, acetonitrile-d3) δ 5.57 (s, 1H), 4.19-3.92 (m, 3H), 1.63 (h, J = 7.1 Hz, 2H), 1.40 (s, 9H), 1.30 (d, J = 7.3 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). LCMS: MS m / z = 231.60 [M+1], t R =1.10 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0790]

[0791] L-Alanine propyl ester hydrochloride. A 4M hydrochloric acid solution in dioxane (16.91 mL) was added to a solution of (tert-butoxycarbonyl)-L-alanine propyl ester (3.91 g, 16.91 mmol) in dichloromethane (10 mL) at room temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure to obtain the product. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.45 (s, 3H), 4.22-4.11 (m, 2H), 4.11-3.99 (m, 1H), 1.68 (dtd, J = 14.0, 7.4, 6.6 Hz, 2H), 1.60 (d, J = 7.2 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). LCMS: MS m / z = 131.94 [M+1], t R =0.32 min; LC system: Thermo Accela1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0792]

[0793] ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine propyl ester. A solution of phenyl dichlorophosphate (0.89 mL, 5.97 mmol) in dichloromethane (12 mL) was added dropwise over 15 minutes to a solution of L-alanine propyl ester hydrochloride (1.0 g, 5.97 mmol) in dichloromethane (12 mL) at 0°C. After the addition was complete, a solution of triethylamine (2.0 mL, 14.32 mmol) in dichloromethane (2.5 mL) was added over 5 minutes. After 3.5 hours, 4-nitrophenol (0.83 g, 5.97 mmol) and triethylamine (1.0 mL, 7.16 mmol) were then added sequentially at 0°C, and the resulting mixture was then allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 x 100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to provide the product. 1H NMR (400 MHz, acetonitrile-d3) δ 8.28-8.20 (m, 2H), 7.49-7.35 (m, 4H), 7.31-7.19 (m, 3H), 4.72-4.56 (m, 1H), 4.14-4.02 (m, 1H), 3.99 (td, J = 6.6, 2.5 Hz, 2H), 1.58 (dtdd, J = 13.9, 7.4, 6.5, 0.9 Hz, 2H), 1.31 (ddd, J = 7.1, 4.2, 1.1 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 31 PNMR(162MHz, acetonitrile-d3)δ-2.12,-2.22. LCMS: MS m / z=409.12[M+1],t R =1.15 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100% to 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R =5.73 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN, 2 mL / min.

[0794] Intermediate 46. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine oxetan-3-ylmethyl ester

[0795]

[0796] ((Benzyloxy)carbonyl)-L-alanine oxetan-3-ylmethyl ester. To a mixture of ((benzyloxy)carbonyl)-L-alanine (6.08 g, 27.24 mmol), oxetan-3-ylmethanol (2 g, 22.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl salt (EDCI) (5.66 g, 29.51 mmol) in acetonitrile (100 mL) was added 4-(dimethylamino)pyridine (DMAP, 4.16 g, 34.05 mmol). The mixture was then stirred at room temperature for 2 hours, after which the reaction mixture was diluted with EtOAc, washed with brine, and the organic solvent was dried over sodium sulfate and then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to give the product. LCMS: MS m / z=280.04 [M+1], t R =1.11 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =2.88 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0797]

[0798] L-Alanine oxetan-3-ylmethyl ester. ((Benzyloxy)carbonyl)-L-alanine oxetan-3-ylmethyl ester (2.2 g, 8 mmol) was dissolved in DCM (25 mL), 500 mg of Pd-C (10%, wet) was added to the solution, the reaction flask was degassed and then inflated with H2 balloon, stirred at room temperature for 2 hours, then the reaction mixture was filtered, the solvent was evaporated under vacuum, and the residue was dried under high vacuum for 5 minutes to give the product. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.77 (dd, J = 7.9, 6.3 Hz, 2H), 4.44 (td, J = 6.1, 2.5 Hz, 2H), 4.38–4.23 (m, 2H), 3.55 (q, J = 7.0 Hz, 1H), 3.34–3.19 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H).

[0799]

[0800] ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine oxetan-3-ylmethyl ester. To a solution of L-alanine oxetan-3-ylmethyl ester (1.19 g, 7.11 mmol) in DCM (20 mL) was added phenyl dichlorophosphate (1.5 g, 7.11 mmol) in one portion. The resulting mixture was cooled to 0° C., and triethylamine (1.44 g, 14.22 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 30 minutes and cooled to 0° C., and p-nitrophenol (0.99 g, 7.1 mmol) was added in one portion, and triethylamine (1.44 g, 14.22 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 30 minutes, diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluting with 0-100% ethyl acetate in hexanes) to give the product. LCMS: MS m / z=437.14[M+1],t R =1.25 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =3.36 min; HPLC system: Agilent 1290 II; column: Phenomenex Kinetex C18, 2.6u 110A, 100×4.6 mm; solvent: A: water containing 0.1% TFA: acetonitrile containing 0.1% TFA; gradient: 2%-98% B, 8.5 min gradient, 1.5 mL / min.

[0801] Intermediate 47. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine cyclobutyl ester

[0802]

[0803] Under a nitrogen atmosphere in an ice bath, to a solution of L-alanine cyclobutyl ester (1.8 g, 10 mmol) in DCM (10 mL) was added phenyl dichlorophosphate (2.1 g, 10 mmol) in one portion. Triethylamine (1.11 g, 11 mmol) was then added dropwise. After removing the ice bath, the resulting mixture was stirred for 2 hours and cooled to 0°C, and p-nitrophenol (2.5 g, 18 mmol) was added in one portion, and triethylamine (1.11 g, 11 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 2 hours, diluted with EtOAc, washed twice with 5% aqueous citric acid solution, then washed with brine, the organic solvent was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluted with 0-100% ethyl acetate in hexane) to give the product. MS m / z=422.0 (M+H) + .

