Substituted pyrimidinone and azapyrimidinone compounds, compositions, and their uses

Abstract

Substituted pyrimidinone and azapyrimidinone compounds of formula (I) and methods of use are disclosed. [Formula 1] TIFF2026515887000108.tif31170

Description

Detailed Description of the Invention

[0001] [Cross - Reference to Related Applications] This application claims the priority of U.S. Provisional Patent Application No. 63 / 498,460, filed on April 26, 2023, which is hereby incorporated by reference in its entirety.

[0002] [Background] There is a continuing need for antibacterial and antiviral compounds.

[0003] [Summary] This disclosure provides a compound having the formula:

[0004] [Chemical Formula] or a pharmaceutically acceptable salt thereof. R1 is (C1 - C8) linear alkyl, (C3 - C8) branched alkyl, (C3 - C8) cycloalkyl, phenylalkyl, alkylcycloalkyl, hydroxy(C1 - C8) linear alkyl, hydroxy(C3 - C8) branched alkyl, alkoxy(C1 - C8) linear alkyl, alkoxy(C3 - C8) branched alkyl, halo(C1 - C8) linear alkyl, or halo(C3 - C8) branched alkyl. R2, R3, and R4 are each independently H, OH, oxy(C1 - C8) linear alkyl, oxy(C1 - C8) branched alkyl, CF3, or F. X is N or C - R5. R5 and R6 are each independently H, F, Cl, CF3, or CH3. R7 and R8 are each independently H, (C1 - C5) linear alkyl, (C1 - C5) branched alkyl or are joined to each other by a C - C bond to form a C3 - C8 cycloalkyl.

[0005] In some embodiments, R1 is octyl. In some embodiments, R1 is hexyl. In some embodiments, R1 is butyl. In some embodiments, R1 is 2-methylpropyl. In some embodiments, R1 is 2-methylbutyl. In some embodiments, R1 is 1,1,1-trifluorobutyl.

[0006] In some embodiments, X is N. In some embodiments, X is C-R5. In some embodiments, R5 is H.

[0007] In some embodiments, R2 is H. In some embodiments, R2 is OH.

[0008] In some embodiments, both R3 and R4 are H. In some embodiments, both R3 and R4 are F. In some embodiments, R3 is OCH3 and R4 is H. In some embodiments, R3 is H and R4 is OCH3.

[0009] In some embodiments, R6 is H. In some embodiments, both R6 and R7 are H. In some embodiments, both R6 and R7 are CH3. In some embodiments, one of R6 and R7 is H and the other is CH3.

[0010] In some embodiments, the compound has the formula:

[0011]

Chemical formula

[0012] In some embodiments, the compound has the formula:

[0013]

Chemical formula

[0014] In some embodiments, the compound is given by formula:

[0015] [ka] or have a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound is given by formula:

[0017] [ka] or have a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the compound is given by formula:

[0019] [ka] or have a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound is given by formula:

[0021] [ka] or have a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is given by formula:

[0023] [ka] or have a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound is given by formula:

[0025] [ka] or have a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound is given by formula:

[0027] [ka] or have a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compound is given by formula:

[0029] [ka] or have a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound is given by formula:

[0031] [ka] or have a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the compound is given by formula:

[0033] [ka] or have a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound is given by formula:

[0035] [ka] or have a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound is given by formula:

[0037] [ka] or have a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the compound is given by formula:

[0039] [ka] or have a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the pharmaceutical composition comprises any compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, diluents, or mixtures of two or more thereof.

[0041] In some embodiments, a method for treating an infection in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, a method for treating an infection of at least one of a wound or ulcer in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, a method for treating an infection of diabetic foot ulcers in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, a method for treating the bladder and / or urinary tract in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, a method for treating a lung infection in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the lung infection is caused by a lung disease. In some embodiments, the lung disease is a genetic disease, an acquired disease, a primary disease, a secondary disease, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergy, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory tract disease, croup, high-altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome. The group consists of parainfluenza, pleural effusion, pleurisy, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, wheezing, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis, Q fever, parainfluenza, respiratory syncytial virus, combinations thereof, and diseases caused by any one or a combination of the above.

[0046] In some embodiments, the lung disease is caused by a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, and omicron coronavirus, or a combination thereof. In some embodiments, coronaviruses include porcine epidemic diarrhea virus (PEDv), Scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-alpha-CoV HuB-2013, bat coronavirus HKU10, Minioptrus bat coronavirus HKU8, Minioptrus bat coronavirus 1, Nyctalus velutinus alpha coronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alpha coronavirus Sachs-2011, HumCoV 229E, 229E-related bat coronavirus, camel alpha coronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63-related bat CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, and Lucheng. Rn rat coronavirus 2, FIPV, TGEV, PRCV, alpha coronavirus 1, mink coronavirus 1, FRCoV-NL-2010, Sorex araneus coronavirus T14, Suncus murinus coronavirus X74, HumCoV OC43, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, Bovine Coronavirus Isolate (Alpaca), Canine Respiratory Coronavirus K37, PHEV, Equine Coronavirus, HKU14, HKU24, Myodes Coronavirus 2 JL14, HKU1, MHV, Rat Coronavirus Parker, HKU4, HKU5, Human MERS-CoV, Camel MERS-CoV, Hedgehog Coronavirus 1, HKU9, Rousette Bat Coronavirus GCCDC1, Eidolon Bat Coronavirus C704, Human SARS-CoV, Palm Civet SARS-CoV, Badger SARS-CoV, Bat SL-CoV RsSHC014, Bat SL-CoV Rs3367, Bat SL-CoVWIV1, HKU3, bat SL-CoV ZC45, bat SL-CoV ZXC21, bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, dog CoV, mink CoV, GD pangolin CoV, bat Hp-beta coronavirus Selected from the group consisting of Zhejiang2013, peacock IBV, avian coronavirus 9203, poultry IBV, avian coronavirus, duck CoV, partridge IBV, goose coronavirus CB17, beluga whale coronavirus SW1, HKU22, HKU19, HKU20, HKU21, HKU11, HKU12, HKU16, HKU27, HKU28, HKU29, HKU18, HKU13, HKU30-UAE, HKU30-Poland, HKU17-USA, HKU17-China, AlCCoV, and HKU15, or combinations thereof. In some embodiments, coronaviruses include HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, Myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rosette bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS-CoV, badger SARS-CoV, bat SL-CoV RsSHC014, bat SL-CoV Rs3367, bat SL-CoV WIV1, HKU3, bat SL-CoV ZC45, and bat SL-CoV It is a betacoronavirus selected from the group consisting of ZXC21, bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, canine CoV, mink CoV, GD pangolin CoV, and bat Hp-betacoronavirus Zhejiang2013, or combinations thereof.

[0047] In some embodiments, a method for treating cystic fibrosis in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, a method for treating pneumonia in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the pneumonia is ventilator-acquired pneumonia.

[0049] In some embodiments, a method for treating an infection in a burn wound in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, a method for treating otitis externa in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, a method for treating bacterial vaginosis in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, a method for treating impetigo in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, a method for treating oral mucositis in a patient in need includes the step of administering to the patient an effective amount of any compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0054] Additional aspects and embodiments will become apparent from the modes for carrying out the invention and from the claims. [Modes for carrying out the invention]

[0055] [Detailed explanation] The embodiments described below are not intended to be exhaustive, nor to limit the invention to the exact forms disclosed in the detailed description below. Rather, the embodiments are selected and described so that those skilled in the art can appreciate and understand the principles and practices of this disclosure.

[0056] This disclosure is based on the formula:

[0057] [ka] [In the formula, R1 is a (C1-C8) linear alkyl, (C3-C8) branched alkyl, (C3-C8) cycloalkyl, phenylalkyl, alkylcycloalkyl, hydroxy(C1-C8) linear alkyl, hydroxy(C3-C8) branched alkyl, alkoxy(C1-C8) linear alkyl, alkoxy(C3-C8) branched alkyl, halo(C1-C8) linear alkyl, or halo(C3-C8) branched alkyl. R2, R3, and R4 are each independently H, OH, oxy(C1-C8) linear alkyl, oxy(C1-C8) branched alkyl, CF3, or F. X is N or C-R5, R5 and R6 are independently H, F, Cl, CF3, or CH3, respectively. R7 and R8 are either independently H, a (C1-C5) linear alkyl, a (C1-C5) branched alkyl, or linked to each other by a CC bond to form a C3-C8 cycloalkyl group. The present invention provides compounds having [a certain characteristic], or pharmaceutically acceptable salts thereof.

[0058] In some embodiments, R1 is a (C1-C8) linear alkyl chain. In some embodiments, the linear alkyl chain is methyl:

[0059] [ka] That is the case.

[0060] In some embodiments, R1 is a (C1-C8) linear alkyl group. In some embodiments, the linear alkyl chain is ethyl:

[0061] [ka] That is the case.

[0062] In some embodiments, R1 is a (C1-C8) linear alkyl group. In some embodiments, the linear alkyl chain is propyl:

[0063] [ka] That is the case.

[0064] In some embodiments, R1 is a (C1-C8) linear alkyl group. In some embodiments, the linear alkyl chain is butyl:

[0065] [ka] That is the case.

[0066] In some embodiments, R1 is a (C1-C8) linear alkyl group. In some embodiments, the linear alkyl chain is pentyl:

[0067] [ka] That is the case.

[0068] In some embodiments, R1 is a (C1-C8) linear alkyl group. In some embodiments, the linear alkyl chain is hexyl:

[0069] [ka] That is the case.

[0070] In some embodiments, R1 is a (C1-C8) linear alkyl group. In some embodiments, the linear alkyl chain is heptyl:

[0071] [ka] That is the case.

[0072] In some embodiments, R1 is a (C1-C8) linear alkyl chain. In some embodiments, the linear alkyl chain is octyl:

[0073] [ka] That is the case.

[0074] In some embodiments, R1 is a (C3-C8) branched alkyl chain. In some embodiments, the branched alkyl chain is 2-methylpropyl:

[0075] [ka] That is the case.

[0076] In some embodiments, R1 is a (C3-C8) branched alkyl chain. In some embodiments, the branched alkyl chain is 2-methylbutyl:

[0077] [ka] That is the case.

[0078] In some embodiments, R1 is a (C3-C8) cycloalkyl group. In some embodiments, the cycloalkyl group is a cyclopropyl group.

[0079] [ka] That is the case.

[0080] In some embodiments, R1 is a (C3-C8) cycloalkyl group. In some embodiments, the cycloalkyl group is cyclobutyl:

[0081] [ka] That is the case.

[0082] In some embodiments, R1 is a (C3-C8) cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopentyl:

[0083] [ka] That is the case.

[0084] In some embodiments, R1 is a (C3-C8) cycloalkyl. In some embodiments, the cycloalkyl is a cyclohexyl:

[0085] [ka] That is the case.

[0086] In some embodiments, R1 is a (C3-C8) cycloalkyl group. In some embodiments, the cycloalkyl group is cycloheptyl:

[0087] [ka] That is the case.

[0088] In some embodiments, R1 is a (C3-C8) cycloalkyl. In some embodiments, the cycloalkyl is cyclooctyl:

[0089] [ka] That is the case.

[0090] In some embodiments, R1 is an aryl compound. In some embodiments, the aryl compound is a phenyl compound.

[0091] [ka] That is the case.

[0092] In some embodiments, R1 is an arylalkyl. In some embodiments, the arylalkyl is benzyl:

[0093] [ka] That is the case.

[0094] In some embodiments, R1 is alkylcycloalkyl. In some embodiments, alkylcycloalkyl is methylcyclohexyl:

[0095] [ka] That is the case.

[0096] In some embodiments, R1 is alkylcycloalkyl. In some embodiments, alkylcycloalkyl is ethylcyclohexyl:

[0097] [ka] That is the case.

[0098] In some embodiments, R1 is a hydroxy(C1-C8) linear alkyl. In some embodiments, the linear alkanol is 1-butanolyl:

[0099] [ka] That is the case.

[0100] In some embodiments, R1 is a hydroxy(C3-C8) branched alkyl group. In some embodiments, the branched alkanol is 3-methyl-1-butanol-3-yl:

[0101] [ka] That is the case.

[0102] In some embodiments, R1 is an alkoxy(C1-C8) linear alkyl group. In some embodiments, the linear alkoxyalkyl group is ethoxyethyl:

[0103] [ka] That is the case.

[0104] In some embodiments, R1 is an alkoxy(C3-C8) branched alkyl group. In some embodiments, the branched alkoxyalkyl group is isopropxyethyl:

[0105] [ka] That is the case.

[0106] In some embodiments, R1 is a halo(C1-C8) linear alkyl group. In some embodiments, the linear haloalkyl group is 1,1,1-trifluorobutyl:

[0107] [ka] That is the case.

[0108] In some embodiments, R1 is a halo(C3-C8) branched alkyl group. In some embodiments, the branched haloalkyl group is 2-trifluoromethylpentyl:

[0109] [ka] That is the case.

[0110] In some embodiments, R2 is H. In some embodiments, R2 is OH.

[0111] In some embodiments, R3 is H. In some embodiments, R3 is F. In some embodiments, R3 is an oxy(C1-C8) linear alkyl group. In some embodiments, R3 is methoxy(OCH3).

[0112] In some embodiments, R4 is H. In some embodiments, R4 is F.

[0113] In some embodiments, both R3 and R4 are H. In some embodiments, both R3 and R4 are F. In some embodiments, R3 is OCH3 and R4 is H. In some embodiments, R3 is H and R4 is OCH3.

[0114] In some embodiments, X is N. In some embodiments, X is C-R5. In some embodiments, R5 is H. In some embodiments, R5 is halogen. In some embodiments, R5 is F. In some embodiments, R5 is CH3.

[0115] In some embodiments, R6 is H. In some embodiments, R6 is a halogen. In some embodiments, R6 is F. In some embodiments, R6 is CF3. In some embodiments, R6 is CH3.

[0116] In some embodiments, both R7 and R8 are H. In some embodiments, both R7 and R8 are CH3. In some embodiments, one of R7 and R8 is H, and the other of R7 and R8 is CH3.

[0117] This disclosure also provides the compounds as described in Table 1. As used herein, the term “Cmpd” refers to the compound of formula (I) or a pharmaceutically acceptable salt thereof, and R1 to R8 and X are defined as R1 to R8 and X in one of the rows of Table 1 labeled Cmpd1 to Cmpd12. For example, in this disclosure or claims, “Cmpd1 as described in Table 1” specifically refers to the compound of formula (I) or a pharmaceutically acceptable salt thereof, and R1 to R8 and X of the compound of formula (I) or a pharmaceutically acceptable salt thereof are as follows:

[0118] [Table 1] Cmpd1 to 12 can be prepared by referring to the compounds of formula (I), Table 1, and the synthesis schemes described in Examples 1 to 10.

[0119] [Table 2]

[0120] In some embodiments, the present disclosure is based on the formula:

[0121] [ka] The invention also provides compounds having the same property, or pharmaceutically acceptable salts thereof.

[0122] The chemical name of the compound of formula (II) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate. The molecular formula of the compound of formula (II) is C 17 H30 The compound is N3O7P. The molecular weight of the compound of formula (II) is 419.41 Da. The compound of formula (II) is also referred to herein as LAI-001, compound (II), or Cmpd1, and such terms are used interchangeably herein. In some embodiments, LAI-001 comprises 2-deoxyribose, a phosphate group, an octyl group, and cytosine.

[0123] In some embodiments, the present disclosure is based on the formula:

[0124] [ka] The invention also provides compounds having the same property, or pharmaceutically acceptable salts thereof.

[0125] The chemical name of the compound of formula (III) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate. The molecular formula of the compound of formula (III) is C 15 H 26 The compound is N3O7P. The molecular weight of the compound of formula (III) is 391.36 Da. The compound of formula (III) is also referred to herein as LAI-002, compound (III), or Cmpd2, and such terms are used interchangeably herein. In some embodiments, LAI-002 comprises 2-deoxyribose, a phosphate group, a hexyl group, and cytosine.

[0126] In some embodiments, the present disclosure is based on the formula:

[0127] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0128] The chemical name of the compound of formula (IV) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate. The molecular formula of the compound of formula (IV) is C 13 H 22 The compound is N3O7P. The molecular weight of the compound of formula (IV) is 363.3 Da. The compound of formula (IV) is also referred to herein as LAI-003, compound (IV), or Cmpd3, and such terms are used interchangeably herein. In some embodiments, LAI-003 comprises 2-deoxyribose, a phosphate group, a 2-methylpropyl group, and cytosine.

[0129] In some embodiments, the present disclosure is based on the formula:

[0130] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0131] The chemical name of the compound of formula (V) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate. The molecular formula of the compound of formula (V) is C 14 H 24 The compound is N3O7P. The molecular weight of the compound of formula (V) is 377.14 Da. The compound of formula (V) is also referred to herein as LAI-004, compound (V), or Cmpd4, and such terms are used interchangeably herein. In some embodiments, LAI-004 comprises 2-deoxyribose, a phosphate group, a 2-methylbutyl group, and cytosine.

