Treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections with highly penetrating prodrugs - Patent Application 20070233633

Abstract

Disclosed are highly permeable prodrugs (HPPs), pharmaceutical compositions, and methods thereof for the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections. HPPs can penetrate one or more biological barriers to reach areas that their corresponding parent drugs may not be able to reach in sufficient quantities. HPPs can be administered to a subject through a variety of routes of administration, such as topical delivery or systemic administration, which transdermal or topical administration offers a variety of additional advantages over the use of the parent drug.

Description

[Technical field]

[0001] This application relates to the field of pharmaceutical compositions and methods for treating the signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections, particularly using therapeutic highly permeable prodrugs, while preventing an overactive immune system and avoiding or minimizing other side effects. [Background technology]

[0002] Bacteria can cause many types of infections in the human body and other living organisms, such as urinary tract infections, gastrointestinal infections, ear infections, strep throat, etc. Many bacteria can cause deadly diseases, such as tuberculosis, streptococcus, syphilis, staphylococcus, aspergillus, tetanus, vibrio cholera, salmonella, clostridium botulinum, E. Coli, etc. Antibiotics are used to treat bacterial infections, but most bacteria reproduce by dividing every few hours, allowing them to evolve rapidly and adapt quickly to new environmental conditions. Mutations occur during replication, and some of these mutations may help individual bacteria survive exposure to antibiotics. Infections caused by antibiotic-resistant bacteria are difficult to treat and sometimes impossible to treat. Each year in the United States, at least 2.8 million people become infected with antibiotic-resistant bacteria or fungi, and more than 35,000 people die as a result (Non-Patent Document 1).

[0003] Protozoa is an informal term for a group of single-celled eukaryotic organisms, either free-living or parasitic, that feed on other microorganisms or on organic matter such as organic tissues and organic debris. Protozoan infections cause diseases in many types of organisms, including plants, animals, and some marine organisms. Many of the most widespread and deadly human diseases, including African sleeping sickness, amoebic dysentery, and malaria, are caused by protozoan infections. The World Health Organization (WHO) estimates that in 2019, there were 229 million new cases of malaria, causing 409,000 deaths (Non-Patent Document 2). Malaria is a mosquito-borne infectious disease that affects humans and other animals, typically causing symptoms that include fever, fatigue, vomiting, and headache. In severe cases, malaria can cause yellow skin, seizures, coma, or death. Malaria is associated with several severe complications, among these being the development of respiratory distress. Like bacteria, protozoa evolve rapidly and adapt quickly to new environmental conditions, resulting in drug resistance. Drug resistance is causing an increasing problem in malaria treatment in the 21st century (Non-Patent Document 3). Resistance is now common to all classes of antimalarial drugs.

[0004] Fungi are multicellular, plant-like organisms. Many fungal infections, such as athlete's foot and yeast infections, are not dangerous to healthy people. However, people with weakened immune systems (due to diseases such as HIV or cancer or serious viral infections) can develop more serious fungal infections. Most fungi reproduce very quickly, which allows them to evolve rapidly and adapt quickly to new environmental conditions, thus becoming drug resistant.

[0005] Viruses are submicroscopic infectious agents that replicate only within the living cells of an organism. Viruses need to use structures of other cells to reproduce. Once inside the human body, viruses can spread rapidly and make a person sick. Examples of common human diseases caused by viruses include the common cold, influenza, chicken pox, and herpes simplex. Many serious diseases are caused by viruses, such as rabies, Ebola virus disease, AIDS (HIV), avian influenza, H1N1, SARS, and COVID-19. Viral infections in animals usually trigger an immune response that eliminates the infecting virus, but the human or animal immune system may overreact and cause the death of the human or animal by its own immune system.