[0804] Separation of Sp and Rp diastereomers. The product was purified by chiral preparative HPLC (Chiralpak IA, 150×4.6 mm, heptane 70%, IPA 30%) to form intermediates 48 and 49:

[0805]

[0806] Intermediate 48. First eluting diastereomer of Intermediate 47: 1 H NMR (400 MHz, methanol-d4) δ 8.33-8.23 (m, 2H), 7.52-7.33 (m, 4H), 7.33-7.17 (m, 3H), 4.96-4.85 (m, 1H), 4.07-3.96 (m, 1H), 2.27 (m, 2H), 2.07-1.91 (m, 2H), 1.83-1.70 (m, 1H), 1.70-1.55 (m, 1H), 1.32 (ddd, J = 7.2, 5.3, 1.2 Hz, 3H). 31 P NMR (162 MHz, methanol-d4) δ 1.36. LCMS: MS m / z = 421.05 [M+1], t R=1.42 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R =8.07 min; HPLC system: Chiralpak IC, 150×4.6 mm, 5 μm, CN=IC00CD-QC005, 1 CV=2.49 mL, CV#1, column valve: position 3, 15 mL / 15 min, 1 mL / min. Pmax=300 bar; solvent valve: D: heptane 70%, #6: IPA 30%.

[0807] Intermediate 49. The second eluting diastereomer of Intermediate 47: 1 H NMR (400 MHz, methanol-d4) δ 8.33-8.23 (m, 2H), 7.52-7.33 (m, 4H), 7.33-7.17 (m, 3H), 4.96-4.85 (m, 1H), 4.07-3.96 (m, 1H), 2.27 (m, 2H), 2.07-1.91 (m, 2H), 1.83-1.70 (m, 1H), 1.70-1.55 (m, 1H), 1.32 (ddd, J = 7.2, 5.3, 1.2 Hz, 3H). 31 P NMR (162 MHz, methanol-d4) δ 1.59. LCMS: MS m / z = 420.90 [M+1], t R =1.42 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18100A, 50×4.6 mm; Solvent: Acetonitrile containing 0.1% acetic acid, Water containing 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN, 2 μL / min. HPLC: t R= 11.50 min; HPLC system: Chiralpak IC, 150×4.6 mm, 5 μm, CN=IC00CD-QC005, 1 CV=2.49 mL, CV#1, column valve: position 3, 15 mL / 15 min, 1 mL / min. Pmax=300 bar; solvent valve: D: heptane 70%, #6: IPA 30%.

[0808] Intermediate 50. ((S)-(Perfluorophenoxy)(phenoxy)phosphoryl)-L-alanine methyl ester

[0809]

[0810] L-Alanine methyl ester hydrochloride (14g, 100mmol) is mixed with 50mL anhydrous DCM, and under atmospheric nitrogen, stir in ice bath.Dichlorophosphoric acid phenyl ester (16.4mL, 110mmol) is added drop-wise in the reaction, and reaction mixture is stirred 30 minutes.Triethylamine (29.4mL, 210mmol) is mixed with 20mL anhydrous DCM and is added drop-wise in the reaction.The reaction is stirred 1 hour.Disposable addition pentafluorophenol (18.4g, 100mmol).Triethylamine (14.7mL, 105mmol) is mixed with 30mL anhydrous DCM and is added drop-wise in the reaction.Reaction mixture is at room temperature stirred 16 hours.

[0811] The reaction was diluted with DCM (50 mL) and washed with water (5 × 10 mL). The organic matter was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a solid. Isopropyl ether (130 mL) was added to the solid. The bulk solid was broken up and then ultrasonicated for 20 minutes, and the mixture was then stirred for 24 hours.

[0812] The solid was collected and washed with a small amount of isopropyl ether (30 mL). The solid was dried under high vacuum to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.40–7.32 (m, 2H), 7.28–7.19 (m, 3H), 4.20 (m, 1H), 3.96–3.85 (m, 1H), 3.74 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H). 31 P NMR (162 MHz, chloroform-d) δ -1.62. 19 F NMR (376MHz, chloroform-d) δ -153.82 (dd, J = 18.5, 2.7Hz), -159.99 (td, J = 21.8, 3.8Hz), -162.65 (dd, J = 22.2, 17.6Hz). LCMS: MS m / z=425.9[M+1], 423.9[M-1], t R=1.68 min; LC system: Thermo Dionex Ultimate 3000 UHPLC; column: Phenomenex Kinetex 2.6μ C18 100A, 50×3 mm; solvent: A: water containing 0.1% acetic acid, B: acetonitrile containing 0.1% acetic acid; gradient: 0 min-0.3 min 5% B, 0.3 min-1.5 min 5-100% B, 1.5 min-2 min 100% B, 2 min-2.2 min 100-5% B, 2 mL / min. HPLC: t R =3.76 min; HPLC system: Agilent 1100 series; column: Phenomenex Gemini 5μC18 110A, 50×4.6 mm; solvent: A: water containing 0.1% TFA, B: acetonitrile containing 0.1% TFA; gradient: 2-98% B in 5 min, 2 mL / min.

[0813] Intermediate 51. ((4-(2-methoxyethoxy)phenoxy)(4-nitrophenoxy)phosphoryl)-L-alanine isocyanate Propyl ester

[0814]

[0815] A solution of 4-nitrophenyl dichlorophosphate (503 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise to a solution of L-alanine isopropyl ester hydrochloride (329 mg, 1.97 mmol) in dichloromethane (20 mL) at 0°C over 10 minutes. After the addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 90 minutes, 4-(2-methoxy-ethoxy)phenol (331 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 20% to 100% ethyl acetate in hexanes) to provide the product. 1 HNMR (400 MHz, methanol-d4) δ 8.32-8.24 (m, 2H), 7.51-7.39 (m, 2H), 7.24-7.12 (m, 2H), 6.97-6.90 (m, 2H), 4.94 (septet, J = 6.2, 3.2 Hz, 1H), 4.12-4.07 (m, 2H), 4.05-3.93 (m, 1H), 3.76-3.68 (m, 2H), 3.41 (d, J = 0.5 Hz, 3H), 1.32 (td, J = 7.1, 1.2 Hz, 3H), 1.19 (dt, J = 6.3, 2.0 Hz, 6H).31 P NMR (162 MHz, methanol-d4) δ -0.86, -1.06. LCMS: MS m / z = 483.06 [M+1], t R =1.39 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100% to 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R =5.58 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN, 2 mL / min.