[0132] In some embodiments, the present disclosure is based on the formula:

[0133] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0134] The chemical name of the compound of formula (VI) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl 1’,1’,1’-trifluorobutyl phosphate. The molecular formula of the compound of formula (VI) is C 13 H 19 F3N3O7P. The molecular weight of the compound of formula (VI) is 417.28 Da. The compound of formula (VI) is also referred to herein as LAI-005, Compound (VI) or Cmpd5, and such terms are used interchangeably herein. In some embodiments, LAI-005 comprises 2-deoxyribose, a phosphate group, a 1,1,1-trifluorobutyl group, and cytosine.

[0135] In some embodiments, the present disclosure provides a compound of the formula:

[0136]

Chemical formula

[0137] The chemical name of the compound of formula (VII) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate. The molecular formula of the compound of formula (VII) is C 13 H 20 F2N3O7P. The molecular weight of the compound of formula (VII) is 399.1 Da. The compound of formula (VII) is also referred to herein as LAI-006, Compound (VII) or Cmpd6, and such terms are used interchangeably herein. In some embodiments, LAI-006 comprises fluorinated 2-deoxyribose, a phosphate group, a butyl group, and cytosine.

[0138] In some embodiments, the present disclosure provides a compound of the formula:

[0139] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0140] The chemical name of the compound of formula (VIII) is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (VIII) is C 13 H 22 The compound is N3O6P. The molecular weight of the compound of formula (VIII) is 347.31 Da. The compound of formula (VIII) is also referred to herein as LAI-007, compound (VIII), or Cmpd7, and such terms are used interchangeably herein. In some embodiments, LAI-007 comprises 2,3-deoxyribose, a phosphate group, a butyl group, and cytosine.

[0141] In some embodiments, the present disclosure is based on the formula:

[0142] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0143] The chemical name of the compound of formula (IX) is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (IX) is C 15 H 26 The compound is N307P. The molecular weight of the compound of formula (IX) is 391.15 Da. The compound of formula (IX) is also referred to herein as LAI-008, compound (IX), or Cmpd8, and such terms are used interchangeably herein. In some embodiments, LAI-008 comprises 2-deoxyribose, a phosphate group, a butyl group, and N,N-dimethylcytosine.

[0144] In some embodiments, the present disclosure is based on the formula:

[0145] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0146] The chemical name of the compound of formula (X) is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (X) is C 14 H 24 The compound is N3O7P. The molecular weight of the compound of formula (X) is 377.14 Da. The compound of formula (X) is also referred to herein as LAI-009, compound (X), or Cmpd9, and such terms are used interchangeably herein. In some embodiments, LAI-009 comprises 2-deoxyribose, a phosphate group, a butyl group, and N-methylcytosine.

[0147] In some embodiments, the present disclosure is based on the formula:

[0148] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0149] The chemical name of the compound of formula (XI) is (2R,3S,5R)-5-(4-amino-2-oxopyridizin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (XI) is C 12 H 21The compound is N4O7P. The molecular weight of the compound of formula (XI) is 364.29 Da. The compound of formula (XI) is also referred to herein as LAI-011, compound (XI), or Cmpd10, and such terms are used interchangeably herein. In some embodiments, LAI-011 comprises 2-deoxyribose, a phosphate group, a butyl group, and an aminotriazine.

[0150] In some embodiments, the present disclosure is based on the formula:

[0151] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0152] The chemical name of the compound of formula (XII) is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (XII) is C 13 H 22 The compound is N3O7P. The molecular weight of the compound of formula (XII) is 363.3 Da. The compound of formula (XII) is also referred to herein as LAI-R-1, compound (XII), or Cmpd11, and these terms are used interchangeably herein. In some embodiments, LAI-R-1 comprises 2-deoxyribose, a phosphate group, a butyl group, and cytosine.

[0153] In some embodiments, the present disclosure is based on the formula:

[0154] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0155] The chemical name of the compound of formula (XIII) is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (XIII) is C 14 H 24 The compound is N3O8P. The molecular weight of the compound of formula (XIII) is 393.33 Da. The compound of formula (XIII) is also referred to herein as LAI-R-5, compound (XIII), or Cmpd12, and such terms are used interchangeably herein. In some embodiments, LAI-R-5 comprises methoxylated 2-deoxyribose, a phosphate group, a butyl group, and cytosine.

[0156] In some embodiments, the present disclosure is based on the formula:

[0157] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0158] The chemical name of the compound of formula (XIV) is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxytetrahydrofuran-2-methylbutyl phosphate. The molecular formula of the compound of formula (XIV) is C 16 H 28 The compound is N3O8P. The molecular weight of the compound of formula (XIV) is 421.38 Da. The compound of formula (XIV) is also referred to herein as LAK-021, compound (XIV), or Cmpd13, and such terms are used interchangeably herein. In some embodiments, LAK-021 comprises methoxylated 2-deoxyribose, a phosphate group, a butyl group, and N,N-dimethylcytosine.

[0159] In some embodiments, the present disclosure is based on the formula:

[0160] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0161] The chemical name of the compound of formula (XV) is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate. The molecular formula of the compound of formula (XV) is C 15 H 26 The compound is N3O6P. The molecular weight of the compound of formula (XV) is 375.36 Da. The compound of formula (XV) is also referred to herein as LAK-022, compound (XV), or Cmpd14, and such terms are used interchangeably herein. In some embodiments, LAK-022 comprises 2,3-deoxyribose, a phosphate group, a butyl group, and N,N-dimethylcytosine.

[0162] In some embodiments, the present disclosure is based on the formula:

[0163] [ka] The compound, or pharmaceutically acceptable salt thereof, is also provided.

[0164] The chemical name of the compound of formula (XVI) is (2R,3S,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate. The molecular formula of the compound of formula (XVI) is C 15 H 24 The formula is F2N3O7P. The molecular weight of the compound of formula (XVI) is 427.15 Da. The compound of formula (XVI) is also referred to herein as LAK-023, compound (XVI), or Cmpd15, and such terms are used interchangeably herein. In some embodiments, LAK-023 comprises fluorinated 2-deoxyribose, a phosphate group, a butyl group, and N,N-dimethylcytosine.

[0165] The compounds of this disclosure are described with reference to the specific compounds shown herein. In addition, any of the compounds of this disclosure may exist in any number of different forms or derivatives within the scope of this disclosure. Alternative forms or derivatives include, for example, pharmaceutically acceptable salts, prodrugs and active metabolites, tautomers, and solid forms including different crystalline forms, polymorphic or amorphous solids including their hydrates and solvates, and other forms.

[0166] Unless otherwise specified, the designation of compounds in this disclosure includes pharmaceutically acceptable salts of such compounds. Therefore, the compounds in this disclosure may be in the form of pharmaceutically acceptable salts or may be formulated as pharmaceutically acceptable salts. The pharmaceutically acceptable salt forms intended in this disclosure include, but are not limited to, mono, bis, tris, tetrakis, etc. The pharmaceutically acceptable salts of this disclosure are nontoxic at the amounts and concentrations in which such pharmaceutically acceptable salts are administered. Preparations of such pharmaceutically acceptable salts of this disclosure can be made pharmacologically usable by modifying the physical characteristics of the compounds in this disclosure without interfering with the exertion of their physiological effects.

[0167] As used herein, the term “pharmaceutically acceptable” with respect to salts and formulation components such as carriers, excipients, and diluents means salts and components that are not harmful to the patient and are compatible with other raw materials, active ingredients, salts, or components. pharmaceutically acceptable includes “veterinary acceptable” and therefore independently includes both human and non-human mammalian applications.

[0168] As used herein, the term “pharmaceutically acceptable salt” refers to salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Such salts include, for example, physiologically acceptable salts listed in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by PHStahl and CGWermuth, Wiley-VCH, New York, 2002, which are known to those skilled in the art. Salt formation may occur at one or more positions with unstable protons. Pharmaceutically acceptable salts of the compounds of this disclosure include both acid addition salts and base addition salts.

[0169] In some embodiments, suitable pharmaceutically acceptable acid addition salts of the compounds of this disclosure may be prepared from inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carboxylic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include, but are not limited to, organic acids of the aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes, some examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, maleic acid, embonic acid (pamonic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylaminosulfonic acid, stearic acid, argenic acid, beta-hydroxybutyric acid, malonic acid, galactic acid, and galacturonic acid. Among the many pharmaceutically acceptable acidic / anionic salts are acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen tartrate, bromide, calcium edetate, cansilate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, glyceptate, gluconate, glutamate, glycolyl arsanylate, hexylresorcinate, hydrobromide, hydrochloride, and hydroxynaphthol. This also includes toethates, iodides, isethions, lactates, lactobions, malates, maleates, malons, mandelates, mesilates, methylsulfates, mucoates, napsylates, nitrates, pamos, pantothenates, phosphates / diphospate, polygalactulates, salicylates, stearates, basic acetates, succinates, sulfates, bisulfates, tannates, tartrates, theoclates, tosylates, and triethiozides.

[0170] In some embodiments, suitable pharmaceutically acceptable base addition salts of the compounds of the Disclosure include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, arginine, and procaine. Any of these salts can be prepared from the compounds of the Disclosure by conventional means, by treating the compounds of the Disclosure with a suitable acid or base. Pharmaceutically acceptable basic / cationic salts also include, to name a few, diethanolamine salts, ammonium salts, ethanolamine salts, piperazine salts, and triethanolamine salts. In some embodiments, pharmaceutically acceptable salts of the Disclosure include monovalent or divalent cations.

[0171] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-001. In some embodiments, the ammonium salt of LAI-001 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate ammonium. In some embodiments, the calcium salt of LAI-001 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate calcium. In some embodiments, the sodium salt of LAI-001 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate sodium. In some embodiments, the potassium salt of LAI-001 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate potassium. In some embodiments, the magnesium salt of LAI-001 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-001 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyloctyl phosphate cobalt.

[0172] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-002. In some embodiments, the ammonium salt of LAI-002 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate ammonium. In some embodiments, the calcium salt of LAI-002 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate calcium. In some embodiments, the sodium salt of LAI-002 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate sodium. In some embodiments, the potassium salt of LAI-002 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate potassium. In some embodiments, the magnesium salt of LAI-002 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-002 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylhexyl phosphate cobalt.

[0173] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-003. In some embodiments, the ammonium salt of LAI-003 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-003 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate calcium. In some embodiments, the sodium salt of LAI-003 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate sodium. In some embodiments, the potassium salt of LAI-003 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-003 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-003 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisobutyl phosphate cobalt.

[0174] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-004. In some embodiments, the ammonium salt of LAI-004 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate ammonium. In some embodiments, the calcium salt of LAI-004 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate calcium. In some embodiments, the sodium salt of LAI-004 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate sodium. In some embodiments, the potassium salt of LAI-004 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate potassium. In some embodiments, the magnesium salt of LAI-004 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-004 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methylisopentyl phosphate cobalt.

[0175] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-005. In some embodiments, the ammonium salt of LAI-005 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl1',1',1'-trifluorobutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-005 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl1',1',1'-trifluorobutyl phosphate calcium. In some embodiments, the sodium salt of LAI-005 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl1',1',1'-trifluorobutyl phosphate sodium. In some embodiments, the potassium salt of LAI-005 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl1',1',1'-trifluorobutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-005 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl1',1',1'-trifluorobutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-005 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuranyl-2-methyl1',1',1'-trifluorobutyl cobalt phosphate.

[0176] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-006. In some embodiments, the ammonium salt of LAI-006 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-006 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAI-006 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAI-006 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-006 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-006 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate cobalt.

[0177] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-007. In some embodiments, the ammonium salt of LAI-007 is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutylphosphate ammonium. In some embodiments, the calcium salt of LAI-007 is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutylphosphate calcium. In some embodiments, the sodium salt of LAI-007 is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutylphosphate sodium. In some embodiments, the potassium salt of LAI-007 is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-007 is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-007 is (2R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuran-2-methylbutyl phosphate cobalt.

[0178] In some embodiments, the pharmaceutically acceptable salts of this disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-008. In some embodiments, the ammonium salt of LAI-008 is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-008 is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAI-008 is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAI-008 is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-008 is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-008 is (2R,3S,5R)-5-(4-(N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate cobalt.

[0179] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-009. In some embodiments, the ammonium salt of LAI-009 is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutylphosphate ammonium. In some embodiments, the calcium salt of LAI-009 is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutylphosphate calcium. In some embodiments, the sodium salt of LAI-009 is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAI-009 is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-009 is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-009 is (2R,3S,5R)-5-(4-N-methylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate cobalt.

[0180] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-011. In some embodiments, the ammonium salt of LAI-011 is (2R,3S,5R)-5-(4-amino-2-oxopyrididine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-011 is (2R,3S,5R)-5-(4-amino-2-oxopyrididine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAI-011 is (2R,3S,5R)-5-(4-amino-2-oxopyrididine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAI-011 is (2R,3S,5R)-5-(4-amino-2-oxopyrididine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-011 is (2R,3S,5R)-5-(4-amino-2-oxopyrididine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-011 is (2R,3S,5R)-5-(4-amino-2-oxopyrididine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate cobalt.

[0181] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-R-1. In some embodiments, the ammonium salt of LAI-R-1 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-R-1 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAI-R-1 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAI-R-1 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-R-1 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-R-1 is (2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-methylbutyl phosphate cobalt.

[0182] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAI-R-5. In some embodiments, the ammonium salt of LAI-R-5 is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAI-R-5 is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAI-R-5 is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAI-R-5 is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAI-R-5 is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAI-R-5 is (2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxytetrahydrofuran-2-methylbutyl phosphate cobalt.

[0183] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAK-021. In some embodiments, the ammonium salt of LAK-021 is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAK-021 is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAK-021 is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAK-021 is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAK-021 is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxy-tetrahydrofuran-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAK-021 is (2R,3S,4R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-3-hydroxy-4-methoxytetrahydrofuran-2-methylbutyl phosphate cobalt.

[0184] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAK-022. In some embodiments, the ammonium salt of LAK-022 is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuranyl-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAK-022 is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuranyl-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAK-022 is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuranyl-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAK-022 is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuranyl-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAK-022 is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuranyl-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAK-022 is (2R,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-tetrahydrofuranyl-2-methylbutyl phosphate cobalt.

[0185] In some embodiments, the pharmaceutically acceptable salts of the present disclosure are selected from the group consisting of ammonium salts, calcium salts, sodium salts, potassium salts, magnesium salts, and cobalt salts of LAK-022. In some embodiments, the ammonium salt of LAK-023 is (2R,3S,5R)-5-(4-N,N-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate ammonium. In some embodiments, the calcium salt of LAK-023 is (2R,3S,5R)-5-(4-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate calcium. In some embodiments, the sodium salt of LAK-023 is (2R,3S,5R)-5-(4-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate sodium. In some embodiments, the potassium salt of LAK-023 is (2R,3S,5R)-5-(4-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate potassium. In some embodiments, the magnesium salt of LAK-023 is (2R,3S,5R)-5-(4-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate magnesium. In some embodiments, the cobalt salt of LAK-023 is (2R,3S,5R)-5-(4-dimethylamino-2-oxopyrimidine-1(2H)-yl)-2,2-difluoro-3-hydroxytetrahydrofuranyl-2-methylbutyl phosphate cobalt.

[0186] The pharmaceutically acceptable salts of the present disclosure may be prepared by standard techniques known in the art to which the disclosure belongs. For example, the free base form of the compounds of the present disclosure may be dissolved in a suitable solvent, such as an aqueous solution or aqueous alcohol solution containing a suitable acid, and then isolated by evaporating the solution. In another example, the salt may be prepared by reacting the free base and the acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, including treatment of the free acid with a suitable inorganic or organic base.

[0187] In addition to the compounds of this disclosure, this disclosure also includes prodrugs (e.g., pharmaceutically acceptable prodrugs), active metabolite derivatives (active metabolites), and pharmaceutically acceptable salts thereof.

[0188] A prodrug is a compound or a pharmaceutically acceptable salt thereof that, when metabolized under physiological conditions or converted by solvolysis, produces a desired active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous handling, administration, and / or metabolic properties. Some prodrugs are enzymatically activated to produce an active compound, or the compound may undergo further chemical reactions to produce an active compound. A prodrug may progress from the prodrug form to the active form in a single step, or it may have one or more intermediate forms, such forms may be active or inactive.

[0189] As described in Chapters 31 - 32 of *The Practice of Medicinal Chemistry* (edited by Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can be conceptually divided into two non - exclusive categories, including bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds that are either inactive or have lower activity compared to the corresponding active drug compound containing one or more protecting groups, and are converted to the active form by metabolism or solvolysis. Both the active drug form and any released metabolites should have acceptably low toxicity. Typically, the formation of the active drug compound involves a metabolic process or a reaction of one of the following types.

[0190] Oxidation reactions: Oxidation reactions are exemplified by reactions including, but not limited to, oxidation of alcohol, carbonyl, and acid functional groups, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon - carbon double bonds, oxidation of nitrogen - containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N - dealkylation, oxidative O - and S - dealkylation, oxidative deamination, and other oxidation reactions.

[0191] Reduction reactions: Reduction reactions are exemplified by reactions including, but not limited to, reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon - carbon double bonds, reduction of nitrogen - containing functional groups, and other reduction reactions.

[0192] Reactions with no change in oxidation state: Reactions with no change in oxidation state are exemplified by reactions including, but not limited to, hydrolysis of esters and ethers, cleavage by hydrolysis of carbon - nitrogen single bonds, cleavage by hydrolysis of non - aromatic heterocycles, hydration and dehydration in multiple bonds, formation of new atomic bonds by dehydration reactions, dehalogenation by hydrolysis, removal of hydrogen halide molecules, and other such reactions.