[0006] Viral, bacterial, protozoal, and fungal infections can become aggressive and life-threatening infections. Common symptoms of most bacterial, protozoal, fungal, and viral infections include fatigue, loss of appetite, weight loss, fever, night sweats, chills, aches, inflammation, cough, shortness of breath, and pains. Typical symptoms of bacterial infections are localized redness, fever, swelling, and pain at the site of infection. Acute inflammation can cause pain, tissue redness (blood vessels and capillary oozing), tissue swelling, and after damaging the tissue, promote bacterial, protozoal, and / or fungal infections, especially in the cavities, urinary tract, digestive system, ears, eyes, and nose. Generally, viral infections are systemic, affecting many different parts of the body simultaneously, causing, for example, runny nose, cough, and body aches. In all cases, bacteria, fungi, and viruses infect one cell or one tissue and then begin to spread throughout the body, infecting many other cells or tissues, and in some cases causing death to the person.

[0007] Viral, bacterial, protozoan, and / or fungal infections all involve an immune system response, causing inflammation and fever. Overactivation or misregulation of the immune system can lead to uncontrollable high fever and severe inflammatory conditions, such as severe inflammation of the lungs, kidneys, liver, brain, and other tissues, as well as acute respiratory distress syndrome (ARDS). ARDS in particular is a type of respiratory failure characterized by the rapid onset of widespread inflammation in the lungs, causing a drop in blood oxygen that can be life-threatening. Symptoms include shortness of breath, rapid breathing, and bluish skin discoloration. Inflammation can lead to fibroids and scarring of tissues, preventing immune cells from entering the infection site and killing the virus, leading to lifelong or chronic infections in which the virus continues to replicate in the body despite the host's defense mechanisms.

[0008] Current nonsteroidal anti-inflammatory drugs (NSAIDs) do not significantly reduce the overall symptoms or duration of respiratory infections. Furthermore, the use of NSAIDs is associated with an increased risk of serious gastrointestinal (GI) toxicity, including gastric and duodenal bleeding, gastric ulcers, gastritis, and GI perforation (see, for example, Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7, and Non-Patent Document 8). Meta-analyses have reported that NSAIDs increase the risk of myocardial infarction or death from cardiovascular disease by 50% to 100% compared to placebo (see Non-Patent Document 9).

[0009] In addition, there is an urgent need to develop effective therapies against new disease outbreaks. For example, more than 275 million people worldwide have been infected with novel coronavirus 2019 (COVID-19, or SARS-CoV-2), and over 5 million have died. Infection with COVID-19 in humans is accompanied by a wide range of clinical respiratory syndromes, ranging from mild upper respiratory tract symptoms such as fever, headache, loss of taste or smell, sore throat, nausea, vomiting, diarrhea, cough, fatigue, anorexia, myalgia, and diarrhea, to progressive, life-threatening viral pneumonia (Non-Patent Documents 10 and 11). With the rapid mutation of COVID and the emergence of new variants, humanity's fight against the pandemic is likely to be intense for the foreseeable future.

[0010] SARS-CoV-2, the etiological agent of COVID-19, is causing the current pandemic. SARS-CoV-2 causes a diverse manifestation that spans from head to toe, seemingly indiscriminately wreaking havoc on multiple organ systems, particularly the lungs, heart, brain, kidneys, and vascular system. The concept of COVID-19 as an endothelial disease provides a unified pathophysiological picture of this raging infection and also provides a framework for rational therapeutic strategies at a time when we have only a very modest evidence base to guide therapeutic efforts to confront this emerging pandemic (Non-Patent Document 12). [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] CDC Antibiotic Resistance Threats in the United States, 2019 (2019 AR Threats Report) [Non-Patent Document 2] WHO World Malaria Report 2020 [Non-Patent Document 3] Sinha, S., et al., Parasite., 2014, 21: 61 [Non-Patent Document 4] Cohn SM, et al., J. Clin. Invest. 1997; 99(6):1367-1379 [Non-Patent Document 5] Tarnawski AS and Ahluwalia A., Curr. Med. Chem. 2012; 19(1):16-27 [Non-Patent Document 6] Fries JF, J. Rheumatol Suppl. 1991; 28:6-10 [Non-Patent Document 7] Garcia Rodriguez LA, et al., Arch. Intern Med. 1998; 158(1):33-9 [Non-Patent Document 8] Richardson C, Emery P., Drug Saf. 1996; 15(4):249-60 [Non-Patent Document 9] Coxib and traditional NSAID Trialists' (CNT) Collaboration. The Lancet, 2013; 382:769-79 [Non-Patent Document 10] Zhu, N., et al., N. Engl. J. Med., 2020, 382: 727-33 [Non-Patent Document 11] Chen, N., et al., Lancet, 2020, 395:507-13 [Non-Patent Document 12] Peter Libby and Thomas Luescher, European Heart Journal (2020) 41, 3038-3044 [Summary of the Invention]