[0816] Intermediate 52. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine butyl ester

[0817]

[0818] A solution of phenyl dichlorophosphate (0.89 mL, 5.97 mmol) in dichloromethane (12 mL) was added dropwise to a solution of L-alanine butyl ester hydrochloride (CAS#81305-85-3, 1.0 g, 5.97 mmol) in dichloromethane (12 mL) at 0°C over 15 minutes. After the addition was complete, a solution of triethylamine (2.0 mL, 14.32 mmol) in dichloromethane (2.5 mL) was added over 5 minutes. After 3.5 hours, 4-nitrophenol (0.83 g, 5.97 mmol) and triethylamine (1.0 mL, 7.16 mmol) were then added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with dichloromethane (50 mL), washed with water (2 x 100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to provide the product. 1H NMR (400 MHz, methanol-d4) δ 8.31–8.23 (m, 1H), 7.52–7.34 (m, 2H), 7.32–7.18 (m, 2H), 4.04 (td, J = 6.6, 2.7 Hz, 2H), 1.60–1.48 (m, 1H), 1.40–1.26 (m, 3H), 0.89 (t, J = 7.4 Hz, 2H). 31 P NMR (162 MHz, methanol-d4) δ -1.36, -1.59. LCMS: MS m / z = 423.13 [M+1], t R =1.22 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0819] Intermediate 53. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 3-methoxypropyl ester

[0820]

[0821] L-Alanine 3-methoxypropyl ester. To a mixture of Cbz-L-alanine (2.80 g, 12.54 mmol), 3-methoxypropanol (1.00 mL, 10.45 mmol), and EDCI (2.11 g, 13.59 mmol) in acetonitrile (40 mL) was added DMAP (1.92 g, 15.68 mmol). The mixture was then stirred at room temperature for 15 hours, then diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 to 50% EtOAc in hexane, 35 minute run) to give Cbz-L-alanine ester (2.78 g), which was dissolved in THF (20 mL) and 20% Pd(OH)2 (800 mg, 1.14 mmol) was added at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours, filtered, concentrated in vacuo, and dried under high vacuum to give the product. 1H NMR (400 MHz, chloroform-d) δ 4.28–4.14 (m, 2H), 3.55 (q, J = 7.0 Hz, 1H), 3.43 (t, J = 6.2 Hz, 2H), 3.32 (s, 3H), 1.98–1.85 (m, 4H), 1.33 (d, J = 7.0 Hz, 3H). LCMS m / z = 161.98 (M+H), t R =0.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0822]

[0823] ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 3-methoxypropyl ester. To a solution of L-alanine 3-methoxypropyl ester (1.32 g, 8.20 mmol) in DCM (20 mL) was added phenyl dichlorophosphate (1.23 mL, 8.20 mmol) quickly in one portion at -78°C. Triethylamine (1.14 mL, 8.20 mmol) was then added over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and cooled to -78°C. p-Nitrophenol (1.14 g, 8.20 mmol) was added in one portion, and triethylamine (1.14 mL, 8.20 mmol) was added over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 2 hours. After dilution with DCM, the mixture was washed with brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.26–8.19 (m, 2H), 7.36 (m, 4H), 7.27–7.15 (m, 3H), 4.20 (m, 2H), 4.17–4.06 (m, 1H), 3.91 (m, 1H), 3.40 (m, 2H), 3.30 (m, 3H), 1.87 (m, 2H), 1.40 (m, 3H). 31 P NMR (162 MHz, chloroform-d) δ -3.07, -3.10. LCMS: m / z = 439.11 (M+H). t R=1.36 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0824] Intermediate 54. (2S)-2-(((Benzyloxy)carbonyl)amino)-3-(4-(((((S)-1-methoxy-1-oxopropyl)- 2-amino)(4-nitrophenoxy)phosphoryl)oxy)phenyl)propionic acid methyl ester

[0825]

[0826] A solution of L-alanine methyl ester hydrochloride (275 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise to a solution of 4-nitrophenyl dichlorophosphate (504 mg, 1.97 mmol) in dichloromethane (20 mL) at 0°C over 10 minutes. After the addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 60 minutes, N-benzyloxycarbonyl-L-tyrosine methyl ester (649 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to provide the product. 1 H NMR (400 MHz, methanol-d4) δ 8.34-8.17 (m, 2H), 7.53-7.37 (m, 2H), 7.37-7.09 (m, 9H), 5.02 (s, 2H), 4.43 (dd, J = 9.4, 5.2 Hz, 1H), 4.19-3.97 (m, 1H), 3.70 (s, 3H), 3.62 (d, J = 4.4 Hz, 3H), 3.16 (dd, J = 14.0, 5.4 Hz, 1H), 2.93 (dd, J = 14.1, 9.8 Hz, 1H), 1.32 (td, J = 7.3, 1.2 Hz, 3H). 31 P NMR (162 MHz, methanol-d4) δ -1.30, -1.51. LCMS: MS m / z = 616.03 [M+1], t R=1.63 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100% to 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R =5.81 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN, 2 mL / min.

[0827] Intermediate 55. (S)-Tetrahydrofuran-3-yl ((4-nitrophenoxy) (phenoxy)

[0828]

[0829] (S)-L-alanine tetrahydrofuran-3-yl ester. To a mixture of N-Cbz-L-alanine (3.31 g, 14.83 mmol), (S)-THF-3-ol (1.0 mL, 12.34 mmol), and EDCI (2.49 g, 16.04 mmol) in acetonitrile (20 mL) was added DMAP (2.26 g, 18.51 mmol). The mixture was then stirred at room temperature for 15 hours before being diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 to 80% EtOAc in hexanes) to afford Cbz-L-alanine 4-THF ester, which was dissolved in THF (20 mL) and 20% palladium hydroxide (433 mg, 0.617 mmol) was added at room temperature. The resulting mixture was stirred at room temperature under H2 gas for 2 h, filtered, and concentrated in vacuo, co-evaporated with DCM multiple times, and dried under high vacuum for 15 h to give the product. 1 H NMR (400MHz, chloroform-d) δ5.37–5.29(m,1H),3.97–3.77(m,4H),3.61–3.52(m,1H),2.27– 2.12(m,1H),2.02(dt,J=12.8,5.6Hz,1H),1.76(s,2H),1.34(dd,J=7.1,1.5Hz,3H). LCMS m / z=159.94(M+H),t R=0.12 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0830]