[0193] A carrier prodrug is, for example, a drug compound containing a transport moiety that improves uptake and / or localized delivery to the site of action. Desirably, in such a carrier prodrug, the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and any released transport moiety are acceptably non-toxic. In prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it may be desirable to utilize a moiety that provides slow release, for example, a particular polymer or other moiety, such as cyclodextrin. Such carrier prodrugs are often advantageous for orally administered drugs. In some cases, the transport moiety provides targeted delivery of the drug. For example, the drug may be conjugated to an antibody or antibody fragment. Carrier prodrugs can be used to improve, for example, one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, decreased toxicity and adverse reactions, and / or improvements in pharmaceutical formulations (e.g., stability, water solubility, suppression of unwanted sensory irritation or physiochemical properties). For example, lipophilicity can be increased by esterification of a hydroxyl group with a lipophilic carboxylic acid or a carboxylic acid group with an alcohol, such as an aliphatic alcohol. Wermuth, supra.

[0194] Metabolites, such as active metabolites, overlap with prodrugs, such as bioprecursor prodrugs, as described above. Therefore, such metabolites are pharmacologically active compounds, or compounds that are further metabolized to become pharmacologically active derivatives produced by metabolic processes within the target body. Of these, active metabolites are such pharmacologically active derivative compounds. Regarding prodrugs, prodrug compounds are generally inactive or less active than their metabolites. Regarding active metabolites, the parent compound may be an active compound or an inactive prodrug. For example, in some compounds, one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacological activity, and / or carboxyl groups can be esterified, for example, by glucuronidation. In some cases, there may be more than one metabolite, where the intermediate metabolite is further metabolized to provide an active metabolite. For example, in some cases, the derivative compound produced by metabolic glucuronidation may be inactive or less active, and can be further metabolized to provide an active metabolite.

[0195] Metabolites of the compounds disclosed herein may be identified using routine techniques known in the art, and their activity may be determined using tests such as those described above, Bertolini et al., 1997, J. Med. Chem., 40:2011~2016; Shan et al., 1997, J Pharm Sci 86(7):756~757; Bagshawe, 1995, Drug Dev. Res., 34:220~230; Wermuth, etc.

[0196] Those skilled in the art will understand that some compounds may exhibit tautomerism. In such cases, the formulas provided herein expressly represent only one of the possible tautomeral forms. Therefore, it should be understood that the compounds of this disclosure are intended to represent any tautomeral form of the revealed compound and are not limited to the specific tautomeral forms shown in the compound drawings.

[0197] In the case of a solid active substance, the compound and salt may exist in different crystalline or polymorphic forms, or may be formulated as a cocrystal, or in an amorphous form, or in any combination thereof (e.g., partially crystalline, partially amorphous, or a mixture of polymorphs), and it will be understood by those skilled in the art that all of these are intended to be within the scope of this disclosure and the specified formulas. Salts are formed by acid / base addition (i.e., a free base or free acid of the compound of interest forms an acid / base reactant with the corresponding added base or added acid, respectively, resulting in an ionic charge interaction), whereas cocrystals are new chemical species formed between neutral compounds, resulting in the compound and additional molecular species in the same crystalline structure.

[0198] In some cases, the compounds of this disclosure may form complexes with acids or bases, including, but are not limited to, base addition salts, for example, ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine; acid addition salts, for example, acetate, acetylsalicylate, besylate, cansylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, and tosylate; and amino acids, for example, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0199] In addition, the compounds of this disclosure are intended to encompass both hydrated or solvated and unhydrated or non-solvated forms. Other examples of solvates include, but are not limited to, the compounds of this disclosure in combination with preferred solvents, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0200] In some embodiments, the compounds of the Disclosure are protonated compounds. As used herein, the term “protonated compound” means a compound of the Disclosure that has been protonated by adding a proton (or a positively charged hydrogen ion) to a proton acceptor site of the compound of the Disclosure. In some embodiments, the proton acceptor site includes any additional proton acceptor sites on either the phosphate group of the compound of the Disclosure or the ribose or butyl group of the compound of the Disclosure.

[0201] As the number of protonated proton-acceptor sites in the compounds of this disclosure increases, the pH obtained when the compounds of this disclosure are dissolved in water having a pH of 7 decreases. Therefore, the amount of protonation of the compounds of this disclosure can be determined by measuring the pH of the water solution after the addition of the compounds of this disclosure. pH indicates the hydrogen ion concentration of a solution. Solutions with a high concentration of hydrogen ions have a low pH and are therefore acidic, while solutions with a low concentration of hydrogen ions have a high pH and are therefore basic. In some embodiments, when the compounds of this disclosure are protonated and dissolved in water (pH 7), such compounds form aqueous solutions having a pH ranging from about pH less than 7 to about pH 1. Where used herein, the term “about” should be read as including a specified amount and variations of 20%, 10%, 5%, 1%, 0.5%, and 0.1% of the specified amount when used with a numerical value. In some embodiments, the compounds of this disclosure are protonated compounds having a pH when dissolved in water ranging from about pH less than 6 to about pH 1. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 5 to about pH 1. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 4.5 to about pH 1. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 4 to about pH 1. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 3 to about pH 1. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 2 to about pH 1. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 3 to about pH 5. In some embodiments, the compounds of the disclosure are protonated compounds having a pH when dissolved in water from about pH 3 to about pH 4.

[0202] In some embodiments, protonation may be carried out by incubating the compounds of the Disclosure in the presence of a strong acid. While the compounds of the Disclosure may be protonated by adding a proton to the reactive site of the compound, other modifications of the compounds of the Disclosure are possible and are intended to be encompassed by the term protonated compound as used herein. In some embodiments, the protonated form of the compounds of the Disclosure may occur by subjecting purified, partially purified, or crude compounds to a low pH (e.g., acidic) environment. In some embodiments, purified or crude compounds may be protonated with acids including phosphoric acid, nitric acid, hydrochloric acid, and acetic acid.

[0203] Other procedures for preparing the protonated compounds of the Disclosure, which are known to those skilled in the art, are equally intended to be within the scope of the Disclosure. In some embodiments, once the compounds of the Disclosure are protonated, such compounds can be separated from any undesirable components, such as excess acid. Those skilled in the art will know of many methods for separating compounds from undesirable components, including but not limited to the use of H+-cation exchangers (e.g., H+-SCX). In some embodiments, the compounds of the Disclosure may be subjected to chromatography after protonation. In some embodiments, the compounds of the Disclosure are spread on a poly(styrene-divinylbenzene)-based resin (e.g., Hamilton's PRP-1 or 3 and Polymer Lab's PLRP) after protonation.

[0204] In some embodiments, the protonated compounds of the Disclosure may be used directly. In some embodiments, the protonated compounds of the Disclosure may be further processed, for example, by precipitation, reverse-phase chromatography, dialysis filtration, or gel filtration, to remove any excess acid or salt. In some embodiments, the protonated compounds of the Disclosure may be concentrated by lyophilization, solvent evaporation, etc. In some embodiments, when suspended in water or saline, the compounds of the Disclosure generally exhibit a pH ranging from about pH 3 to about pH 5, depending on the level of protonation / acidification, which is determined by how much acid is used in the acidification process. In some embodiments, the compounds of the Disclosure may be protonated by passing over a cation exchange column loaded with hydrogen ions.

[0205] In some embodiments, the use of butyl groups in the compounds of the Disclosure prevents or limits substantial nuclease degradation of the compounds of the Disclosure, including, but not limited to, exonuclease degradation. In some embodiments, butyl groups are positioned to protect the ribose of the compounds of the Disclosure. The rate of acid degradation may be determined using analytical HPLC for evaluating the loss of functional molecules, or by other preferred methods. Acid degradation is generally measured as a function of time. In some embodiments, the compounds of the Disclosure are also nuclease-resistant, which allows such compounds to maintain activity (e.g., pH stability) in an in vivo setting. The rate of degradation of the compounds of the Disclosure in a nuclease-containing setting may be determined by methods known to those skilled in the art, such as mass spectrometry. Nuclease degradation is generally measured as a function of time. In some embodiments, a reference compound is used when determining the degree or rate of acid or nuclease degradation.

[0206] Compounds of the Disclosure, according to certain embodiments, are useful as antimicrobial agents active against any microorganism. As used herein, the terms “microorganism,” “microbial,” and similar terms refer to bacteria, fungi, protozoa, viruses, yeasts, etc. As used herein, the term “antimicrobial agent” refers to a compound of the Disclosure that has the ability to kill or inhibit the growth of a microorganism or to reduce the severity of a microbial infection. A non-exclusive list of bacteria against which the compounds of the Disclosure are effective includes, but is not limited to, Gram-positive bacteria, Gram-negative bacteria, slow-growing bacteria and acid-fast bacteria, and all species belonging to the following genera: Aerococcus, Listeria, Streptomyces, Chlamydia, Lactobacillus, Eubacterium, Burkholderia, Stentrophomonas, Achromobacter, Arachnid, Mycobacterium, Peptostreptococcus, Staphylococcus, Corynebacterium, Erysipeloth rix, Dermatophilus, Rhodococcus, Pseudomonas, Streptococcus, Bacillus, Peptococcus, Pneumococcus, Micrococcus, Neisseria, Klebsiella, Kurthia, Nocardia, Ser ratia, Rothia, Escherichia, Propionibacterium, Actinomyces, Helicobacter, Enterococcus, Shigella, Vibrio, Clostridium, Salmonella, Yersinia, and Haemophilus.

[0207] A non-limiting list of fungi in which the compounds of this disclosure are effective includes, but is not limited to, Trichophyton, Epidermophyton, Microsporum, Candida albicans and other Candida species, Pityrosporum orbiculare, Trichophyton mentagrophytes, Trichophyton rubrum, Epidermophyton floccosurn, and Trichophyton tonsurans. A non-limiting list of viruses in which the compounds of this disclosure are effective includes, but is not limited to, enveloped viruses, human immunodeficiency virus (HIV), herpes simplex virus (HSV), cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), coronavirus, and influenza virus.

[0208] In some embodiments, the compounds of the Disclosure are useful in both therapeutic and non-therapeutic medical applications. In some embodiments, including non-therapeutic medical applications, the antimicrobial effect of the compounds of the Disclosure enables the use of the compounds for sterilization (e.g., sterilization of a patient's skin or the surface of an object such as a surgical instrument) or sanitization (e.g., cleaning of a surface or instrument to ensure that there are no disease-causing microorganisms on the surface at undesirable concentrations). In some embodiments, the compounds of the Disclosure are effective in combating microbial contamination of laboratory cultures, consumables (e.g., food or beverage preparations), medical devices, hospital equipment, or industrial processes. Therapeutic applications of the compounds of the Disclosure are described herein.

[0209] This disclosure also provides pharmaceutical compositions. As used herein, the term “pharmaceutical composition” means a pharmaceutical preparation containing the compounds of this disclosure or pharmaceutically acceptable salts thereof, which is suitable for administration to a patient for therapeutic purposes. As used herein, the term “patient” means a living organism treated with the compounds of this disclosure, including, but not limited to, humans, other primates (e.g., monkeys, chimpanzees, etc.), companion animals (e.g., dogs, cats, horses, etc.), livestock (e.g., goats, sheep, pigs, cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and any mammals such as wild and zoo animals (e.g., wolves, bears, deer, etc.).

[0210] In some embodiments, the composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound of the Disclosure, including, but not limited to, one or more pharmaceutically acceptable carriers, excipients, or diluents. The carriers, excipients, or diluents may take a wide variety of forms depending on the desired form of the preparation for administration.

[0211] As used herein, the term “carrier” includes, but is not limited to, calcium carbonate, calcium phosphate, various sugars, e.g., lactose, glucose, or sucrose, various starches, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and physiologically acceptable liquids for use as solvents or suspensions, such as sterile solutions of water for injection (WFI), physiological saline solutions, dextrose solutions, Hanks’ solution, Ringer’s solution, vegetable oils, mineral oils, animal oils, polyethylene glycol, liquid paraffin, etc.

[0212] As used herein, the term “excipient” generally includes, but is not limited to, fillers, binders, disintegrants, flow enhancers, lubricants, complexing agents, solubilizers, stabilizers, preservatives, and surfactants, which may be selected to facilitate the administration of compounds by a particular route. Suitable excipients include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, siloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed oil, mineral oil, polyethylene glycol (e.g., PEG4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, crosca Lumellose sodium, alginic acid, casein, divinylbenzene methacrylate copolymer, doxate sodium, cyclodextrin (e.g., 2-hydroxypropyl-delta-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, di-fatty acid esters of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, e.g., sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or spray-dried lactose, sucrose,It may also include fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrate, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, etc.

[0213] As will be understood by those skilled in the art, any diluent known in the art may be used in accordance with the present disclosure. In some embodiments of the present disclosure, the diluent is water-soluble. In some embodiments of the present disclosure, the diluent is water-insoluble. As used herein, the term "diluent" includes, but is not limited to, water, physiological saline, phosphate buffered saline (PBS), dextrose, glycerol, ethanol, buffered sodium acetate solution or buffered ammonium acetate solution, etc., and combinations thereof.

[0214] In some embodiments, the pharmaceutical composition of the present disclosure includes at least one additional active ingredient. As used herein, the term "active ingredient" refers to a therapeutically active compound and any prodrug thereof, as well as pharmaceutically acceptable salts, hydrates, and solvates of the compound and prodrug. The additional active ingredient may be combined with the compound of the present disclosure and administered either separately or in the same pharmaceutical composition. The amount of the additional active ingredient to be administered may be determined by those skilled in the art based on the therapy with the compound of the present disclosure.

[0215] In some embodiments, the composition is a pharmaceutical composition for human use. As used herein, the term "pharmaceutical composition for human use" refers to a pharmaceutical composition intended for administration to humans.

[0216] The pharmaceutical compositions of this disclosure are suitable for administration to patients by any suitable means, including, but not limited to, means used for administering conventional antimicrobial agents. The pharmaceutical compositions of this disclosure may be administered by any applicable route that a person skilled in the art would consider, including, but not limited to, oral, intravenous ("IV") injection or infusion, intravesical, subcutaneous ("SC"), intramuscular ("IM"), intraperitoneal, intradermal, intraocular, inhalation (and intrapulmonary), intranasal, percutaneous, on the skin, subdermal, topical, mucosal, nasal, ophthalmic, cutaneous impression, vaginal, intrauterine, intracervical, and rectal. Such dosage forms should enable the compounds of this disclosure to reach target cells. Other factors, which are well known in the art, include considerations such as toxicity and dosage form that may interfere with the compound or composition exerting its effect. The technology and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005.

[0217] In some embodiments, the pharmaceutical compositions of this disclosure are suitable for topical administration. As used herein, the term “topical administration” refers to the administration of the compounds of this disclosure to the surface of a patient’s skin such that the compounds of this disclosure pass through the skin layers. Transdermal administration and transmucosal administration are also encompassed within the term “topical administration.” As used herein, the term “transdermal” refers to the passage of the compounds of this disclosure across at least one skin layer of a patient. As used herein, “transmucosal” refers to the passage of the compounds of this disclosure across the mucous membranes of a patient. Unless otherwise stated or implied, the terms “topical administration,” “transdermal administration,” and “transmucosal administration” are interchangeable herein.

[0218] Various topical delivery systems for delivering bioactive compounds to a patient's microorganisms are well known in the art. Such systems, depending on the selection of an appropriate carrier in the art, include, but are not limited to, lotions, creams, gels, oils, ointments, solutions, suspensions, emulsions, and the like. In some embodiments, the pharmaceutical composition is administered in the form of a gel containing a polyhydric alcohol.

[0219] Suitable carriers include, but are not limited to, plant or mineral oils, white petrolatum (e.g., white soft paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (e.g., greater than C12). In some embodiments, a carrier is selected such that the compounds of the Disclosure are soluble. In some embodiments, emulsifiers, stabilizers, humectants, and antioxidants, as well as active ingredients that impart color or fragrance, if desired, may also be included. In some embodiments, organic solvents or co-solvents such as ethanol or propanol may be used in the pharmaceutical compositions of the Disclosure. In some embodiments, evaporation of the solvent leaves a residue on the treated surface to inhibit reinfection. In some embodiments, a suitable penetrating agent is used to permeate the barrier. Such penetrating agents are generally known in the Art and, but are not limited to, bile salts and fusidic acid derivatives. In some embodiments, detergents may be used to facilitate permeation. In some embodiments, a topical cream is formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, to which a small amount of the compound of the present disclosure, dissolved in a solvent (e.g., oil), is mixed. The specific topical delivery system used depends on the location of the microorganism.

[0220] In some embodiments, other materials may be added to the topical pharmaceutical compositions of this disclosure to provide additional moisturizing effects and improve the viscosity of the pharmaceutical compositions. Examples of such compounds include, but are not limited to, cetyl ester waxes, stearyl alcohol, cetyl alcohol, glycerin, methylparaben, propylparaben, quaternium-15, humectants, volatile methylsiloxane fluids, and polydiorganosiloxane-polyoxyalkylenes. See, for example, U.S. Patents 5,153,230 and 4,421,769. In some embodiments, if it is desirable that the pharmaceutical composition have additional cleansing effects, chemicals such as sodium lauryl sulfate or metal salts of carboxylic acids may be added.