[0012] The present disclosure provides highly permeable prodrugs (HPPs) that can be used to treat the signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections while avoiding or minimizing various of the above-mentioned disadvantages of existing therapeutic agents such as NSAIDs.

[0013] In one embodiment, the present disclosure provides a highly penetrating prodrug (HPP) of structure L-1, or a stereoisomer or pharma- ceutically acceptable salt thereof, capable of penetrating one or more biological barriers, for use in the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections, or related pathologies.

[0014] JPEG2025504448000002.jpg3992

[0015] During the ceremony, F, as a functional unit, is the molecular portion of the active pharmaceutical ingredient (i.e., the parent drug molecule); T is a basic group containing a protonatable nitrogen as a transport unit; L1, L2, and L4 together form a linker, such that the compound of structure L-1 can be hydrolyzed or metabolized under physiological conditions to release functional unit F and form the active pharmaceutical ingredient (i.e., the parent drug molecule) or a biologically active metabolite thereof.

[0016] In some embodiments, the functional unit (F) of the HPP is a portion of a parent drug selected from 5-lipoxygenase activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), other anti-inflammatory drugs, and any combination thereof.

[0017] In some embodiments, the transport unit (T) of the HPP of structure L-1 comprises a protonatable amine group that can facilitate transport or traversal of the HPP through one or more biological barriers, and the HPP can be cleaved, typically by hydrolysis under physiological conditions, to release the active parent drug moiety after administration to a subject. In certain embodiments, the protonatable amine group is substantially protonated at physiological pH. In certain embodiments, the amine group can be reversibly protonated. In certain embodiments, the transport unit can be cleaved from the functional unit after the HPP has permeated across one or more biological barriers to reach a target site within the subject.

[0018] In some embodiments, the transport unit of HPP is a protonatable amine selected from substituted primary amines, unsubstituted primary amines, substituted secondary amines, unsubstituted secondary amines, substituted tertiary amines, unsubstituted tertiary amines, and heterocyclyl groups that contain a protonatable nitrogen in the ring.

[0019] In some embodiments, the linker (L1, L2, and L4 taken together) covalently links the functional unit of the HPP to the transport unit via a covalent bond that can be cleaved after the HPP penetrates across one or more biological barriers. The cleavable covalent bond can be, for example, a bond in a functional group selected from ester, amide, thioester, carbonate, carbamate, ether, thioether, phosphate, and oxime, and in some preferred embodiments, the functional group is an ester or amide.

[0020] In some embodiments, the linker (L1, L2, and L4 taken together) is selected from the group consisting of C(=O)-O, C(=O)-S, C(=O)-NH, C(=O)-O-CH(L3)-O, C(=O)-O-CH(L3)-S, C(=O)-O-CH(L3)-NH, C(=O)-S-CH(L3)-O, C(=O)-S-CH(L3)-S, C(=O)-S-CH(L3)-NH, P(=O)(-O-L3)-O, OP(=O)(-O-L3), C(=S)-O, C(=NH)-O, C(=NH)-S, C(=N-OL3)-NH, C(=NH-OL3)-O, C(=NH-OL3)-S, OC(=O), SC(=O), NH-C (=O), O-CH(L3)-OC(=O), S-CH(L3)-OC(=O), O-CH(L3)-SC(=O), S-CH(L3)-SC(=O), O-CH(L3)-NH-C(=O), OC(=S), OC(=N-OL3), SC(=N-OL3), and NH-C(=N-OL3), where each L3 is independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, and substituted and unsubstituted alkylamino.