[0831] (S)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine tetrahydrofuran-3-yl ester. To a solution of (S)-L-alanine tetrahydrofuran-3-yl ester (1.45 g, 9.10 mmol) in DCM (20 mL) was added phenyl dichlorophosphate (1.37 mL, 9.10 mmol) quickly in one portion at -78°C. Triethylamine (1.27 mL, 9.10 mmol) was then added over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and cooled to -78°C. p-Nitrophenol (1.27 g, 9.10 mmol) was added in one portion, and triethylamine (1.27 mL, 9.10 mmol) was added over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 2 hours. After dilution with DCM, the mixture was washed with brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give the product. 1 H NMR (400MHz, chloroform-d) δ8.22(m,2H),7.49–7.31(m,4H),7.30–7.12(m,3H),5.29(m,1H),4. 14(m,1H),4.00–3.79(m,4H),3.82–3.60(m,1H),2.17(m,1H),1.95(m,1H),1.40(m,3H). 31 P NMR (162 MHz, chloroform-d) δ -3.18, -3.20. LCMS: m / z = 437.05 (M+H), t R=1.41 min; LC system: ThermoAccela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0832] Intermediate 56. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 3-morpholinopropyl ester

[0833]

[0834] A solution of 4-nitrophenyl dichlorophosphate (503 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise to a solution of L-alanine 3-morpholinopropyl ester hydrochloride (496 mg, 1.97 mmol) in dichloromethane (20 mL) at 0°C over 10 minutes. After the addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 90 minutes, phenol (185 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 20%-100% ethyl acetate in hexane) to provide the product. 1 H NMR (400MHz, methanol-d4) δ8.32-8.24(m,2H),7.51-7.39(m,2H),7.24-7.12(m,2H),6.97-6.90(m,2H),4.94(m,1H),4.12-4.07(m ,2H),4.05-3.93(m,1H),3.76-3.68(m,2H),3.41(d,J=0.5Hz,3H),1.32(td,J=7.1,1.2Hz,3H),1.19(dt,J=6.3,2.0Hz,6H). 31 P NMR (162MHz, acetonitrile-d3) δ-2.12,-2.22. LCMS: MS m / z=494.35[M+1],t R=1.03 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0835] Intermediate 57. (R)-tetrahydrofuran-3-yl ((4-nitrophenoxy) (phenoxy)

[0836]

[0837] (R)-L-alanine tetrahydrofuran-3-yl ester. To a mixture of N-Cbz-L-alanine (3.31 g, 14.83 mmol), (R)-THF-3-ol (1.0 mL, 12.34 mmol), and EDCI (2.49 g, 16.04 mmol) in acetonitrile (20 mL) was added DMAP (2.26 g, 18.51 mmol). The mixture was then stirred at room temperature for 15 hours before being diluted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 to 50% EtOAc in hexanes, 35 minute runs) to afford Cbz-L-alanine ester (2.78 g), which was dissolved in THF (20 mL) and 20% Pd(OH)2 (433 mg, 0.617 mmol) was added at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4.5 hours, filtered, concentrated in vacuo, and dried under high vacuum to give the product. 1 H NMR (400MHz, chloroform-d) δ5.32(ddt,J=6.5,4.3,1.9Hz,1H),3.98–3.78(m,4H),3.56(q,J=7.0Hz,1 H),2.19(dtd,J=13.7,8.4,6.4Hz,1H),2.05–1.92(m,1H),1.79(s,2H),1.34(d,J=7.0Hz,3H). LCMS: m / z=159.92(M+H), t R=0.21 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0838]

[0839] (R)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine tetrahydrofuran-3-yl ester. To a solution of (R)-L-alanine tetrahydrofuran-3-yl ester (1.66 g, 10.44 mmol) in DCM (40 mL) was added phenyl dichlorophosphate (1.56 mL, 10.44 mmol) quickly in one portion at -78°C. Triethylamine (1.45 mL, 10.44 mmol) was then added over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 30 minutes and cooled to -78°C. p-Nitrophenol (1.45 g, 10.44 mmol) was added in one portion and triethylamine (1.45 mL, 10.44 mmol) was added over 5 minutes at -78°C. After removing the dry ice bath, the resulting mixture was stirred for 2 hours. After dilution with DCM, the mixture was washed with brine, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to give the product. 1 H NMR (400MHz, chloroform-d) δ8.22(m,2H),7.43–7.31(m,4H),7.25–7.14(m,3H),5.29(m,1H),4.21–4.10( m,1H),3.93–3.79(m,4H),3.79–3.71(m,1H),2.17(m,1H),1.97–1.85(m,1H),1.44–1.37(m,3H). 31 P NMR (162 MHz, chloroform-d) δ -3.24, -3.26. LCMS: m / z = 437.02 (M+H), t R=1.42 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0840] Intermediate 58. (Chloro(phenoxy)thiophosphoryl)-L-alanine methyl ester

[0841]

[0842] At -78 ℃ under argon atmosphere, thiophosphoryl chloride (5.08mL, 50.0mmol) and triethylamine (6.97mL, 50.0mmol) are added successively to the solution of phenol (4.70mg, 50.0mmol) in TBME (72mL).Then the reaction mixture is warmed to room temperature. After 1 hour, the gained mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in dichloromethane (72mL), and L-alanine methyl ester hydrochloride (6.97mg, 50.0mmol) is added. The gained suspension is cooled to -78 ℃, and triethylamine (13.9mL, 100mmol) is added dropwise. The reaction mixture is then warmed to room temperature. After 16 hours, the reaction mixture is concentrated under reduced pressure, and TBME (100mL) is added to the residue. The gained white solid is removed by vacuum filtration, and the filtrate is concentrated under reduced pressure to obtain the product directly used in the next step. 1 H NMR (400 MHz, chloroform-d1) δ 7.45–7.12 (m, 5H), 4.67–4.44 (m, 1H), 4.44–4.24 (m, 1H), 3.81 (s, 1.5H), 3.78 (s, 1.5H), 1.53 (app t, J = 6.8 Hz, 3H). 31 P NMR (162 MHz, chloroform-d1) δ 64.78 (s), 64.63 (s).