[0221] In some embodiments, a wide variety of non-volatile emollients are useful in the pharmaceutical compositions of the Disclosure. Non-limiting examples of such non-volatile emollients are found in McCutcheon's, Vol. 2 Functional Materials, North American Edition, (1992), pp. 137–168, and in the CTFA Cosmetic Ingredient Handbook, 2nd edition (1992), with Skin-Conditioning Agents on pp. 572–575 and Skin Protectants on pp. 580. In some embodiments, non-volatile emollients include silicones, hydrocarbons, esters, and mixtures thereof. In some embodiments, esters include esters of monofunctional and difunctional fatty acids esterified with alcohols and polyols (i.e., alcohols having two or more hydroxyl groups). In some embodiments, long-chain esters of long-chain fatty acids are utilized in the pharmaceutical compositions of the Disclosure (i.e., C10–40 fatty acids esterified with C10–40 fatty alcohols). Non-limiting examples of esters useful in the pharmaceutical compositions of this disclosure include, but are not limited to, those selected from the group consisting of diisopropyl adipate, isopropyl myristate, isopropyl palmitate, myristyl propionate, ethylene glycol distearate, 2-ethylhexyl palmitate, isodecyl neopentanoate, C12-15 alcohol benzoates, di-2-ethylhexyl maleate, cetyl palmitate, myristyl myristate, stearyl stearate, cetyl stearate, behenyl behenrate, and mixtures thereof.

[0222] Examples of silicone emollients useful in the pharmaceutical compositions of this disclosure include, but are not limited to, polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes. Preferred commercially available polyalkylsiloxanes include polydimethylsiloxane, also known as dimethicone, and non-limited examples include the Vicasil® series sold by General Electric Company and the Dow Corning® 200 series sold by Dow Corning Corporation. Among the many commercially available polyalkylsiloxanes are cyclomethicone (Dow Corning® 244 fluid, Dow Corning® 344 fluid, Dow Corning® 245 fluid, and Dow Corning® 345). A preferred commercially available trimethylsiloxysilicate is sold as a mixture with dimethicone, as Dow Corning® 593 fluid. Dimethiconol, a hydroxyl-terminated dimethyl silicone, is also useful in the pharmaceutical compositions of this disclosure. Suitable commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e.g., Dow Corning® 1401, 1402, and 1403 fluids). Suitable commercially available polyalkylarylsiloxanes include SF1075 methylphenyl fluid (sold by General Electric Company) and 556 cosmetic-grade phenyl trimethicone fluid (sold by Dow Corning Corporation).

[0223] Hydrocarbons suitable for use in the pharmaceutical compositions of this disclosure include, but are not limited to, linear and branched hydrocarbons having about 10 to about 30 carbon atoms. In some embodiments, the linear and branched hydrocarbons have about 12 to about 24 carbon atoms. In some embodiments, the linear and branched hydrocarbons have about 16 to about 22 carbon atoms. Non-limiting examples of such hydrocarbon materials include, among many, dodecane, squalane, cholesterol, pentahydrogenated polyisobutylene, docosane (i.e., C22 hydrocarbon), hexadecane, and isohexadecane (a commercially available hydrocarbon sold by Presperse, South Plainsfield, NJ as Permethyl® 101A).

[0224] In some embodiments, the topical pharmaceutical compositions of the Disclosure contain propylene glycol. In some embodiments, propylene glycol acts as a surfactant to aid in the penetration, contact, and absorption of the compounds of the Disclosure. In some embodiments, propylene glycol serves as a preservative. In some embodiments, the pharmaceutical compositions of the Disclosure contain a nonionic surfactant, such as polysorbate. Such surfactants provide better surface contact of the pharmaceutical compositions of the Disclosure with mucous membranes (such as vaginal mucosa) by further reducing surface tension.

[0225] The topical pharmaceutical compositions of this disclosure may optionally be formulated in a lipid-soluble phase, such as an emulsion and a liposome dispersion. In some embodiments, the liposome formulation can extend the circulation time of the compounds of this disclosure, increase the permeability of the compounds of this disclosure, and improve the overall efficacy of the compounds of this disclosure as antimicrobial agents. In some embodiments, the compounds of this disclosure may be combined with lipids, cationic lipids, or anionic lipids. In some embodiments, the resulting emulsion or liposome suspension can effectively increase the in vivo half-life of the activity of the pharmaceutical composition of this disclosure, along with the quality of stabilizing the pH of the compounds of this disclosure. Examples of suitable anionic lipids for use in the pharmaceutical compositions of this disclosure include, but are not limited to, cardiolipin, dimyristoyl, dipalmitoyl, dioleoylphosphatidylcholine, phosphatidylglycerol, palmitoyloleoylphosphatidylcholine, phosphatidylglycerol, phosphatidic acid, lysophosphatidic acid, phosphatidylserine, phosphatidylinositol, and the anionic forms of cholesterol.

[0226] In some embodiments, the compounds of the Disclosure are incorporated into liposomes. In some embodiments, neutral lipids, cholesterol, and / or polyethylene glycol (PEG) are utilized in such liposomes. In some embodiments, the liposome composition comprises partially hydrogenated soybean phosphatidylcholine (PHSC), cholesterol, methoxy-terminated PEG (mPEG), and / or distearoyl phosphatidylethanolamine (DSPE). The liposomes may be prepared according to any preferred method known in the Art.

[0227] In some embodiments, topical administration is via nasal spray or suppositories (rectal or vaginal). Suppositories are prepared by mixing the compounds of the Disclosure with a lipid vehicle, e.g., theobroma oil, cocoa butter, glycerin, gelatin, polyoxyethylene glycol, etc. In some embodiments, topical administration includes transdermal patches or bandages, such as adhesive bandages, impregnated with the compounds of the Disclosure, and optionally one or more carriers, excipients, or diluents known in the Art. In some embodiments, such bandages include, but are not limited to, semipermeable membranes, foams, hydrocolloids, and calcium alginate swabs. In some embodiments, dosage administration is continuous rather than intermittent throughout the dosage regimen.

[0228] In some embodiments, the pharmaceutical compositions of the Disclosure are suitable for oral administration. As used herein, the term “oral administration” refers to the administration of the compounds of the Disclosure into the mouth of a patient for ingestion into the gastrointestinal tract. In some embodiments, the pharmaceutical compositions of the Disclosure may be formulated into conventional oral dosage forms, including, but not limited to, capsules, tablets, powders, and liquid preparations, e.g., suspensions, solutions, elixirs, syrups, concentrated droplets, etc. In some embodiments, the compounds of the Disclosure may be combined with solid excipients, and the resulting mixture may be optionally crushed, the granular mixture may be optionally processed, and suitable excipients may be added if desired to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic, or oily solutions), etc. In some embodiments, suitable excipients for use in the oral pharmaceutical compositions of this disclosure include, but are not limited to, fillers, sugars including, for example, lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP or povidone); and oily excipients including plant and animal oils such as sunflower oil, olive oil, or cod liver oil. In some embodiments, the oral pharmaceutical compositions of the Disclosure may also contain disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate; lubricants, such as talc or magnesium stearate; plasticizers, such as glycerol or sorbitol; sweeteners, such as sucrose, fructose, lactose, or aspartame; natural or artificial flavorings, such as peppermint, wintergreen oil, or cherry flavorings; or dyes or pigments that can be used to identify or characterize different doses or combinations. In some embodiments, the oral pharmaceutical compositions of the Disclosure may also contain a sugar-coated tablet core with a suitable coating.In some embodiments, a concentrated sugar solution may be used, which may optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture.

[0229] In some embodiments, the pharmaceutical compositions of the present disclosure, which may be used orally, include, but are not limited to, gelatin-based press-fit capsules ("gel caps") and gelatin-based soft-seal capsules, as well as plasticizers such as glycerol or sorbitol. In some embodiments, the press-fit capsules may contain the compounds of the present disclosure in miscible with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In some embodiments including soft capsules, the active compounds may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol.

[0230] In some embodiments, the pharmaceutical compositions of the Disclosure are suitable for inhalation administration. As used herein, the term “inhalation administration” refers to the delivery of the compounds of the Disclosure by passage through the patient’s nose or mouth and through the patient’s lung wall during inhalation. In some embodiments, the pharmaceutical compositions of the Disclosure suitable for inhalation administration may be formulated as a dry powder or as a suitable liquid, suspension or aerosol. In some embodiments, the powders and liquids may be formulated with suitable additives known in the Art. In some embodiments, the powders may contain a suitable powder base such as lactose or starch. In some embodiments, the liquids may contain propylene glycol, sterile water, ethanol, sodium chloride, and other additives, e.g., acids, alkalis, and buffer salts. In some embodiments, such liquids or suspensions may be administered by inhalation via a spray, pump, atomizer, nebulizer, etc. In some embodiments, the pharmaceutical compositions of the Disclosure suitable for inhalation administration are, but are not limited to, corticosteroids, e.g., fluticasone propionate. Mometasone phlomate; beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone phlomate; beta-agonists, e.g., albuterol, salmeterol, and formoterol; anticholinergics, e.g., ipratropium bromide or tiotropium bromide; vasodilators, e.g., treprostinal and iloprost; enzymes, e.g., DNAases; therapeutic proteins; immunoglobulin antibodies; oligonucleotides, e.g., single-stranded or double-stranded DNA or RNA, siRNA; antibiotics, e.g., tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate, which may be used in combination with other inhalation therapies.

[0231] In some embodiments, the pharmaceutical compositions of this disclosure are suitable for intravesical administration. As used herein, the term “intravesical administration” refers to the direct delivery of the compounds of this disclosure to the patient’s bladder. In some embodiments, the pharmaceutical compositions are administered via a catheter. In some embodiments, the catheter is a urethral catheter.

[0232] In some embodiments, the pharmaceutical compositions of the Disclosure are suitable for parenteral administration. As used herein, the term “parenteral administration” means that the compounds of the Disclosure are injected or infused into a patient, and includes, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intraventricular, intracapsular, intraorbital, intracardiac, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, intraspinal, intracerebrospinal, and intrasternal injections and infusions. In some embodiments, the pharmaceutical compositions of the Disclosure suitable for parenteral administration may be formulated in a physiologically suitable buffer or solution, for example, a sterile liquid solution containing physiological saline solution, Hanks' solution, or Ringer's solution. In some embodiments, the pharmaceutical compositions of the Disclosure suitable for parenteral administration may be prepared as a dispersion in a non-aqueous solution, for example, glycerol, propylene glycol, ethanol, liquid polyethylene glycol, triacetin, vegetable oil, etc. In some embodiments, the solution may also contain preservatives, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In addition, pharmaceutical compositions of the present disclosure suitable for parenteral administration may be formulated in solid form, for example, lyophilized form, and redissolved or suspended before use. In some embodiments, the pharmaceutical composition is administered via a needle.

[0233] In some embodiments, the Disclosure provides methods and compositions for pre-treating a catheter with a compound of the Disclosure to prevent infection after the catheter has been inserted into a patient. In some embodiments, the Method of the Disclosure includes coating the catheter with a compound of the Disclosure before inserting the catheter into a patient. In some embodiments, the Disclosure provides compositions comprising a catheter coated with a compound of the Disclosure. In some embodiments, such methods and compositions may be used as a preventive measure against infection in a patient.

[0234] This disclosure also provides methods of treatment. As used herein, the terms “to treat,” “treatment,” “therapy,” and similar terms refer to the administration of a compound or pharmaceutical composition of this disclosure in an amount effective to prevent, alleviate or induce remission of one or more symptoms (i.e., indications) of a disease or condition, and / or to extend the survival of the patient being treated. In some embodiments, “to treat,” “treatment,” “therapy,” and similar terms also include, but are not limited to, reducing or eliminating infection in a patient.

[0235] When performing the method of the Disclosure, an effective amount of the Compound of the Disclosure is administered to a patient in need. As used herein, the term “effective amount” means, in the context of administration, an amount of the Compound of the Disclosure or a pharmaceutical composition that, when administered to a patient, is sufficient to prevent, alleviate or induce remission of one or more symptoms (i.e., indications) of a disease or condition, and / or to prolong the survival of the patient being treated. Such an amount should not result in any or little adverse events in the patient being treated. Similarly, such an amount should not result in any or little toxic effects in the patient being treated. As those skilled in the art will understand, the amount of the compound or pharmaceutical composition of the Disclosure will vary, but is not limited, depending on several factors, including the activity of the compound of the Disclosure (in vitro, e.g., compound versus target of the Disclosure, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), the type of patient being treated, the patient's age, size, weight, and systemic medical conditions, patient-related disorders, and the medication regimen used in treatment.

[0236] In some embodiments of this disclosure, the effective amount of the compound of this disclosure to be delivered to a patient in need may be quantified by determining the amount of the compound of this disclosure in micrograms per kilogram of the patient's body weight. In some embodiments, the amount of the compound of this disclosure administered to the patient is from about 0.1 to about 1000 milligrams (mg) of the compound of this disclosure per kilogram (kg) of the patient's body weight. In some embodiments, the amount of the compound of this disclosure administered to the patient is from about 0.1 to about 500 mg of the compound of this disclosure per kg of the patient's body weight. In some embodiments, the amount of the compound of this disclosure administered to the patient is from about 0.1 to about 300 mg of the compound of this disclosure per kg of the patient's body weight. In some embodiments, the amount of the compound of this disclosure administered to the patient is from about 0.1 to about 200 mg of the compound of this disclosure per kg of the patient's body weight. In some embodiments, the amount of the compound of this disclosure administered to the patient is from about 0.1 to about 100 mg of the compound of this disclosure per kg of the patient's body weight. As those skilled in the art will understand, multiple doses may be used.

[0237] In some embodiments of this disclosure, the compounds of this disclosure are administered as a multi-dose regimen. As used herein, the term “multi-dose regimen” refers to a treatment period of more than one day. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately two days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately three days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately four days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately five days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately six days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately seven days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately fourteen days. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately one month. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately two months. In some embodiments of this disclosure, a multi-dose regimen is a period of up to approximately three months. In some embodiments of this disclosure, the multi-dose regimen is for a maximum period of approximately 4 months. In some embodiments of this disclosure, the multi-dose regimen is for a maximum period of approximately 5 months. In some embodiments of this disclosure, the multi-dose regimen is for a maximum period of approximately 6 months. Other periods may be used herein.

[0238] In some embodiments of this disclosure, the compounds of this disclosure are administered as part of a chronic treatment regimen. As used herein, the term “chronic treatment regimen” refers to treatment with the compounds of this disclosure over a long period of time throughout the patient’s lifetime. In some embodiments, chronic treatment is a lifetime treatment.

[0239] In some embodiments of this disclosure, the compounds of this disclosure are administered as a single dose. In some embodiments of this disclosure, the compounds of this disclosure are administered as a single unit dose. As used herein, the term “unit dose” refers to a given amount of the compound of this disclosure. The amount of the compound of this disclosure is generally equal to the amount of the compound of this disclosure that would be administered to a patient, or a convenient proportion of such an amount, for example, half or one-third of such an amount. According to the methods of this disclosure, the terms “single dose” and “single unit dose” include embodiments in which the composition may be administered as a single application and may be administered as multiple applications.

[0240] In some embodiments, the compounds of the Disclosure may be used in combination with one or more additional active ingredients for treating the same disease or condition. In some embodiments, such combinations include administration of the compounds of the Disclosure and one or more additional active ingredients at different times, or co-administration of the compounds of the Disclosure and one or more additional active ingredients. In some embodiments, the dosage may be modified in a manner well known to those skilled in the art to match the reduction in the amount administered compared to the compounds of the Disclosure or one or more additional active ingredients used in combination, for example, the compounds of the Disclosure or one or more additional active ingredients used alone. In some embodiments, co-administration includes simultaneous administration of the compounds of the Disclosure and additional active ingredients in the same dosage form, simultaneous administration of the compounds of the Disclosure and additional active ingredients in different dosage forms, and separate administration of the compounds of the Disclosure and additional active ingredients.

[0241] Concomitant use includes use with one or more additional active ingredients or other medical procedures, where one or more additional active ingredients or other medical procedures may be administered at a different time from the compound or pharmaceutical composition of the Disclosure (e.g., within a short period of time such as a few hours (e.g., 1, 2, 3, 4 to 24 hours, etc.), or within a longer period of time such as 1 to 2 days, 2 to 4 days, 4 to 7 days, 1 to 4 weeks, etc.), or concurrently with the compound or pharmaceutical composition of the Disclosure. Concomitant use also includes use with one or more additional active ingredients or other medical procedures administered once or rarely, such as surgery, together with the compound or pharmaceutical composition of the Disclosure administered within a short or longer period of time before or after the administration of one or more additional active ingredients or other medical procedures.