[0021] Another aspect of the present disclosure provides a pharmaceutical composition for the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections and related conditions comprising a highly permeable prodrug (HPP) of the structure disclosed herein and a pharma- ceutically acceptable carrier.

[0022] The pharma- ceutically acceptable carrier may be selected from alcohol, acetone, esters, cellulose, mannitol, croscarmellose sodium, vegetable oils, hydroxypropylmethylcellulose, water, aqueous solutions, and the like. Another aspect of the disclosure provides a method of permeating one or more biological barriers in a biological subject, the method comprising administering HPP or a pharmaceutical composition thereof to the biological subject. In certain embodiments, the HPP exhibits at least about 20 times, at least about 50 times, at least about 100 times, at least about 200 times, at least about 300 times, at least about 500 times, or at least about 1000 times greater permeability through one or more biological barriers than its parent drug.

[0023] Another aspect of the disclosure provides a method of treating signs, symptoms, and / or complications of a viral, bacterial, protozoan, and / or fungal infection, or related condition, in a biological subject in need of treatment by administering to the subject a therapeutically effective amount of HPP or a pharmaceutical composition thereof. Another aspect of the disclosure provides use of an HPP of the disclosure in the manufacture of a medicament for the treatment of signs, symptoms, and complications of a viral, bacterial, protozoal, and / or fungal infection, or related condition, in a biological subject.

[0024] Another aspect of the present disclosure provides a transdermal pharmaceutical composition comprising an HPP as disclosed herein, adapted for transdermal administration to treat signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections and related conditions, the composition comprising aspirin, another nonsteroidal anti-inflammatory drug (NSAID), a highly permeable prodrug of another anti-inflammatory drug, or any combination thereof.

[0025] Another aspect of the present disclosure provides a method of treating signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections and related conditions in a biological subject, comprising administering to the biological subject a pharmaceutical composition comprising a highly penetrating prodrug as described above. Other aspects and advantages of the present disclosure will be better understood with consideration of the following figures, detailed description, examples, and claims. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 shows Kaplan-Meier survival curves for an efficacy study of survival of Balb / c mice treated with HPP after challenge with a lethal dose of mouse-adapted influenza A PR / 8 / 34 (H1N1). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] I. Treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and fungal infections In one aspect, the disclosure provides HPP for the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoan, and / or fungal infections, such as fever, acute respiratory distress syndrome (ARDS), pneumonia, inflammation of the brain, kidney, liver, blood vessels, and other tissues, and blood clotting (coagulation), caused by viruses, bacteria, protozoa, and / or fungi in humans and animals.

[0028] One aspect of the present disclosure is directed to a strategy of treating viral, bacterial, protozoan, and fungal infections to alleviate fever and inflammation, prevent immune system overreactions that cause complications, and then allow the immune system to eliminate the viruses, bacteria, protozoans, and fungi in a well-controlled manner, so that all viral, bacterial, protozoan, and fungal infections are very mild and well tolerated.The immune system is able to recognize and kill non-drug-resistant and drug-resistant viruses, bacteria, protozoans, and fungi alike, so that the problem of drug resistance is not an issue at all.

[0029] The prodrugs of the present disclosure are designed to prevent the immune system from overreacting to viral, bacterial, protozoan, and fungal infections, while prodrugs of aspirin, diclofenac, and other anti-inflammatory drugs can kill viruses, bacteria, protozoans, and / or fungi.

[0030] In certain embodiments, the complication is pneumonia. In certain embodiments, the complication is acute respiratory distress syndrome (ARDS). In certain embodiments, the complication is chronic obstructive pulmonary disease (COPD). In certain embodiments, the complication is blood clotting (clotting). In certain embodiments, the complication is a heart attack. In certain embodiments, the complication is sepsis. In certain embodiments, complications include acute respiratory distress syndrome, pneumonia, and inflammation of the brain, lungs, kidneys, liver, pancreas, gastrointestinal (GI) system, blood vessels, and other tissues.