[0843] Intermediate 59. ((((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(4-nitrophenoxy)phosphine ((((S)-1-cyclohexyloxy-1-oxopropan-2-yl)amino)(4-nitrophenoxy)phosphoryl) (4-amino-L-alanine cyclohexyl ester)

[0844]

[0845] To (S)-1-(cyclohexyloxy)-1-oxopropyl-2-ammonium chloride intermediate 11 (680 mg, 3.27 mmol) in THF (10 mL) was added 4-nitrophenyl dichlorophosphate (838 mg, 3.27 mmol). The resulting mixture was cooled in an ice bath, and a THF (2 mL) solution of triethylamine (1.0 mL, 6.54 mmol) was added over 30 minutes. The resulting mixture was stirred under an ice bath for 1.5 hours, and a THF (2 mL) solution of (S)-1-(2-ethylbutoxy)-1-oxopropyl-2-ammonium chloride (687 mg, 3.27 mmol) was added over 30 minutes under an ice bath. The resulting mixture was stirred in an ice bath for 1.5 hours, diluted with EtOAc, washed with water and brine, concentrated in vacuo, and the resulting residue was purified by preparative HPLC (Phenomenex Gemini-NX 10μ C18 110°A 250×30 mm column, 0%-100% acetonitrile / water gradient, 25 minute run) to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (m, 2H), 7.38 (m, 2H), 4.77 (m, 1H), 4.15–3.91 (m, 4H), 3.60 (m, 2H), 1.91–1.77 (m, 2H), 1.75–1.67 (m, 2H), 1.51 (m, 2H), 1.45–1.23 (m, 15H), 0.88 (m, 6H). 31 P NMR (162 MHz, chloroform-d) δ 8.04. LCMS: MS m / z = 528.10 [M+1].

[0846] Intermediate 60. 4-Nitrophenyl-N,N'-cyclohexyl L-alanine ester phosphorodiamidate

[0847]

[0848] (S)-2-aminopropionic acid cyclohexyl ester hydrochloride. L-Alanine (891 mg, 10 mmol) was mixed with cyclohexanol (10 mL). Trimethylsilyl chloride (12.7 mL, 100 mmol) was added dropwise and stirred for 20 minutes. The reaction mixture was heated to 60 ° C and stirred for 16 hours. The reaction was concentrated under reduced pressure and azeotroped with toluene (5×) to obtain an oil. Hexane (100 mL) was added and stirred for 15 hours to obtain a solid, which was collected, washed with hexane (100 mL) and dried under high vacuum to obtain the product. 1H NMR (400MHz, DMSO-d6) δ8.45(s,3H),4.77(tt,J=8.4,3.7Hz,1H),4.02(q,J=7.2Hz,1H),1.71(m,4H),1.53–1.17(m,9H).

[0849]

[0850] 4-nitrophenyl-N, N'-cyclohexyl L-alanine ester phosphorodiamidate. 4-nitrophenyl dichlorophosphate (256mg, 1mmol) is dissolved in anhydrous dichloromethane (10mL) and stirred in an ice bath under atmospheric nitrogen. Disposable addition of (S)-2-aminopropionic acid cyclohexyl ester hydrochloride (415mg, 2mmol). Triethylamine (698 μL, 5mmol) is added dropwise and stirred for 2 hours. The reaction is diluted with dichloromethane (15mL) and washed with 2% citric acid aqueous solution (20mL). Organic matter is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product is passed through SiO2 column chromatography (12g SiO2 Combiflash HP Gold post, 0-50% ethyl acetate / hexane) purification to obtain product. 1 H NMR (400MHz, DMSO-d6) δ8.30–8.13(m,2H),7.49–7.27(m,2H),5.50(m,2H),4.62(m,2H),3.85(m,2H),1.67(m,8H),1.51–1.18(m,18H). 31 P NMR (162MHz, DMSO-d6) δ9.50. MS m / z=526.0[M+1],524.1[M-1].

[0851] Intermediate 61. 4-Nitrophenyl-N,N'-isopropyl L-alanine ester phosphorodiamidate

[0852]

[0853] To a solution of L-alanine isopropyl ester HCl salt (1.97 g, 11.72 mmol) in DCM (20 mL) was added 4-nitrophenyl dichlorophosphate (1.5 g, 5.86 mmol) in one portion. The resulting mixture was cooled to approximately 0° C., and triethylamine (2.37 g, 23.44 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for approximately 30 minutes and stirred overnight. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluted with 0-100% ethyl acetate in hexane) to give the product. LCMS: MS m / z=445.96[M+1].

[0854] Intermediate 62. 4-Nitrophenyl-N,N'-cyclobutylmethyl L-alaninate phosphorodiamidate

[0855]

[0856] To a solution of L-alanine cyclobutyl methyl ester HCl salt (1.51 g, 7.8 mmol) in DCM (20 mL) was added 4-nitrophenyl dichlorophosphate (1 g, 3.9 mmol) in one portion. The resulting mixture was cooled to 0 ° C. and triethylamine (1.58 g, 15.6 mmol) was added dropwise. After removing the ice bath, the resulting mixture was stirred for 30 minutes and stirred overnight. The reaction mixture was then diluted with EtOAc, washed with water and brine, the organic solvent was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluted with 0-100% ethyl acetate in hexane) to give the product. LCMS: MS m / z=497.98[M+1].