[0242] In some embodiments, the Disclosure provides the delivery of the compounds or pharmaceutical compositions of the Disclosure and one or more additional active ingredients, delivered by different or the same route of administration. In some embodiments, co-administration for any route of administration includes the delivery of any pharmaceutical composition, the compounds or pharmaceutical compositions of the Disclosure and one or more additional active ingredients, delivered together by the same route of administration, including pharmaceutical compositions in which two compounds are chemically bonded in such a manner that such compounds maintain their therapeutic activity when administered. In some embodiments, one or more additional active ingredients may be co-administered with the compounds or pharmaceutical compositions of the Disclosure. In some embodiments, co-administration co-administration includes the administration of a co-formulation or a formulation of chemically bonded compounds, or the administration of two or more compounds in separate formulations within a short time interval (e.g., 1 hour, 2 hours, 3 hours, up to 24 hours, etc.) delivered by the same or different routes. In some embodiments, co-administration of separate formulations includes co-administration by delivery via a single device, e.g., the same inhalation device, the same syringe, etc., or administration from separate devices within a short time interval. In some embodiments, co-formulations of the compounds or pharmaceutical compositions of the Disclosure and one or more additional active ingredients delivered by the same route include combined preparations of materials that can be administered by a single device, which include separate compounds combined in one formulation, or compounds that are chemically bonded but modified to still maintain their biological activity. In some embodiments, such chemically bonded compounds may have a bond that is substantially maintained in vivo, or the bond may break in vivo to separate the two active ingredients.

[0243] This disclosure also provides methods for treating infections in patients who require them. In some embodiments, the method includes the step of administering an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a patient. As used herein, the term “infection” refers to any microbial infection of a patient’s body. An infection includes the entry of microorganisms into the patient’s body and their subsequent proliferation within the patient’s body.

[0244] This disclosure also provides a method for treating infections of lower extremity ulcers in patients who require it. In some embodiments, the method includes the step of administering to a patient an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term “infection” means any microbial infection of the patient’s body. An infection includes the entry of microorganisms into the patient’s body and their subsequent proliferation within the patient’s body. As used herein, the term “lower extremity” means the lower extremities of the patient’s body, including, but not limited to, the hips, thighs, legs, ankles, and feet. As used herein, the term “ulcer” means an open wound found anywhere on the patient’s lower extremities.

[0245] In some embodiments, the Disclosure provides a method for treating an infection of a diabetic foot ulcer in a patient who needs it. In some embodiments, the method comprises the step of administering an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, the patient has type 1 diabetes or type 2 diabetes. As used herein, the term “diabetic foot ulcer” refers to an open wound located anywhere on the patient’s foot. In some embodiments, the wound is located on the heel, midfoot, and / or forefoot of the patient’s foot. As used herein, the term “to treat” in the context of diabetic foot ulcers also includes, but is not limited to, reducing or eliminating the infection in the patient, which in some embodiments means limiting the progression in size, area, and / or depth of the foot ulcer; reducing the size, area, and / or depth of the foot ulcer; increasing the healing rate and / or reducing the time to healing; healing of the foot ulcer (about 100% epithelialization without drainage); and / or resulting in a reduction in the incidence of amputation or a delay in the time to amputation.

[0246] In some embodiments, the patient is human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using the compound or a pharmaceutically acceptable salt thereof in a lotion, paste, gel, cream, ointment, oil or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multi-dose regimen. In some embodiments, the multi-dose regimen is for a period of up to about one month. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to about two months. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to about three months. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to about four months. Other periods may be used herein.

[0247] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0248] This disclosure also provides methods for treating urinary tract infections in patients who require them. In some embodiments, the method includes the step of administering to a patient an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term “urinary tract” refers to, but is not limited to, the organs of the patient’s body that produce, store, and excrete urine, including, but not limited to, the kidneys, ureters, bladder, and urethra. As used herein, the term “urinary tract infection” refers to an infection of the patient’s urinary tract, including, but not limited to, simple urinary tract infections and complicated urinary tract infections. As used herein, the term “simple urinary tract infection” refers to a microbial infection of the patient’s structurally and functionally normal urinary tract. As used herein, the term “complicated urinary tract infection” refers to a microbial infection of the patient’s structurally and functionally abnormal urinary tract. In some embodiments, the complicated urinary tract infection is a catheter-associated urinary tract infection. As used herein, the term “catheter-associated urinary tract infection” refers to a complicated urinary tract infection that occurs in a patient with an indwelling urinary catheter.

[0249] In some embodiments, the patient is human. In some embodiments, administration is intravesical. In some embodiments, administration is carried out using the compounds of this disclosure or pharmaceutically acceptable salts thereof in liquid or suspension form. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, administration is carried out as a multi-dose regimen. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 2 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 3 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 4 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 5 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 6 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 7 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 14 days. In some embodiments of this disclosure, administration is carried out as a chronic treatment regimen. Other periods may be used herein.

[0250] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0251] This disclosure also provides methods for treating pulmonary infections in patients in need. In some embodiments, the method includes the step of administering an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a patient. As used herein, the term “pulmonary infection” refers to an infection of one or both of the patient’s lungs. In some embodiments, a pulmonary infection results from a lung disease. As used herein, the term “lung disease” refers to both infectious and non-infectious-induced diseases as well as respiratory system dysfunction.

[0252] Non-limited examples of lung diseases include, but are not limited to, genetic disorders, acquired disorders, primary disorders, secondary disorders, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory tract disease, croup, high-altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, and neonatal respiratory distress syndrome. This includes parainfluenza, pleural effusion, pleurisy, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, wheezing, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis, Q fever, parainfluenza, respiratory syncytial virus, combinations thereof, and diseases caused by any one or combination of the above.

[0253] In some embodiments, the lung disease is caused by a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, and omicron coronavirus, or a combination thereof.

[0254] In some embodiments, coronaviruses include porcine epidemic diarrhea virus (PEDv), Scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-alpha-CoV HuB-2013, bat coronavirus HKU10, Minioptrus bat coronavirus HKU8, Minioptrus bat coronavirus 1, Nyctalus velutinus alpha coronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alpha coronavirus Sachs-2011, HumCoV 229E, 229E-related bat coronavirus, camel alpha coronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63-related bat CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, and Lucheng. Rn rat coronavirus 2, FIPV, TGEV, PRCV, alpha coronavirus 1, mink coronavirus 1, FRCoV-NL-2010, Sorex araneus coronavirus T14, Suncus murinus coronavirus X74, HumCoV OC43, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, Bovine Coronavirus Isolate Alpaca, Canine Respiratory Coronavirus K37, PHEV, Equine Coronavirus, HKU14, HKU24, Myodes Coronavirus 2 JL14, HKU1, MHV, Rat Coronavirus Parker, HKU4, HKU5, Human MERS-CoV, Camel MERS-CoV, Hedgehog Coronavirus 1, HKU9, Rousette Bat Coronavirus GCCDC1, Eidolon Bat Coronavirus C704, Human SARS-CoV, Palm Civet SARS-CoV, Badger SARS-CoV, Bat SL-CoV RsSHC014, Bat SL-CoV Rs3367, Bat SL-CoV WIV1, HKU3, Bat SL-CoV ZC45, Bat SL-CoV ZXC21, Bat CoV RaTG13, Bat CoVSelected from the group consisting of RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, canine CoV, mink CoV, GD pangolin CoV, bat Hp-betacoronavirus Zhejiang2013, peacock IBV, avian coronavirus 9203, poultry IBV, avian coronavirus, duck CoV, partridge IBV, goose coronavirus CB17, beluga whale coronavirus SW1, HKU22, HKU19, HKU20, HKU21, HKU11, HKU12, HKU16, HKU27, HKU28, HKU29, HKU18, HKU13, HKU30-UAE, HKU30-Poland, HKU17-USA, HKU17-China, AlCCoV, and HKU15, or combinations thereof.

[0255] In some embodiments, coronaviruses include HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, Myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rosette bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS-CoV, badger SARS-CoV, bat SL-CoV RsSHC014, bat SL-CoV Rs3367, bat SL-CoV WIV1, HKU3, bat SL-CoV ZC45, and bat SL-CoV It is a betacoronavirus selected from the group consisting of ZXC21, bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, canine CoV, mink CoV, GD pangolin CoV, and bat Hp-betacoronavirus Zhejiang2013, or combinations thereof.

[0256] In some embodiments of this disclosure, a method is provided for treating pulmonary infections resulting from cystic fibrosis in patients in need thereof. In some embodiments, the method comprises the step of administering to a patient an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term “cystic fibrosis” refers to a genetic disorder that causes the production of abnormally thick mucus, resulting in pulmonary infections, as well as damage to the lungs, digestive system, and other organs in the patient’s body.

[0257] In some embodiments, administration is by inhalation. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the patient is human. In some embodiments, administration is carried out using the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the form of a liquid, suspension or dry powder. In some embodiments, administration is carried out as a multi-dose regimen. In some embodiments, the multi-dose regimen is for a period of up to about one month. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about two months. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about three months. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about four months. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about five months. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about six months. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about seven months. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about eight months. Other terms may be used in this specification.

[0258] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0259] In some embodiments of this disclosure, a method is provided for treating pneumonia in a patient in need thereof. In some embodiments, the method includes the step of administering to a patient an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof. As used herein, the term “pneumonia” refers to a microbial infection of one or both lungs of a patient resulting in inflammation of the lung tissue. In some embodiments, the pneumonia is ventilator-acquired pneumonia. As used herein, the term “ventilator-acquired pneumonia” refers to pneumonia occurring in a patient connected to a mechanical ventilator. Ventilator-acquired pneumonia includes pneumonia that appears more than about 48 hours after the patient has been intubated and received mechanical ventilation.

[0260] In some embodiments, administration is by inhalation. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the patient is human. In some embodiments, administration is carried out using the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the form of a liquid, suspension or dry powder. In some embodiments, administration is carried out as a multi-dose regimen. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 7 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 14 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 21 days. In some embodiments, the multi-dose regimen is for a period of up to about 1 month. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 2 months. Other periods may be used herein.

[0261] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0262] This disclosure also provides a method for treating infections in burn wounds in patients who require it. In some embodiments, the method includes the step of administering an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof to a patient. As used herein, the term “burn wound” refers to a burn to a patient’s body, which involves damage to the patient’s skin and, if applicable, to the tissues beneath the patient’s skin. There are three main types of burn degrees known to those skilled in the art, but which include, first-degree, second-degree, and third-degree burns. In some embodiments, the method for treating infections in burn wounds contemplated by this disclosure is used to treat first-degree, second-degree, and / or third-degree burns.

[0263] In some embodiments, the patient is human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using the compounds of the Disclosure or pharmaceutically acceptable salts thereof in lotions, creams, ointments, oils, liquids, suspensions, emulsions or other viscous compositions. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multi-dose regimen. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 2 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 3 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 4 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 5 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 6 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 7 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 14 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 21 days. In some embodiments, the multi-dose regimen is for a period of up to approximately 1 month. In some embodiments, the multi-dose regimen is for a period of up to approximately 2 months. Other periods may be used herein.

[0264] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0265] This disclosure also provides a method for treating otitis externa in patients in need. In some embodiments, the method includes the step of administering an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof to a patient. As used herein, the term “otitis externa” refers to an infection of the external auditory canal of a patient.

[0266] In some embodiments, the patient is human. In some embodiments, administration is a direct topical administration into the patient's external auditory canal. In some embodiments, administration is carried out using the compounds of the Disclosure or pharmaceutically acceptable salts thereof in a liquid, suspension, lotion, paste, gel, cream, ointment, oil or other viscous composition. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, administration is carried out as a multi-dose regimen. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 7 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 14 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 21 days. In some embodiments, the multi-dose regimen is for a period of up to about 1 month. Other periods may be used herein.

[0267] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0268] This disclosure also provides a method for treating bacterial vaginosis in patients in need. In some embodiments, the method includes the step of administering an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof to the patient. As used herein, the term “bacterial vaginosis” refers to an infection of the patient’s vagina caused by a naturally occurring bacterial overgrowth in the vagina.

[0269] In some embodiments, the patient is a female human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using the compounds of the Disclosure or pharmaceutically acceptable salts thereof in lotions, gels, creams, ointments, oils, liquids, suspensions, emulsions or other viscous compositions. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multi-dose regimen. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 7 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 14 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 21 days. In some embodiments, the multi-dose regimen is for a period of up to about 1 month. Other periods may be used herein.

[0270] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0271] This disclosure also provides a method for treating impetigo in patients in need. In some embodiments, the method includes the step of administering an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof to a patient. As used herein, the term “impetigo” refers to a skin infection of a patient that results in vesicles, pustules, yellowish scabs, etc.

[0272] In some embodiments, the patient is human. In some embodiments, the administration is topical. In some embodiments, the administration is carried out using the compounds of the Disclosure or pharmaceutically acceptable salts thereof in lotions, gels, creams, ointments, oils, liquids, suspensions, emulsions or other viscous compositions. In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multi-dose regimen. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 2 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 3 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 4 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 5 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 6 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 7 days. In some embodiments of the Disclosure, the multi-dose regimen is for a period of up to about 14 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to approximately 21 days. In some embodiments, the multi-dose regimen is for a period of up to approximately 1 month. Other periods may be used herein.

[0273] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0274] This disclosure also provides methods for treating oral mucositis in patients who require it. In some embodiments, the method includes the step of administering an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof to a patient. As used herein, the term “oral mucositis” refers to inflammation and ulceration in the mouth. Oral mucositis is a common complication experienced by patients undergoing cancer chemotherapy or radiation therapy. Oral mucositis can lead to several problems, including pain, nutritional problems as a result of being unable to eat, and an increased risk of infection due to open wounds in the mucosa. Oral mucositis can have a significant impact on the quality of life of cancer patients and may limit the effectiveness of certain treatment options (i.e., requiring a reduction in subsequent chemotherapy doses). Oral mucositis is also a serious side effect of bone marrow transplantation.

[0275] In some embodiments, the patient is a human. In some embodiments, administration is a direct topical administration to the patient's oral cavity. In some embodiments, administration is carried out using the compound of the Disclosure or a pharmaceutically acceptable salt thereof in a liquid, suspension, lotion, paste, gel, cream, ointment, oil or other viscous composition. In some embodiments, administration is carried out using the compound of the Disclosure in an oral rinse. In some embodiments, the compound of the Disclosure is present in a pharmaceutical composition in an amount from about 1% to about 20% (weight / weight). In some embodiments, the compound of the Disclosure is present in a pharmaceutical composition in an amount from about 5% to about 15% (weight / weight). In some embodiments, the compound of the Disclosure is present in a pharmaceutical composition in an amount from about 30% to about 50% (weight / weight).

[0276] In some embodiments, the patient is administered at least one additional active ingredient. In some embodiments, the administration is carried out as a multi-dose regimen. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to about 7 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to about 14 days. In some embodiments of this disclosure, the multi-dose regimen is for a period of up to about 21 days. In some embodiments, the multi-dose regimen is for a period of up to about 1 month. Other periods may be used herein.

[0277] In some embodiments, administration is performed once or multiple times per day. In some embodiments, administration is performed once per day. In some embodiments, administration is performed twice per day. In some embodiments, administration is performed three times per day. In some embodiments, administration is performed four times per day.

[0278] This disclosure also provides kits. In some embodiments, the kits include the compounds or pharmaceutically acceptable salts thereof according to the disclosure, or the pharmaceutical compositions according to the disclosure. As used herein, the term “kit” means any manufactured product, such as a package or container, that contains the compounds or pharmaceutically acceptable salts thereof according to the disclosure, or the pharmaceutical compositions according to the disclosure. In some embodiments, the compounds or pharmaceutically acceptable salts thereof according to the disclosure, or the pharmaceutical compositions according to the disclosure, are packaged in vials, bottles, tubes, flasks or patches, which may further be packaged in boxes, envelopes, bags, etc. In some embodiments, the compounds or pharmaceutically acceptable salts thereof according to the disclosure, or the pharmaceutical compositions according to the disclosure, are approved for administration to patients by the U.S. Food and Drug Administration, or a similar regulatory body in the United States or in a jurisdiction or territory outside the United States. In some embodiments, the kits include written instructions for use and / or other information indicating that the compounds or pharmaceutically acceptable salts thereof according to the disclosure, or the pharmaceutical compositions according to the disclosure, are suitable for or approved for administration to patients. In some embodiments, the compounds or compositions of the Disclosure are packaged in unit dose or single-dose form, for example, single-dose pills, capsules, etc. In some embodiments, the kit includes a dispenser.

[0279] This disclosure also provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals. As used herein, the term “pharmaceutical” refers to the pharmaceutical composition according to this disclosure. In some embodiments, the pharmaceutical composition is contained in any manufactured product, such as a package or container.

[0280] In addition to the aspects and embodiments described and provided elsewhere in this disclosure, the following non-limiting list of embodiments is also contemplated.

[0281] 1. Formula:

[0282] [ka] [In the formula, R1 is a (C1-C8) linear alkyl, (C3-C8) branched alkyl, (C3-C8) cycloalkyl, phenylalkyl, alkylcycloalkyl, hydroxy(C1-C8) linear alkyl, hydroxy(C3-C8) branched alkyl, alkoxy(C1-C8) linear alkyl, alkoxy(C3-C8) branched alkyl, halo(C1-C8) linear alkyl, or halo(C3-C8) branched alkyl. R2, R3, and R4 are each independently H, OH, oxy(C1-C8) linear alkyl, oxy(C1-C8) branched alkyl, CF3, or F. X is N or C-R5, R5 and R6 are independently H, F, Cl, CF3, or CH3, respectively. R7 and R8 are either independently H, a (C1-C5) linear alkyl, a (C1-C5) branched alkyl, or linked to each other by a CC bond to form a C3-C8 cycloalkyl group. Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0283] 2. The compound described in Clause 1, wherein R1 is octyl.