[0857] Intermediate 63. (1r,4S)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-((tert-butoxy (carbonyl)amino)cyclohexyl ester

[0858]

[0859] (1r,4S)-((benzyloxy)carbonyl)-L-alanine 4-((tert-butoxycarbonyl)amino)cyclohexyl ester. 4-Dimethylaminopyridine (2.84 g, 23 mmol) was added to a solution of tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (4.00 g, 19.0 mmol), ((benzyloxy)carbonyl)-L-alanine (4.98 g, 22.0 mmol), and EDCI (3.13 g, 20.0 mmol) in acetonitrile (100 mL) at room temperature. After 4 hours, the reaction mixture was diluted with dichloromethane (200 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to provide the product. 1 H NMR(400MHz, CDCl3)δ7.40–7.28(m,5H),5.29(br d,J=7.7Hz,1H),5.10(s,2H),4.78–4.60(m,1H),4.47–4.19(m,2H),3.45(s,1H),2.08–1.89(m,4H),1.54–1.34(m,14H),1.28–1.16(m,2H). LCMS: MS m / z=420.99[M+1].

[0860]

[0861] (1r,4S)-((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 4-((tert-butoxycarbonyl)amino)cyclohexyl ester. A hydrogen balloon was attached to a flask containing a solution of (1r,4S)-((benzyloxy)carbonyl)-L-alanine 4-((tert-butoxycarbonyl)amino)cyclohexyl ester (1.96 g, 4.66 mmol) and palladium on carbon (10 wt %, 2.0 g) in tetrahydrofuran (50 mL) at room temperature under an argon atmosphere. The vessel was evacuated and refilled with a hydrogen atmosphere (3×), and the reaction mixture was stirred vigorously. After 1.5 hours, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to provide the crude Cbz deprotected material. The crude residue was dissolved in dichloromethane (23 mL) and the resulting mixture was cooled to 0°C. Phenyl dichlorophosphate (0.70 mL, 4.7 mmol) and triethylamine (0.66 mL, 4.7 mmol) were added sequentially. After 1 hour, 4-nitrophenol (660 mg, 4.74 mmol) and triethylamine (0.66 mL, 4.7 mmol) were then added. After 1.5 hours, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to give the product. 1 H NMR (400MHz, chloroform-d1) δ8.26–8.18(m,2H),7.43–7.30(m,4H),7.25–7.17(m,3H),4.77–4.58(m,1H),4.40(br s,1H),4.18–3.99(m,1H),3.93–3.80(m,1H),3.44(br s,1H),2.07–1.87(m,4H),1.52–1.36(m,14H),1.30–1.16(m,2H). 31 P NMR (162 MHz, chloroform-d1) δ-3.15 (s). LCMS: MS m / z=563.88 [M+1].

[0862] Intermediate 64. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ((1r,4S)-4-((tert-butoxy (carbonyl)amino)cyclohexyl)methyl ester

[0863] Method 1.

[0864]

[0865] ((Benzyloxy)carbonyl)-L-alanine ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester. Cbz-L-alanine (223 mg, 1.00 mmol) was dissolved in anhydrous MeCN (10 mL). trans-1-(Boc-amino)-4-(hydroxymethyl)cyclohexane (229 mg, 1.00 mmol) and EDCI (230 mg, 1.2 mmol) were added to the reaction, which was then stirred for 25 minutes. DMAP (122 mg, 1 mmol) was added in one portion, and the reaction was stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with 5% aqueous citric acid (2×5 mL) followed by brine (10 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO2 column chromatography (12 g SiO2 Combiflash HPGold column, 0-40% ethyl acetate / hexane). Fractions containing the desired product were combined and concentrated under reduced pressure to afford the product. 1 H NMR (400MHz, chloroform-d) δ7.41–7.27(m,5H),5.29(d,J=7.6Hz,1H),5.11(s,2H),4.47–4.24(m,2H),3.96 (d,J=6.6Hz,2H),3.37(bs,1H),2.03(m,2H),1.78(m,2H),1.58(m,2H),1.44(m,12H),1.10(m,4H).

[0866]

[0867] ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester. ((benzyloxy)carbonyl)-L-alanine ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester (348 mg, 0.800 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran. Degussa type 10% palladium on carbon (25 mg) was added to the reaction, which was then stirred under atmospheric hydrogen for 3 hours. The palladium on carbon was filtered off, and the filtrate was used in the next reaction without further purification. Phenyl dichlorophosphate (119 μL, 0.800 mmol) was dissolved in 15 mL of anhydrous dichloromethane and stirred in an ice bath under atmospheric nitrogen. The above filtrate was then added dropwise to the reaction solution, which was then stirred for 30 minutes. Triethylamine (120 μ L, 0.88 mmol) was added dropwise and stirred for 1 hour. Disposable p-nitrophenol (100 mg, 0.72 mmol) was added dropwise. Triethylamine (123 μ L, 0.88 mol) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane (10 mL) and washed with water (3 × 10 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO column chromatography (12 g SiO Combiflash HP Gold column, 0-40% ethyl acetate / hexane). The fractions containing the desired product were combined and concentrated under reduced pressure to obtain the product. 1 H NMR (400 MHz, chloroform-d) δ 8.27–8.18 (m, 2H), 7.44–7.30 (m, 4H), 7.27–7.17 (m, 3H), 4.35 (s, 1H), 4.22–4.06 (m, 1H), 3.99–3.88 (m, 2H), 3.85 (t, J=10.6 Hz, 1H), 3.36 (s, 1H), 2.03 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H), 1.48–1.36 (m, 12H), 1.15–0.98 (m, 4H). 31 P NMR (162 MHz, chloroform-d) δ 3.12, 3.13. LCMS: MS m / z = 478.2 [M+1].

[0868] Method 2.

[0869]

[0870] ((Benzyloxy)carbonyl)-L-alanine ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester. trans-1-((tert-butoxycarbonyl)amino)-4-(hydroxymethyl)cyclohexane (510 mg, 2.18 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (509 g, 2.62 mmol) were added to a solution of Z-Ala-OH (489 g, 2.18 mmol) in acetonitrile (22 mL) at room temperature. After 30 minutes, 4-(dimethylamino)pyridine (267 mg, 2.18 mmol) was added. After 18 hours, the reaction was diluted with ethyl acetate (100 mL), and the resulting mixture was washed with 10% aqueous citric acid (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography eluting with 0-50% methanol in ethyl acetate to give the product. 1 H NMR (400MHz, chloroform-d) δ7.41-7.29(m,5H),5.28(s,1H),5.11(s,2H),4.46-4.27(m,2H),3.96(d,J=6.6Hz,2H),3 .37(s,1H),2.03(s,2H),1.78(s,2H),1.56(s,2H),1.44(s,9H),1.42(d,J=7.2Hz,3H),1.08(t,J=9.7Hz,4H). LCMS: MS m / z=434.87[M+1],t R =1.21 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100% to 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R =5.96 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN, 2 mL / min.

[0871]

[0872] ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl L-alaninate. Palladium on carbon (198 mg, 10 wt%) was added to a solution of ((benzyloxy)carbonyl)-L-alaninate (719 g, 1.65 mmol) in tetrahydrofuran (24 mL) purged with argon. The mixture was then purged with hydrogen and stirred at room temperature. After 1 hour, the mixture was filtered through celite, the filter was rinsed with tetrahydrofuran, and the volatiles were removed under reduced pressure to obtain the product. 1 H NMR (400MHz, chloroform-d) δ4.38 (s, 1H), 4.02-3.85 (m, 2H), 3.55 (q, J = 7.0Hz, 1H), 3.38 (s, 1H), 2.04 (d, J = 7. 1Hz, 2H), 1.83-1.73 (m, 2H), 1.63 (s, 2H), 1.44 (s, 10H), 1.34 (d, J = 7.0Hz, 3H), 1.09 (t, J = 10.0Hz, 4H). LCMS: MS m / z=300.93[M+1],t R =0.65 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; solvent: acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μL / min.

[0873]

[0874] ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester. To a solution of L-alanine ((1r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl ester (553 mg, 1.65 mmol) in tetrahydrofuran (24 mL) was slowly added a solution of phenyl dichlorophosphate (247 μL, 1.65 mmol) in dichloromethane (30 mL) at 0°C over 15 minutes. After the addition was complete, triethylamine (0.26 mL, 1.82 mmol) was added dropwise. After 1 hour, 4-nitrophenol (240 mg, 1.65 mmol) and triethylamine (0.26 mL, 1.82 mmol) were then added sequentially at 0°C, and the resulting mixture was then allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (3×75 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexane) to give the product. 1 H NMR (400MHz, chloroform-d) δ8.23 (ddd, J=9.3, 1.3, 0.6Hz, 2H), 7.44–7.31 (m, 4H) ,7.25–7.16(m,3H),4.36(s,1H),4.22–4.06(m,1H),3.96–3.90(m,2H),3 .84(t,J=10.6Hz,1H),3.36(s,1H),2.02(s,2H),1.83–1.68(m,2H),1.57 (s, 2H), 1.44 (s, 9H), 1.41 (dd, J = 7.1, 3.2Hz, 3H), 1.06 (t, J = 9.6Hz, 3H). 31 P NMR (162 MHz, chloroform-d) δ - 3.13 (d, J = 2.9 Hz). LCMS: MS m / z=577.8[M+1],t R =1.28 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100% to 2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R=6.35 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN, 2 mL / min.

[0875] Intermediate 65. 4-Nitrophenyl-N,N'-butyl L-alaninate phosphorodiamidate

[0876]

[0877] (tert-Butoxycarbonyl)-L-alanine butyl ester. Boc-L-alanine (380 mg, 2.0 mmol) is dissolved in anhydrous MeCN (10 mL). 1-Butanol (920 μL, 10.0 mmol) and EDCI (460 mg, 2.4 mmol) are added to the reaction, which is then stirred for 15 minutes. DMAP (240 mg, 2.0 mmol) is added once and the reaction is stirred for 14 hours. The reaction mixture is diluted with ethyl acetate (15 mL) and washed with saturated sodium bicarbonate aqueous solution (2 × 10 mL) and then with brine (5 mL). The organic extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue is purified by SiO2 column chromatography (12 g SiO2 Combiflash HP Gold column, 0-20% ethyl acetate / hexane). The fractions containing the desired product are combined and concentrated under reduced pressure to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.04 (m, 1H), 4.29 (m, 1H), 4.18–4.07 (m, 2H), 1.67–1.59 (m, 2H), 1.44 (s, 9H), 1.38 (m, 5H), 0.93 (t, J = 7.4 Hz, 3H).

[0878]

[0879] 4-nitrophenyl-N, N'-butyl L-alanine ester phosphorodiamidate. (tert-Butoxycarbonyl)-L-alanine butyl ester (291mg, 1.18mmol) is dissolved in 7mL 4M HCl in dioxane solution and stirred for 1 hour. The reaction mixture is concentrated under reduced pressure to obtain an oily substance, which is then dissolved in anhydrous dichloromethane (10mL) and stirred in an ice bath under atmospheric nitrogen. 4-nitrophenyl dichlorophosphate (152mg, 0.59mmol) is added once and the reaction is stirred for 10 minutes. Triethylamine (270μL, 1.95mmol) is dissolved in 1mL anhydrous dichloromethane and added dropwise to the reaction solution. The reaction mixture is stirred for 1 hour. Triethylamine (270μL, 1.95mmol) is dissolved in 700μL anhydrous dichloromethane and added dropwise to the reaction. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (3 × 20 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by SiO column chromatography (12 g SiO Combiflash HPGold column, 0-50% ethyl acetate / hexane). The fractions containing the desired product were combined and concentrated under reduced pressure to give the product. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.27–8.15 (m, 2H), 7.43–7.34 (m, 2H), 4.19–3.98 (m, 5H), 3.80–3.61 (m, 1H), 3.58 (m, 2H), 1.67–1.59 (m, 4H), 1.45–1.30 (m, 10H), 0.93 (m, 6H). 31 P NMR (162 MHz, chloroform-d) δ 7.93. LCMS: MS m / z = 474.0 [M+1].