[0284] 3. The compound described in Clause 1, wherein R1 is hexyl.

[0285] 4. The compound described in Clause 1, wherein R1 is butyl.

[0286] 5. The compound described in Clause 1, wherein R1 is 2-methylpropyl.

[0287] 6. The compound described in Clause 1, wherein R1 is 2-methylbutyl.

[0288] 7. The compound according to Clause 1, wherein R1 is 1,1,1-trifluorobutyl.

[0289] 8. A compound described in any one of clauses 1 to 7, wherein X is N.

[0290] 9. A compound described in any one of clauses 1 to 7, wherein X is C-R5.

[0291] 10. A compound as described in Clause 9, wherein R5 is H.

[0292] 11. A compound described in any one of clauses 1 to 10, wherein R2 is H.

[0293] 12. A compound described in any one of clauses 1 to 10, wherein R2 is OH.

[0294] 13. A compound according to any one of clauses 1 to 12, wherein both R3 and R4 are H.

[0295] 14. A compound according to any one of clauses 1 to 12, wherein both R3 and R4 are F.

[0296] 15. A compound according to any one of clauses 1 to 12, wherein R3 is OCH3 and R4 is H.

[0297] 16. A compound according to any one of clauses 1 to 12, wherein R3 is H and R4 is OCH3.

[0298] 17. A compound described in any one of clauses 1 to 16, wherein R6 is H.

[0299] 18. A compound according to any one of clauses 1 to 17, wherein both R6 and R7 are H.

[0300] 19. A compound according to any one of clauses 1 to 17, wherein both R6 and R7 are CH3.

[0301] 20. A compound according to any one of clauses 1 to 17, wherein one of R6 and R7 is H and the other of R6 and R7 is CH3.

[0302] 21. Formula:

[0303] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0304] 22. Formula:

[0305] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0306] 23. Formula:

[0307] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0308] 24. Formula:

[0309] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0310] 25. Formula:

[0311] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0312] 26. Formula:

[0313] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0314] 27. Formula:

[0315] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0316] 28. Formula:

[0317] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0318] 29. Formula:

[0319] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0320] 30. Formula:

[0321] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0322] 31. Formula:

[0323] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0324] 32. Formula:

[0325] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0326] 33. Formula:

[0327] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0328] 34. Formula:

[0329] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0330] 35. Formula:

[0331] [ka] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

[0332] 36. A pharmaceutical composition comprising a compound described in any one of clauses 1 to 35, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, diluents, or mixtures of two or more thereof.

[0333] 37. A method for treating an infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0334] 38. A method for treating an infection of at least one of a wound or ulcer in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0335] 39. A method for treating an infection of a diabetic foot ulcer in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0336] 40. A method for treating a bladder and / or urinary tract infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0337] 41. A method for treating a pulmonary infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0338] 42. The method described in Clause 41, wherein a lung infection is caused by a lung disease.

[0339] 43. Lung diseases include hereditary diseases, acquired diseases, primary diseases, secondary diseases, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory tract disease, croup, high-altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, pleurisy, The method according to Clause 42, selected from the group consisting of pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, wheezing, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis, Q fever, parainfluenza, respiratory syncytial virus, combinations thereof, and diseases caused by any one or combination of the above.

[0340] 44. A lung disease caused by coronavirus, as described in Clause 42.

[0341] 45. The method according to Clause 44, wherein the coronavirus is selected from the group consisting of alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, and omicron coronavirus, or combinations thereof.

[0342] 46. ​​Coronaviruses include: swine epidemic diarrhea virus (PEDv), Scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-alpha-CoV HuB-2013, bat coronavirus HKU10, Minioptrus bat coronavirus HKU8, Minioptrus bat coronavirus 1, Nyctalus velutinus alpha coronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alpha coronavirus Sachs-2011, HumCoV 229E, 229E-related bat coronavirus, camel alpha coronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63-related bat CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, Lucheng Rn rat coronavirus 2, FIPV, TGEV, PRCV, alpha coronavirus 1, mink coronavirus 1, FRCoV-NL-2010, Sorex araneus coronavirus T14, Suncus murinus coronavirus X74, HumCoV OC43, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, Bovine Coronavirus Isolate Alpaca, Canine Respiratory Coronavirus K37, PHEV, Equine Coronavirus, HKU14, HKU24, Myodes Coronavirus 2 JL14, HKU1, MHV, Rat Coronavirus Parker, HKU4, HKU5, Human MERS-CoV, Camel MERS-CoV, Hedgehog Coronavirus 1, HKU9, Rousette Bat Coronavirus GCCDC1, Eidolon Bat Coronavirus C704, Human SARS-CoV, Palm Civet SARS-CoV, Badger SARS-CoV, Bat SL-CoV RsSHC014, Bat SL-CoV Rs3367, Bat SL-CoV WIV1, HKU3, Bat SL-CoV ZC45, Bat SL-CoV ZXC21, Bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, dog CoV, mink CoV, GD pangolin CoV, bat Hp-beta coronavirusThe method described in Clause 44, selected from the group consisting of Zhejiang2013, peacock IBV, avian coronavirus 9203, poultry IBV, avian coronavirus, duck CoV, partridge IBV, goose coronavirus CB17, beluga whale coronavirus SW1, HKU22, HKU19, HKU20, HKU21, HKU11, HKU12, HKU16, HKU27, HKU28, HKU29, HKU18, HKU13, HKU30-UAE, HKU30-Poland, HKU17-USA, HKU17-China, AlCCoV, and HKU15, or combinations thereof.

[0343] 47. Coronaviruses include HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, Myodes coronavirus 2 JL14, HKU1, MHV, rat coronavirus parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rosette bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS-CoV, badger SARS-CoV, bat SL-CoV RsSHC014, bat SL-CoV Rs3367, bat SL-CoV WIV1, HKU3, bat SL-CoV ZC45, and bat SL-CoV The method according to Clause 44, wherein the betacoronavirus is selected from the group consisting of ZXC21, bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, canine CoV, mink CoV, GD pangolin CoV, and bat Hp-betacoronavirus Zhejiang2013, or combinations thereof.

[0344] 48. A method for treating cystic fibrosis in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0345] 49. A method for treating pneumonia in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0346] 50. The method according to Article 49, wherein the pneumonia is ventilator-dependent pneumonia.

[0347] 51. A method for treating an infection in a burn wound in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0348] 52. A method for treating otitis externa in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0349] 53. A method for treating bacterial vaginosis in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0350] 54. A method for treating impetigo in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the provisions 1 to 35, or a pharmaceutically acceptable salt thereof.

[0351] 55. A method for treating oral mucositis in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of the compounds described in any one of the clauses 1 to 35, or a pharmaceutically acceptable salt thereof.

[0352] [Examples] Examples relating to this disclosure are described below. In most cases, alternative techniques may be used. The examples are illustrative and do not limit or restrict the scope of the invention as expressed in the claims.

[0353] [Example 1] Synthesis of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyloctyl hydrogen phosphate (LAI-001)

[0354] [ka] Phosphorus oxychloride (POCl3) (2.46 ml, 26.40 mmol) was added to a stirred solution of 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (CAS No. 951-77-9) (5.0 g, 22.00 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Octane-1-ol (4.1 mL, 26.40 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 16 hours. After the completion of the reaction, which was monitored by high-pressure liquid chromatography (LCMS) attached to a mass spectrum detector, the reaction mixture was poured into diethyl ether (1000 mL) and washed with 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), and the solvent was removed by freeze-drying. The crude mixture was purified by reverse-phase column chromatography (C18, SiO2, 0-11% acetonitrile in water and 0.1% formic acid in water), and the fraction containing the product was directly freeze-dried to obtain pure ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyloctyl hydrogen phosphate (LAI-001) (605 mg, 6%) as a white solid. 1H-NMR 400MHz, DMSO-d6: δ8.29(s,2H), 7.88~7.86(d,J=8.00Hz,1H), 6.14~6.12(t,J=4.00Hz ,1H), 5.85~5.83(d,J=8.00Hz,1H), 4.23(bs,1H), 4.00~3.98(t,J=4.00Hz,1H), 3.97~ 3.89(m,3H), 3.81~3.76(m,2H), 2.25~2.49(m,1H), 2.19~2.13(m,1H), 2.06~2.041(m, 1H).2.02~1.99(m,1H), 1.54~1.50(m,2H), 1.24(bs,10H), 0.86~0.83(t,J=6.0Hz,3H). 13 C-NMR 100MHz, DMSO-d6: 13.88, 22.02, 25.16, 28.61, 30.00, 30.07, 31.18, 64.85, 64. 90, 65.14, 65.20, 70.05, 85.41, 85.59, 85.66, 94.07, 142.68, 150.09, 161.51. 31 P NMR 162MHz, DMSO-d6:-0.906. Elemental analysis: N: 9.21%; C: 45.93%; H: 7.00%. LCMS(m / z):420.32[MH] + .

[0355] [Example 2] Synthesis of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methylhexyl hydrogen phosphate (LAI-002)

[0356] [ka] Phosphorus oxychloride (POCl3) (2.46 ml, 26.40 mmol) was added to a stirred solution of 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (CAS No. 951-77-9) (5.0 g, 22.00 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Hexane-1-ol (3.3 mL, 26.40 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), freeze-dried to obtain the crude product, which was purified by reverse-phase column chromatography (C18, SiO2, 0-11% acetonitrile in water and 0.1% formic acid in water). Further purification by preparative HPLC yielded ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methylhexyl hydrogen phosphate (LAI-002) (511 mg, 6%) as a white solid.

[0357] Preparative HPLC purification method: Column / Dimensions: Sunfire-C18 (19 × 150 × 5 μm); Mobile Phase A: 0.1% formic acid (aqueous solution) in water; Mobile Phase B: Acetonitrile; Gradient (time / %B): 0 / 5, 1 / 5, 10 / 30, 11 / 30, 11.10 / 100, 13 / 100, 13.1 / 5, 16 / 5; Flow Rate: 18 ml / min; Solubility: Acetonitrile + THF + Water. 1H-NMR 400MHz, DMSO-d6: δ8.01(s,2H), 7.83~7.81(d,J=8.00Hz,1H), 6.16~6.13( t,J=6.00Hz,1H), 5.82~5.80(d,J=8.00Hz,1H), 5.43(bs,1H), 4.23~4.20(m ,1H), 4.00~3.95(m,3H), 3.93~3.79(m,2H), 2.16~2.12(m,1H), 2.04~1.99 (m,1H), 1.55~1.50(m,2H), 1.30~1.22(m,6H), 0.86~0.83(t,J=6.0Hz,3H). 13 C-NMR 100MHz, DMSO-d6:13.84, 22.00, 24.84, 29.97, 30.04, 30.87, 64.88, 64.93, 65.14, 65.20, 70.09, 85.39, 85.57, 85.65, 94.07, 142.57, 150.39, 161.75. 31 P NMR 162MHz, DMSO-d6:-0.976. Elemental analysis: N: 10.74%; C: 40.17%; H: 6.12%. LCMS(m / z):390.29[MH] + .

[0358] [Example 3] Synthesis of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methylisobutylhydrogen phosphate (LAI-003)

[0359] [ka] Phosphorus oxychloride (POCl3) (2.46 ml, 26.40 mmol) was added to a stirred solution of 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (CAS No. 951-77-9) (5.0 g, 22.00 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Isobutanol (2.4 mL, 26.40 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for another 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), freeze-dried to obtain the crude product, which was purified by reverse-phase column chromatography (C18, SiO2, 0-15% acetonitrile in water and 0.1% formic acid in water). Further purification by preparative HPLC yielded ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methylisobutylhydrogen phosphate (LAI-003) (733 mg, 9%) as a white solid.

[0360] Preparative HPLC purification method: Column / Dimensions: Sunfire-C18 (19 × 150 × 5 μm); Mobile Phase A: 0.1% formic acid (aqueous solution) in water; Mobile Phase B: Acetonitrile; Gradient (time / %B): 0 / 5, 1 / 5, 10 / 30, 11 / 30, 11.10 / 100, 13 / 100, 13.1 / 5, 16 / 5; Flow Rate: 18 ml / min; Solubility: Acetonitrile + THF + Water. 1H-NMR 400MHz, DMSO-d6: δ8.10(s,2H), 7.84~7.82(d,J=8.00Hz,1H), 6.16~6.12(t,J=8.00Hz,1H), 5.83~5.81(d,J=8.00Hz,1H), 5.40(bs,1H), 4.23~4. 21(m,1H), 4.00~3.92(m,3H), 3.59~3.56(t,J=6.00Hz,2H), 2.19~2.13(m ,1H), 2.07~2.00(m,1H), 1.99~1.76(m,1H), 0.87~0.85(d,J=8.0Hz,6H). 13 C NMR 100MHz, DMSO-d6: 18.74, 28.60, 28.67, 64.86, 64.91, 70.08, 71.28, 71.34, 85.44, 85.61, 85.69, 94.07, 142.67, 150.19, 161.58. 31 P NMR 162MHz, DMSO-d6:-0.939. Elemental analysis: N: 10.09%; C: 43.95%; H: 6.64%. LCMS(m / z):364[MH] + .

[0361] [Example 4] Synthesis of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methylisopentyl hydrogen phosphate (LAI-004)

[0362] [ka] Phosphorus oxychloride (POCl3) (2.46 ml, 26.40 mmol) was added to a stirred solution of 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (CAS No. 951-77-9) (5.0 g, 22.00 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Isoamyl alcohol (2.87 mL, 26.40 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and a 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), freeze-dried to obtain the crude product, which was purified by reverse-phase column chromatography (C18, SiO2, 0-15% acetonitrile in water and 0.1% formic acid in water). Further purification by preparative HPLC yielded ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methylisopentyl hydrogen phosphate (LAI-004) (675 mg, 8%) as a white solid.

[0363] Preparative HPLC purification method: Column / Dimensions: Sunfire-C18 (19 × 150 × 5 μm); Mobile Phase A: 0.1% formic acid (aqueous solution) in water; Mobile Phase B: Acetonitrile; Gradient (time / %B): 0 / 5, 1 / 5, 10 / 30, 11 / 30, 11.10 / 100, 13 / 100, 13.1 / 5, 16 / 5; Flow Rate: 18 ml / min; Solubility: Acetonitrile + THF + Water. 1H-NMR 400MHz, DMSO-d6: δ8.42(s,2H), 7.90~7.89(d,J=7.6Hz,1H), 6.15~6.12(t,J=6.00Hz,1H), 5.869~5.850(d,J=7.6Hz,1H), 5.50(bs,1H), 4.24~4. 22(m,1H), 4.00~3.96(m,3H), 3.92~3.37(m,2H), 2.17~2.14(m,1H), 2.0 7~2.02(m,1H), 1.67~1.62(m,1H), 1.46~1.41(m,2H), 0.87~0.84(m,6H). 13 C-NMR 100MHz, DMSO-d6: 11.00, 16.00, 22.28, 24.12, 25.15, 34.96, 35.03, 63.55, 63.60, 64. 92, 64.97, 69.67, 69.72, 70.10, 85.38, 85.55, 85.62, 94.06, 142.53, 150.54, 161.88. 31 P NMR 162MHz, DMSO-d6:-0.815. Elemental analysis: N: 10.49%; C: 42.24%; H: 6.45%. LCMS(m / z):378.32[MH] + .

[0364] [Example 5] Synthesis of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl(4,4,4-trifluorobutyl)hydrogen phosphate (LAI-005)

[0365] [ka] Phosphorus oxychloride (POCl3) (2.46 ml, 26.40 mmol) was added to a stirred solution of 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (CAS No. 951-77-9) (5.0 g, 22.00 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. 4,4,4-trifluorobutan-1-ol (2.8 mL, 26.40 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), freeze-dried to obtain the crude product, which was subjected to reverse-phase column chromatography (C18, SiO2, 0-14% acetonitrile in water and 0.1% formic acid in water). Further purification by preparative HPLC yielded ((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl(4,4,4-trifluorobutyl)hydrogen phosphate (LAI-005) (415 mg, 5%) as a white solid.

[0366] Preparative HPLC purification method: Column / Dimensions: Cross-bridge (X-BRIDGE) (19×250, 5μm); Mobile phase A: 0.1% formic acid; Mobile phase B: Acetonitrile; Gradient (time / %B): 0 / 5, 1 / 5, 5 / 18, 8.6 / 18, 8.7 / 100, 12 / 100, 12.1 / 5, 15 / 5; Flow rate: 18 ml / min; Solubility: Water + THF. 1H-NMR 400MHz, DMSO-d6: δ8.26(s,2H), 7.89~7.87(d,J=8.0Hz,1H), 6.15~6.12(t,J=6.00Hz,1H), 5.85~5.83(d,J=8.0Hz,1H), 5.41 (bs,1H), 4.24~4.21(m,1H), 4.00~3.83(m,5H), 2.49~2.27(m,2H), 2.15~2.13(m,1H), 2.05~2.01(m,1H), 1.78~1.74(m,2H). 13 C-NMR 100MHz, DMSO-d6: 22.97, 28.92, 29.20, 29.48, 29.76, 63.36, 63.41, 64.85, 64.90, 70.07 , 85.48, 85.69, 85.76, 94.06, 123.49, 126.24, 128.98, 131.73, 142.84, 149.84, 161.32. 19 F NMR 377MHz, DMSO-d6:-64.82(t). 31 P NMR 162MHz, DMSO-d6:-1.006. Elemental analysis: N: 9.41%; C: 35.69%; H: 4.90%. LCMS(m / z):418.26[MH] + .

[0367] [Example 6] Synthesis of ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methylbutyl hydrogen phosphate (LAI-006)

[0368] [ka] Phosphorus oxychloride (POCl3) (3.55 ml, 37.99 mmol) was added to a stirred solution of 4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (95058-81-4) (5.00 g, 18.99 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere, at 0°C, along with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Butan-1-ol (8.69 mL, 94.98 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and a 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), freeze-dried to obtain the crude product, which was subjected to reverse-phase column chromatography (C18, SiO2, 0-14% acetonitrile in water and 0.1% formic acid in water). The fraction containing the product was freeze-dried to obtain ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methylbutylhydrogen phosphate (LAI-006) (493 mg, 7%) as a white solid. 1 H-NMR 400MHz, DMSO-d6: δ7.97(s,2H), 7.68~7.66(d,J=8.00Hz,1H), 6.17~6.13(t,J=8.00Hz,1H), 5.87~5.85(d,J=8.00 Hz,1H), 4.14~3.98(m,4H), 3.86~3.84(m,2H), 1.57~1.50(m,2H), 1.34~1.29(m,2H)0.88~0.84(t,J=7.40Hz,3H). 13 C-NMR 100MHz, DMSO-d6: 13.46, 18.27, 31.88, 31.95, 63.82, 65.37, 65.43, 68.97, 69.20, 69.4 3, 78.70, 83.45, 83.78, 84.06, 94.80, 120.10, 122.66, 125.23, 141.30, 152.92, 164.22. 19F NMR 377MHz, DMSO-d6:-116.34(m). 31 P NMR 162MHz, DMSO-d6:-1.310. Elemental analysis: N: 9.72%; C: 37.03%; H: 5.14%. LCMS(m / z):398.36[MH] + .

[0369] [Example 7] Synthesis of ((2S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methylbutylhydrogen phosphate (LAI-007)

[0370] [ka] Phosphorus oxychloride (POCl 3) (2.65 ml, 28.40 mmol) was added to a stirred solution of 4-amino-1-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (7481-89-2) (3.00 g, 14.20 mmol) in trimethyl phosphate (50 mL) with a 4 Å molecular sieve (w / w) under an N2 atmosphere at 0°C, and the mixture was stirred at 0°C for 2 hours. Butan-1-ol (1.95 mL, 21.30 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 16 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and a 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (pH approximately 2.0), freeze-dried to obtain the crude product, which was subjected to reverse-phase column chromatography (C18, SiO2, 0-11% acetonitrile in water and 0.1% formic acid in water). The fraction containing the product was freeze-dried to obtain pure ((2S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methylbutylhydrogen phosphate (LAI-007) (517 mg, 10%) as a white solid. 1H-NMR 400MHz, DMSO-d6:δ8.04(s,2H), 7.92~7.90(d,J=8.00Hz,1H), 5.95~5.93(m, 1H), 5.81~5.79(d,J=8.00Hz,1H), 4.17(bs,1H), 4.07~4.04(m,1H), 3.96~3.9 2(m,1H), 3.84~3.79(m,2H), 2.30~2.26(m,1H), 1.96~1.92(m,2H), 1.81~1.7 8(m,1H), 1.55~1.49(m,2H), 1.35~1.29(m,2H), 0.89~0.85(t,J=7.40Hz,3H). 13 C NMR 100MHz, DMSO-d6:13.53, 18.39, 24.46, 31.97, 32.09, 32.16, 64.69, 64.74, 65.57, 80.09, 80.16, 86.44, 93.42, 142.89, 149.72, 161.25. 31 P NMR 162MHz, DMSO-d6:-0.898. Elemental analysis: N: 11.12%; C: 41.48%; H: 6.24%. LCMS(m / z):348.31[MH] + .

[0371] [Example 8] Synthesis of butyl(((2R,3S,5R)-5-(4-(N,N-dimethylamino)-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)hydrogen phosphate (LAI-008)

[0372] [ka] Step 1: Synthesis of 4-amino-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one: Under an N2 atmosphere, 4-amino-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (40.0 g, 176.05 mmol) was stirred in pyridine (800 mL) at 0°C. Imidazole (59.92 g, 880.02 mmol) was added, and the solution was stirred at 0°C for 30 minutes. Tert-butyldimethylsilyl chloride (TBDMS-Cl) (79.61 g, 528.16 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by LC-MS), the product was extracted in ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (eluted with 15% ethyl acetate in petroleum ether) to obtain pure 4-amino-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (LAI-001-1) (20 g, 74%) as a pale yellow solid.

[0373] Step 2: Synthesis of 1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4-(dimethylamino)pyrimidine-2(1H)-one: Under an N2 atmosphere, 300 mL of DMF at 0°C contained a stirred solution of 4-amino-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (30.0 g, 65.89 mmol). Sodium hydride (26.35 g, 658.96 mmol) was added in small portions, and the reaction mixture was stirred at room temperature for 30 minutes. Methyl iodide (41.02 mL, 658.96 mmol) was added dropwise, and the reaction mixture was stirred for 16 hours. After the reaction was complete (monitored by LC-MS), the product was extracted in ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (eluted with 60% ethyl acetate in petroleum ether) to obtain pure 1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4-(dimethylamino)pyrimidine-2(1H)-one (LAI-008-1b) (24.0 g, 75%) as a pale yellow solid.

[0374] Step 3: Synthesis of 4-(N,N-dimethylamino)-1-((2R,4S,5R)-4-hydroxy-5-(hydroxylmethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one: To a stirred solution of pure 1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4-(dimethylamino)pyrimidine-2(1H)-one (4.0 g, 8.27 mmol) in THF (80 ml), 4 M HCl (20 mL, 5 vols) in MeOH was added at 0°C. The reaction mixture was stirred for 2 hours and then heated at 30°C for another 30 minutes. The reaction was monitored by LC-MS. The solvent was evaporated to obtain the crude product, which was then triturated with MeOH and diethyl ether to obtain pure 4-(dimethylamino)-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (LAI-008-2) (1.7 g, 70%) as a white solid.

[0375] Step 4: Synthesis of butyl(((2R,3S,5R)-5-(4-(N,N-dimethylamino)-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)hydrogen phosphate: Phosphorus oxychloride (POCl3) (2.7 ml, 29.39 mmol) was added to a stirred solution of 4-(dimethylamino)-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one (7.5 g, 29.39 mmol) in trimethyl phosphate (75 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Butan-1-ol (8.07 mL, 88.19 mmol) was added to the solution, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and a 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (30 mL) at approximately pH 2.0, lyophilized, and the crude product was obtained. This was subjected to reverse-phase column chromatography (C18, silica) and eluted with 0-14% acetonitrile in water (using 0.1% formic acid in water). For further purification, the crude compound was purified by preparative HPLC to obtain butyl(((2R,3S,5R)-5-(4-(dimethylamino)-2-oxopyrimidine-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)hydrogen phosphate (LAI-008) (864 mg, 7.5%) as a white solid.

[0376] Preparative HPLC purification method: Column / Dimensions: Synergy Polar C18 (19 x 250 mm, 5 μm); Mobile Phase A: 0.1% Formic Acid in Water; Mobile Phase B: Acetonitrile; Gradient (Time / %B): 0 / 2, 2 / 2, 15 / 25, 15.1 / 98, 17 / 98, 17.1 / 2, 20 / 2; Flow Rate: 18 ml / min; Solubility: THF 11H NMR 400MHz, DMSO-d6: δ7.74~7.72(d,J=8.0Hz,1H), 6.21~6.17(t,J=6.6Hz,1H) , 6.04~6.02(d,J=7.6Hz,1H), 5.39(bs,1H), 4.22~4.20(d,J=2.8Hz,1H), 4.0 3~3.83(m,5H), 3.04(s,6H), 2.14~2.11(m,1H), 2.01~1.99(m,1H), 1.56~1.5 1(m,2H), 1.34~1.29(m,2H), 1.34~1.29(m,2H), 0.88~0.85(t,J=7.2Hz,3H). 13 C NMR 100MHz, DMSO-d6:13.48, 18.26, 65.58, 65.64, 65.72, 70.27, 84.88, 84.96, 85.01, 91.69, 140.95, 153.63, 162.50. 31 P NMR 162MHz, DMSO-d6:-1.417. Elemental analysis: N: 10.34%; C: 44.03%; H: 6.70%; S: 0.01%. LCMS(m / z):392.28[MH] + .

[0377] [Example 9] Synthesis of butyl(((2R,3S,5R)-3-hydroxy-5-(4-(N-methylamino)-2-oxopyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl)hydrogen phosphate (LAI-009)

[0378] [ka] Step 1: Synthesis of ((2R,3S,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate: Under an N2 atmosphere, 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (20.0 g, 87.70 mmol) was stirred in 200 mL of THF:DMF (1:1) at 0°C. TEA (50.61 mL, 350.81 mmol) was added, and the mixture was stirred at 0°C for 1.5 hours. Subsequently, acetic anhydride (26.68 mL, 263.31 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 16 hours. After the reaction was complete (monitored by LC-MS), the product was extracted in ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (eluted with 62% ethyl acetate in petroleum ether) to obtain pure ((2R,3S,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate (LAI-009-01) (20 g, 73%) as a white solid.

[0379] Step 2: Synthesis of ((2R,3S,5R)-3-acetoxy-5-(2-oxo-4-thioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate: Under an N2 atmosphere, methyl ((2R,3S,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)acetate (20.0 g, 64.08 mmol) was stirred in 1-4 dioxane (200 mL) at 0°C. Phosphorus pentasulfide (15.13 g, 66.65 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (eluted with 41% ethyl acetate in petroleum ether) to obtain pure ((2R,3S,5R)-3-acetoxy-5-(2-oxo-4-thioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate (LAI-009-02) (12.5 g, 95%) as a pale yellow solid.

[0380] Step 3: Synthesis of 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(N-methylamino)pyrimidine-2(1H)-one: A stirred solution of methyl((2R,3S,5R)-3-acetoxy-5-(2-oxo-4-thioxo-3,4-dihydropyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate (12.5 g, 38.09 mmol) in methylamine (100 ml) in THF was heated in a steel cylinder at 50°C for 16 hours. The reaction mixture was concentrated to obtain the crude product, which was triturated with pentane to obtain pure 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(methylamino)pyrimidine-2(1H)-one (LAI-009-03) (6.37 g, 69%) as a white solid.

[0381] Step 4: Synthesis of butyl(((2R,3S,5R)-3-hydroxy-5-(4-(N-methylamino)-2-oxopyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl)hydrogen phosphate: Phosphorus oxychloride (POCl3) (3.7 ml, 39.62 mmol) was added to a stirred solution of 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(methylamino)pyrimidine-2(1H)-one (6.37 g, 26.41 mmol) in trimethyl phosphate (60 mL) under an N2 atmosphere at 0°C with a 4 Å molecular sieve (w / w), and the mixture was stirred at 0°C for 2 hours. Butan-1-ol (3.4 mL, 37.70 mmol) was added, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and a 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (30 mL) at approximately pH 2.0 and lyophilized. After freeze-drying was complete, the crude reaction mixture was subjected to reverse-phase column chromatography (C18, silica), and the product was eluted with 0-14% acetonitrile in water (using 0.1% formic acid in water). For further purification, the crude compound was purified by preparative HPLC to obtain butyl(((2R,3S,5R)-3-hydroxy-5-(4-(methylamino)-2-oxopyrimidine-1(2H)-yl)tetrahydrofuran-2-yl)methyl)hydrogen phosphate (LAI-009) (508 mg, 5%) as a white solid.

[0382] Preparative HPLC purification method: Column / Dimensions: Synergy Polar C18 (19×250) 5μm; Mobile Phase A: 0.1% formic acid in water; Mobile Phase B: Acetonitrile; Gradient (time / %B): 0 / 2, 2 / 2, 10 / 40, 10.1 / 98, 12 / 98, 12.1 / 2, 15 / 2; Flow Rate: 18 ml / min; Solubility: Acetonitrile + Water + THF. 1H-NMR 400MHz, DMSO-d6: δ8.13(s,1H), 7.81(s,1H), 7.60~7.59(d,J=7.2Hz,1H), 6.19 ~6.17(t,J=4.00Hz,1H), 5.74~5.72(d,J=8.0Hz,1H), 5.41(bs,1H), 4.21~4.19( m,1H), 4.00~3.82(m,5H), 2.76~2.75(t,J=2.0Hz,2H), 2.11~2.10(m,1H), 1.98~ 1.96(m,1H), 1.55~1.50(m,2H), 1.34~1.29(m,2H), 0.88~0.85(t,J=7.4Hz,3H). 13 C NMR 100MHz, DMSO-d6:13.48, 18.27, 27.14, 31.88, 31.95, 65.43, 65.48, 65.55, 65.60, 70.23, 54.88, 94.78, 139.63, 154.02, 162.88. 31 P NMR 162MHz, DMSO-d6:-1.252. Elemental analysis: N: 10.12%; C: 41.66%; H: 6.46%; S: 0.16%. LCMS(m / z):378.29[MH] + .

[0383] [Example 10] Synthesis of ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methylbutyl hydrogen phosphate (LAI-011)

[0384] [ka] Step 1: Synthesis of (2R,3S,5R)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl4-methylbenzoate (LAI-011-2): To a suspension of 1,2,4-triazine-3,5-(2H,4H)-dione (10 g, 0.08849 mmol) and (NH4)2SO4 (1.16 g, 0.004424 mmol) in HMDS, SM-15 (27.4 g, 0.07078 mmol) was added, and the reaction mixture was stirred under nitrogen at 140°C for 16 hours. After 16 hours, the reaction mixture was concentrated under reduced pressure. This resulting oil was added to copper(I) iodide (16.8 g, 0.08848 mmol) in chloroform (100 mL), and the reaction mixture was stirred at 25°C for 2 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was quenched with water (100 mL) and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated to obtain the crude product, which was purified by column chromatography (60-120, silica). The product was eluted in petroleum ether with 30-40% ethyl acetate, the fraction containing the product was concentrated, and the compound was recrystallized in ethyl acetate to obtain (2R,3S,5R)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl-4-methylbenzoate (LAI-011-2) (6g, 14% yield).

[0385] Steps 2 and 3: 5-amino-2-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,2,4-triazine-3(2H)-one: Triazole (6.6 g, 0.096768 mmol) was dissolved in dry acetonitrile, and the resulting solution was cooled to 0°C under a nitrogen atmosphere. Phosphorus oxychloride (POCl3) (1.99 mL, 0.021504 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 10 minutes. Trimethylamine (13.9 mL, 0.096768 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 20 minutes. LAI-011-2 (5 g) prepared as described above was added, and the reaction mixture was stirred at 25°C for another 16 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into a saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated to obtain crude LAI-011-3 (5.3 g, 95% yield), which was treated with 23% NH3 in methanol (50 mL). The reaction mixture was heated at 60°C for 16 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was concentrated and recrystallized in 10% methanol (20 mL) in dichloromethane to obtain 5-amino-2-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,2,4-triazine-3(2H)-one (LAI-011-4) (1.9 g, 81% yield).

[0386] Step 4: Synthesis of ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methylbutylhydrogen phosphate: Phosphorus oxychloride (POCl3) (3.55 ml, 37.99 mmol) was added to a stirred solution of 5-amino-2-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1,2,4-triazine-3(2H)-one (5.00 g, 21.92 mmol) in trimethyl phosphate (50 mL) under an N2 atmosphere at 0°C, along with a 4 Å molecular sieve (w / w), and the mixture was stirred for 2 hours. Butan-1-ol (9.67 mL, 109.64 mmol) was added, and the reaction mixture was stirred at 0°C for 5 hours. After the completion of the reaction, which was monitored by LC-MS, the reaction mixture was poured into diethyl ether (1000 mL) and a 10% saturated sodium bicarbonate solution (60 mL). The aqueous layer was acidified with 1N HCl (30 mL) at approximately pH 2.0 and lyophilized. After freeze-drying was complete, the crude reaction mixture was subjected to reverse-phase column chromatography (C18, silica). The product was eluted in water with 0-15% acetonitrile (using 0.1% formic acid in water), and the product-containing fraction was freeze-dried to obtain pure ((2R,3R,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methylbutylhydrogen phosphate (LAI-011) (0.18810 g) as a white solid. 1 H-NMR 400MHz, DMSO-d6: δ7.95(d,J=26.5Hz,1H), 7.50(s,1H), 6.44(t,J=6.1Hz,1H), 4.27(t,J=5.1Hz,1H), 3.78(m,J=5.1Hz) ,1H), 2.36(m,J=6.3Hz,1H), 2.05(m,J=4.4Hz,1H), 1.48(q,J=7.1Hz,1H), 1.28(m,J=7.4Hz,1H), 0.86(t,J=7.4Hz,1H). 13 C NMR 100MHz, DMSO-d6:13.51, 18.29, 31.87, 31.94, 37.02, 65.20, 65.26, 66.18, 66.23, 70.71, 84.68, 84.76, 85.30, 127.53, 153.10, 158.68. 31P NMR 162 MHz, DMSO-d6: -1.658. Elemental analysis: N: 14.68%; C: 37.82%; H: 5.82%; S: below detection level. LC-MS (m / z): 365.18 [MHz] + .