[0880] Intermediate 66. (2S)-2-(((Benzyloxy)carbonyl)amino)-3-(4-(((((S)-1-isopropoxy-1-oxo)- (4-nitrophenoxy)phosphoryl)oxy)phenyl)propionic acid methyl ester

[0881]

[0882] A solution of 4-nitrophenyl dichlorophosphate (504 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise to a solution of L-alanine isopropyl ester hydrochloride (330 mg, 1.97 mmol) in dichloromethane (20 mL) at 0°C over 10 minutes. After the addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 60 minutes, N-benzyloxycarbonyl-L-tyrosine methyl ester (649 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were added sequentially at 0°C, and the resulting mixture was then allowed to warm to room temperature. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 20%-100% ethyl acetate in hexane) to provide the product. 1 HNMR (400MHz, methanol-d4) δ8.32-8.22(m,2H),7.49-7.37(m,2H),7.35-7.13(m,9 H),5.02(s,2H),4.93(pd,J=6.3,1.1Hz,1H),4.43(dd,J=9.4,5.2Hz,1H),4. 00(dtd,J=10.1,7.7,6.5Hz,1H),3.70(s,3H),3.15(dd,J=14.0,5.4Hz,1H), 2.93(dd,J=13.9,9.6Hz,1H), 1.32(td,J=7.2,1.2Hz,3H), 1.20-1.16(m,6H). 31 P NMR (162 MHz, methanol-d4) δ -1.26, -1.49. LCMS: MS m / z = 644.11 [M+1], t R =1.56 min; LC system: Thermo Accela 1250 UHPLC; MS system: ThermoLCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100%-2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R=6.21 min; HPLC system: Agilent 1100 series; column: Gemini 5μC18 110A, 50×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-9.0 min 2-95% ACN, 9.0 min-10.0 min 95% ACN, 2 mL / min.

[0883] Intermediate 67. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-morpholinoethyl ester

[0884]

[0885] A solution of 4-nitrophenyl dichlorophosphate (505 mg, 1.97 mmol) in dichloromethane (20 mL) was added dropwise to a solution of L-alanine 2-morpholinoethyl ester hydrochloride (496 mg, 1.97 mmol) in dichloromethane (20 mL) at 0°C over 10 minutes. After the addition was complete, triethylamine (0.55 mL, 3.93 mmol) was added dropwise. After 90 minutes, phenol (185 mg, 1.97 mmol) and triethylamine (0.28 mL, 1.97 mmol) were added sequentially at 0°C, and the resulting mixture was allowed to warm to room temperature. After 30 minutes, the reaction mixture was washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluting with 20%-100% ethyl acetate in hexane) to give the product. 1 H NMR (400MHz, CDCl3) δ8.28-8.14(m,2H),7.41-7.29(m,4H),7.24-7.16(m,4H),6.87-6.81(m, 1H), 4.14-4.04 (bs, 2H), 2.61-2.57 (bs, 4H), 2.45-3.40 (bs, 4H), 1.42 (dt, J = 6.3, 2.0Hz, 6H). 31 P NMR (162MHz, CDCl3) δ-2.70. LCMS: MS m / z=480.27[M+1], t R =0.96 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, Water containing 0.1% formic acid; Gradient: 2-100% acetonitrile from 0 min to 1.8 min, 100%-2% acetonitrile from 1.8 min to 1.85 min, 2% ACN from 1.85 min to 2.00 min, 1800 μL / min. HPLC: t R=5.23 min; HPLC system: Agilent 1100 series; column: Kinetx 2.6u 100A C18, 100 mm×4.6 mm; solvent: acetonitrile containing 0.1% TFA, water containing 0.1% TFA; gradient: 0 min-8.5 min 2-98% ACN, 8.5 min-10.0 min 98% ACN, 1.5 mL / min.

[0886] Intermediate 68. ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-(diisopropylamino)ethyl ester

[0887]

[0888] 2-(Diisopropylamino)ethyl ((Benzyloxy)carbonyl)-L-alaninate. At room temperature, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.06 g, 10.8 mmol) was added to a solution of Z-Ala-OH (2.00 g, 8.96 mmol) and 2-(diisopropylamino)ethanol (3.2 mL, 17.9 mmol) in acetonitrile (125 mL)...

Claims

1. An isolated compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

2. An isolated compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

3. An isolated compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

4. A pharmaceutical preparation comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

5. A method for preparing a medicament for treating a Pneumoviridae virus infection in a person in need thereof, characterized in that Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

6. A method for preparing a medicament for treating a Picornaviridae viral infection in a person in need thereof, characterized in that Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the Picornaviridae virus infection is a human rhinovirus infection.

7. A method for preparing a medicament for treating a Flaviviridae virus infection in a person in need thereof, characterized in that: Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the Flaviviridae virus infection is a dengue virus infection.

8. A method for preparing a medicament for treating a Flaviviridae virus infection in a person in need thereof, characterized in that: Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the Flaviviridae virus infection is HCV infection.

9. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a human Pneumoviridae virus infection, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

10. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a human Picornaviridae virus infection, wherein the Picornaviridae virus infection is a human rhinovirus infection.

11. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Flaviviridae virus infection in a human, wherein the Flaviviridae virus infection is a dengue virus infection.

12. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a Flaviviridae virus infection in a human, wherein the Flaviviridae virus infection is HCV infection.

13. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in treating a Pneumoviridae virus infection in a human in need thereof, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

14. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in treating a Picornaviridae viral infection in a human in need thereof, wherein the Picornaviridae viral infection is a human rhinovirus infection.

15. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in treating a Flaviviridae infection in a human in need thereof, wherein the Flaviviridae infection is dengue virus.

16. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in treating a Flaviviridae infection in a human in need of infection, wherein the Flaviviridae infection is an HCV infection.

17. A method for preparing a medicament for treating or preventing a respiratory ailment exacerbated by a viral infection in a person in need thereof, characterized in that: Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the respiratory disorder is chronic obstructive pulmonary disease, wherein the viral infection is caused by respiratory syncytial virus.

18. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing worsening of respiratory conditions caused by viral infection in humans, wherein the respiratory condition is chronic obstructive pulmonary disease, wherein the viral infection is caused by respiratory syncytial virus.

19. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an exacerbation of a respiratory condition caused by a viral infection in a human in need thereof, wherein the respiratory condition is chronic obstructive pulmonary disease, wherein the viral infection is caused by respiratory syncytial virus.

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