[0387] [Example 11] Minimum inhibitory concentration MIC testing is performed using the microdilution procedure for each organism group (Müller-Hinton culture medium) as established by the Committee on Clinical Laboratory Standards (CLSI;3-7). MIC plates are prepared according to CLSI(3-7). Automated liquid handlers are used for continuous dilution and liquid transport to prepare the test plates. Automated liquid handlers used in this study include MultiDrop 384 (Labsystems, Helsinki, Finland) and BioMeC 2000 (Beckman Coulter, Fullerton CA). The solution is diluted to the desired pH using 1M citrate or 1M NaOH buffer. Standardized inoculum for each test organism is prepared according to the CLSI method (3, 5-7) and equalized to 0.5 McFarland standard in appropriate medium, followed by an additional 1:20 dilution (1:10 for anaerobic organisms).

[0388] Next, using Biomech 2000, 10 μL of 0.5 McFarland suspension diluted to low to high drug concentrations was inoculated into plates, resulting in approximately 5 × 10 wells. 5 The final concentration should be determined at CFU / mL. Uninoculated plates should be incubated in test medium to evaluate drug solubility. The plates should be stacked in 3 to 4 layers, the top plate covered with a sterile lid, and incubated for 18 to 24 hours according to CLSI. The MIC should be recorded as the lowest concentration of each compound that inhibited visible growth of the organism. MIC data collected at pH 3 should be summarized in Tables 2 and 3. MIC data collected at pH 4-5 should be summarized in Table 4.

[0389] [Table 3]

[0390] [Table 4] TIFF2026515887000090.tif51169

[0391] [Table 5]

[0392] [Example 12] Treatment of human patients with infectious diseases A human patient is identified as having an infection. A pharmaceutical composition containing an effective amount of any compound described herein is administered in a manner consistent with the specific infection diagnosed. The patient is monitored until symptoms are relieved or remission occurs, and if such administration is deemed necessary or beneficial for treatment, the pharmaceutical composition may be administered one or more additional times.

[0393] [Example 13] Treatment of human patients with wound or ulcer infections A human patient is identified as having an infection of a wound or ulcer. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, such as at the site of the wound or ulcer. The patient is monitored until the symptoms are relieved or remission, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0394] [Example 14] Treatment of human patients with lower extremity infections A human patient is identified as having a lower extremity infection. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, such as at the site of the lower extremity infection. The patient is monitored until the symptoms are relieved or remission, and if it is determined that such administration is necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0395] [Example 15] Treatment of human patients with diabetic foot ulcer infections A human patient is identified as having a diabetic foot ulcer. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, such as at the site of the diabetic foot ulcer. The patient is monitored until the symptoms are relieved or remission, and if it is determined that such administration is necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0396] [Example 16] Treatment of human patients with bladder and / or urinary tract infections A human patient is identified as having a bladder and / or urinary tract infection. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, for example, via a catheter. The patient is monitored until symptoms are relieved or remission, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0397] [Example 17] Treatment of human patients with lung infections A human patient is identified as having a lung infection. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, for example, via a nebulizer. The patient is monitored until the symptoms are relieved or remission, and if it is determined that such administration is necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0398] [Example 18] Treatment of human patients with lung infections caused by lung diseases Human patients with genetic disorders, acquired disorders, primary disorders, secondary disorders, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory tract disease, croup, high-altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, pleurisy, pneumothorax The patient is identified as having a pulmonary infection resulting from a lung disease such as primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, wheezing, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis, Q fever, parainfluenza, respiratory syncytial virus, a combination thereof, or any one or a combination of the above. An effective amount of a pharmaceutical composition containing any of the compounds described herein is administered to the patient, for example, via a nebulizer. The patient is monitored until the symptoms are relieved or remission occurs, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0399] [Example 19] Treatment of patients with lung disease caused by coronavirus Patients have tested positive for: Porcine Epidemic Diarrhea Virus (PEDv), Scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-alpha-CoV HuB-2013, bat coronavirus HKU10, Minioptrus bat coronavirus HKU8, Minioptrus bat coronavirus 1, Nyctalus velutinus alpha coronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alpha coronavirus Sachs-2011, HumCoV 229E, 229E-related bat coronavirus, camel alpha coronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63-related bat CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, and Lucheng Rn rat coronavirus 2, FIPV, TGEV, PRCV, alpha coronavirus 1, mink coronavirus 1, FRCoV-NL-2010, Sorex araneus coronavirus T14, Suncus murinus coronavirus X74, HumCoV OC43, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, Bovine Coronavirus Isolate Alpaca, Canine Respiratory Coronavirus K37, PHEV, Equine Coronavirus, HKU14, HKU24, Myodes Coronavirus 2 JL14, HKU1, MHV, Rat Coronavirus Parker, HKU4, HKU5, Human MERS-CoV, Camel MERS-CoV, Hedgehog Coronavirus 1, HKU9, Rousette Bat Coronavirus GCCDC1, Eidolon Bat Coronavirus C704, Human SARS-CoV, Palm Civet SARS-CoV, Badger SARS-CoV, Bat SL-CoV RsSHC014, Bat SL-CoV Rs3367, Bat SL-CoV WIV1, HKU3, Bat SL-CoV ZC45, Bat SL-CoV ZXC21, Bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, dog CoV, mink CoV, GD pangolin CoV, bat Hp-beta coronavirusZhejiang2013, peacock IBV, avian coronavirus 9203, poultry IBV, avian coronavirus, duck CoV, partridge IBV, goose coronavirus CB17, beluga whale coronavirus SW1, HKU22, HKU19, HKU20, HKU21, HKU11, HKU12, HKU16, HKU27, HKU28, HKU29, HKU18, HKU13, HKU30-UAE, HKU30-Poland, HKU17-USA, HKU17-China, AlCCoV, and HKU15, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, Bovine Coronavirus Isolate Alpaca, Canine Respiratory Coronavirus K37, PHEV, Equine Coronavirus, HKU14, HKU24, Myodes Coronavirus 2 JL14, HKU1, MHV, Rat Coronavirus Parker, HKU4, HKU5, Human MERS-CoV, Camel MERS-CoV, Hedgehog Coronavirus 1, HKU9, Rousette Bat Coronavirus GCCDC1, Eidolon Bat Coronavirus C704, Human SARS-CoV, Palm Civet SARS-CoV, Badger SARS-CoV, Bat SL-CoV RsSHC014, Bat SL-CoV Rs3367, Bat SL-CoV WIV1, HKU3, Bat SL-CoV ZC45, Bat SL-CoV ZXC21, Bat CoV Patients are identified as having lung disease caused by coronaviruses such as RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, canine CoV, mink CoV, GD pangolin CoV, and bat Hp-betacoronavirus Zhejiang2013, or combinations thereof. A pharmaceutical composition containing an effective amount of any of the compounds described herein is administered to the patient, for example, via a nebulizer. The patient is monitored until symptoms are relieved or remission occurs, and if such administration is determined to be necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0400] [Example 20] Treatment of human patients with lung infections caused by cystic fibrosis A human patient is identified as having a pulmonary infection resulting from cystic fibrosis. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, such as via a nebulizer. The patient is monitored until symptoms are relieved or remission occurs, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0401] [Example 21] Treatment of human patients with pneumonia A human patient is identified as having pneumonia. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, for example, via a nebulizer. The patient is monitored until the symptoms are relieved or remission, and if it is determined that such administration is necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0402] [Example 22] Treatment of human patients with pneumonia requiring mechanical ventilation A human patient is identified as having ventilator-acquired pneumonia. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, for example, via a nebulizer. The patient is monitored until symptoms are relieved or remission occurs, and if such administration is deemed necessary or beneficial to the treatment, the pharmaceutical composition may be administered one or more additional times.

[0403] [Example 23] Treatment of human patients with burn infections A human patient is identified as having an infection in a burn wound. A pharmaceutical composition containing an effective amount of any compound described herein is administered to the patient, either topically or otherwise, at the site of the burn wound. The patient is monitored until the symptoms are relieved or remission, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0404] [Example 24] Treatment of human patients with otitis externa A human patient is identified as having otitis externa. A pharmaceutical composition containing an effective amount of any compound described herein is administered topically, directly to the patient's ear canal, etc. The patient is monitored until the symptoms are relieved or in remission, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0405] [Example 25] Treatment of female human patients with bacterial vaginosis A female human patient is identified as having bacterial vaginosis. A pharmaceutical composition containing an effective amount of any compound described herein is administered topically, either on or inside the patient's vagina. The patient is monitored until the symptoms are relieved or in remission, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0406] [Example 26] Treatment of human patients with impetigo A human patient is identified as having impetigo. A pharmaceutical composition containing an effective amount of any compound described herein is administered topically, etc., to the areas of the patient's vesicles, pustules and / or yellowish crusts. The patient is monitored until the symptoms are relieved or in remission, and if such administration is determined to be necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0407] [Example 27] Treatment of human patients with oral mucositis A human patient is identified as having oral mucositis. A pharmaceutical composition containing an effective amount of any compound described herein is administered topically, directly to the patient's external auditory canal, etc. The patient is monitored until the symptoms are relieved or remission, and if such administration is deemed necessary or helpful for treatment, the pharmaceutical composition may be administered one or more additional times.

[0408] While embodiments have been disclosed above, the present invention is not limited to the disclosed embodiments. Rather, this application is intended to cover all variations, uses, or adaptations of the present invention using its general principles. Furthermore, this application is intended to cover any deviations from this disclosure that fall within known or customary practices in the art to which the present invention relates and within the limitations of the appended claims.

Claims

1. formula: 【Chemistry 1】 [In the formula, R １ is a (C １ -C ８ ) linear alkyl, (C ３ -C ８ ) branched alkyl, (C ３ -C ８ ) cycloalkyl, phenylalkyl, alkylcycloalkyl, hydroxy(C １ -C ８ ) linear alkyl, hydroxy(C ３ -C ８ ) branched alkyl, alkoxy(C １ -C ８ ) linear alkyl, alkoxy(C ３ -C ８ ) branched alkyl, halo(C １ -C ８ ) linear alkyl, or halo(C ３ -C ８ ) branched alkyl, and R ２ , R ３ , and R ４ These are H, OH, and oxy(C) respectively, independently. １ ~C ８ ) Linear alkyl, oxy(C １ ~C ８ ) Branched-chain alkyl, CF ３ , or F, X is N or C-R ５ And, R ５ and R ６ These are H, F, Cl, and CF, respectively, independently. ３ , or CH ３ And, R ７ and R ８ These are H and (C) respectively, independently. １ ~C ５ ) Linear alkyl, (C １ ~C ５ ) Branched alkyl or linked to each other by C-C bonds, ３ ~C ８ [Forms cycloalkyl] Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

2. R １ The compound according to claim 1, wherein is octyl.

3. R １ The compound according to claim 1, wherein is hexyl.

4. R １ The compound according to claim 1, wherein is butyl.

5. R １ The compound according to claim 1, wherein is 2-methylpropyl.

6. R １ The compound according to claim 1, wherein is 2-methylbutyl.

7. R １ The compound according to claim 1, wherein is 1,1,1-trifluorobutyl.

8. A compound according to any one of claims 1 to 7, wherein X is N.

9. X is CR ５ The compound according to any one of claims 1 to 7.

10. R ５ The compound according to claim 9, wherein is H.

11. R ２ The compound according to any one of claims 1 to 10, wherein is H.

12. R ２ The compound according to any one of claims 1 to 10, wherein is OH.

13. R ３ and R ４ The compound according to any one of claims 1 to 12, wherein all of them are H.

14. R ３ and R ４ The compound according to any one of claims 1 to 12, wherein all of them are F.

15. R ３ ga OCH ３ And R ４ The compound according to any one of claims 1 to 12, wherein is H.

16. R ３ H is R ４ ga OCH ３ The compound according to any one of claims 1 to 12.

17. R ６ The compound according to any one of claims 1 to 16, wherein is H.

18. R ６ and R ７ The compound according to any one of claims 1 to 17, wherein all of them are H.

19. R ６ and R ７ All of them are CH ３ The compound according to any one of claims 1 to 17.

20. R ６ and R ７ One of them is H, and R ６ and R ７ The other is CH ３ The compound according to any one of claims 1 to 17.

21. formula: 【Chemistry 2】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

22. formula: 【Transformation 3】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

23. formula: 【Chemistry 4】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

24. formula: 【Transformation 5】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

25. formula: 【Transformation 6】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

26. formula: 【Transformation 7】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

27. formula: 【Transformation 8】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

28. formula: 【Chemistry 9】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

29. formula: 【Chemistry 10】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

30. formula: 【Chemistry 11】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

31. formula: 【Chemistry 12】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

32. formula: 【Chemistry 13】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

33. formula: 【Chemistry 14】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

34. formula: 【Chemistry 15】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

35. formula: 【Chemistry 16】 Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, diluents, or mixtures of two or more thereof.

37. A method for treating an infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

38. A method for treating an infection of at least one of a wound or ulcer in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

39. A method for treating an infection of a diabetic foot ulcer in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

40. A method for treating a bladder and / or urinary tract infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

41. A method for treating a pulmonary infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

42. The method according to claim 41, wherein the lung infection is caused by a lung disease.

43. The aforementioned lung diseases include hereditary diseases, acquired diseases, primary diseases, secondary diseases, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiectasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory tract disease, croup, high-altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, and pleurisy. The method according to claim 42, selected from the group consisting of pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis, smoking, wheezing, acute respiratory distress syndrome, infectious diseases, SARS, tuberculosis, psittacosis, Q fever, parainfluenza, respiratory syncytial virus, combinations thereof, and diseases caused by any one or a combination of the above.

44. The method according to claim 42, wherein the lung disease is caused by a coronavirus.

45. The method according to claim 44, wherein the coronavirus is selected from the group consisting of alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, and omicron coronavirus, or combinations thereof.

46. The aforementioned coronaviruses include porcine epidemic diarrhea virus (PEDv), Scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-alpha-CoV HuB-2013, bat coronavirus HKU10, Minioptrus bat coronavirus HKU8, Minioptrus bat coronavirus 1, Nyctalus velutinus alpha coronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alpha coronavirus Sachs-2011, HumCoV 229E, 229E-related bat coronavirus, camel alpha coronavirus, alpaca respiratory coronavirus, HumCoV NL63, and NL63-related bat CoV. BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, Lucheng Rn rat coronavirus 2, FIPV, TGEV, PRCV, alpha coronavirus 1, mink coronavirus 1, FRCoV-NL-2010, Sorex araneus coronavirus T14, Suncus murinus coronavirus X74, HumCoV OC43, HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, Bovine Coronavirus Isolate Alpaca, Canine Respiratory Coronavirus K37, PHEV, Equine Coronavirus, HKU14, HKU24, Myodes Coronavirus 2JL14, HKU1, MHV, Rat Coronavirus Parker, HKU4, HKU5, Human MERS-CoV, Camel MERS-CoV, Hedgehog Coronavirus 1, HKU9, Rousette Bat Coronavirus GCCDC1, Eidolon Bat Coronavirus C704, Human SARS-CoV, Palm Civet SARS-CoV, Badger SARS-CoV, Bat SL-CoV RsSHC014, Bat SL-CoV Rs3367, Bat SL-CoV WIV1, HKU3, Bat SL-CoV ZC45, Bat SL-CoV ZXC21, Bat CoV RaTG13, Bat CoV RmYN02, Human SARS-CoV-2, Feline CoV, Tiger CoV, Dog CoV, Mink CoV, GD Pangolin CoV, Bat HPV-BetacoronavirusThe method according to claim 44, selected from the group consisting of Zhejiang2013, peacock IBV, avian coronavirus 9203, poultry IBV, avian coronavirus, duck CoV, partridge IBV, goose coronavirus CB17, beluga whale coronavirus SW1, HKU22, HKU19, HKU20, HKU21, HKU11, HKU12, HKU16, HKU27, HKU28, HKU29, HKU18, HKU13, HKU30-UAE, HKU30-Poland, HKU17-USA, HKU17-China, AlCCoV, and HKU15, or combinations thereof.

47. The aforementioned coronaviruses include HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, Myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rosette bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS-CoV, badger SARS-CoV, and bat SL-CoV. The method according to claim 44, wherein the betacoronavirus is selected from the group consisting of RsSHC014, bat SL-CoV Rs3367, bat SL-CoV WIV1, HKU3, bat SL-CoV ZC45, bat SL-CoV ZXC21, bat CoV RaTG13, bat CoV RmYN02, human SARS-CoV-2, feline CoV, tiger CoV, canine CoV, mink CoV, GD pangolin CoV, and bat Hp-betacoronavirus Zhejiang2013, or combinations thereof.

48. A method for treating cystic fibrosis in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

49. A method for treating pneumonia in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

50. The method according to claim 49, wherein the pneumonia is ventilator-acquired pneumonia.

51. A method for treating an infection in a burn wound in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

52. A method for treating otitis externa in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

53. A method for treating bacterial vaginosis in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

54. A method for treating impetigo in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

55. A method for treating oral mucositis in a patient in need thereof, comprising the step of administering to the patient an effective amount of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

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