[0031] II. Structure of highly permeable prodrugs One aspect of the present disclosure provides highly permeable prodrugs (HPPs) that can be used to treat signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections. As used herein, the term "highly permeable prodrug" or "HPP" refers to a compound comprising a functional unit covalently linked to a transport unit via a linker that is capable of permeating one or more biological barriers for use in treating signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections, or associated pathologies, comprising the structure L-1:

[0032] JPEG2025504448000003.jpg3992 or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0033] Functional Unit (F) The functional unit of a HPP comprises a portion of the parent drug such that the HPP can penetrate or cross one or more biological barriers and can be cleaved to release the parent drug itself or a metabolite of the parent drug.

[0034] In certain embodiments, the functional unit may be hydrophilic, lipophilic, or amphiphilic (both hydrophilic and lipophilic). The lipophilic portion of the functional unit may be inherent or may be achieved by converting one or more hydrophilic portions of the functional unit into lipophilic portions. For example, the lipophilic portion of the functional unit is generated by converting one or more hydrophilic groups of the functional unit into lipophilic groups via organic synthesis. Examples of hydrophilic groups include, but are not limited to, carboxylic acid groups, hydroxyl groups, thiol groups, amine groups, phosphate / phosphonate groups, guanidine groups, and carbonyl groups. Lipophilic portions generated via modification of these hydrophilic groups include, but are not limited to, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates, and oximes. In certain embodiments, the functional unit is converted into a more lipophilic portion by acetylation or acylation (alkanoylation). In certain embodiments, the functional units are converted to more lipophilic moieties via esterification.

[0035] In certain embodiments, the parent drug of HPP is a drug that can be used alone or in combination with other drug(s) to treat acute respiratory distress syndrome, pneumonia, and other tissue inflammation caused by viruses and / or bacteria and / or fungi in humans and animals. Also, compounds that include the structure of the parent drug, metabolites of the parent drug, or related compounds of the parent drug that are agents that can be metabolized to the parent drug or metabolites of the parent drug after HPP has penetrated one or more biological barriers can be used. Furthermore, related compounds of the parent drug include compounds that are analogs or mimetics of the parent drug, or metabolites of the parent drug, or agents that can be metabolized to analogs or mimetics of the parent drug, or metabolites of the parent drug after HPP has penetrated one or more biological barriers.

[0036] In certain embodiments, the functional unit is a molecular portion of an active pharmaceutical ingredient (i.e., a parent drug molecule) selected from 5-lipoxygenase activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, and anti-inflammatory agents.

[0037] The moieties of the parent drug or its related compounds can be further converted to lipophilic moieties as described above.The major classes of drugs that can be used to treat acute respiratory distress syndrome, pneumonia, other tissue inflammation, and other complications caused by viruses, bacteria, protozoa, and / or fungi in humans and animals include nonsteroidal anti-inflammatory drugs (NSAIDs), leukotriene receptor antagonists, 5-lipoxygenase inhibitors, and 5-lipoxygenase-activating protein (FLAP) inhibitors.

[0038] Transportation unit (T) The transport unit of the HPP comprises a protonatable amine group that can facilitate transport or traversal of the HPP through one or more biological barriers (e.g., more than about 20 times, more than about 50 times, more than about 100 times, more than about 300 times, more than about 500 times, more than about 1000 times faster than the parent drug). In certain embodiments, the protonatable amine group is substantially protonated at physiological pH. In certain embodiments, the amine group can be reversibly protonated. In certain embodiments, the transport unit can be cleaved from the functional unit after the HPP has permeated across one or more biological barriers.

[0039] In certain embodiments, the transport unit is selected from the group consisting of Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, and Structure W-6:

[0040] JPEG2025504448000004.jpg93162

[0041] (In the formula, R at each occurrence is independently selected from a bond, substituted and unsubstituted alkylene, substituted and unsubstituted cycloalkylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted arylene, and substituted and unsubstituted heteroarylene, where any CH2 in R can be optionally further replaced with O, S, or NR3, where R3 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C7 alkyl. 10 is aryl, R1 and R2 are independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; or alternatively, R1 and R2, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl, which optionally further contains 1 or 2 additional heteroatoms independently selected from O, S, and N;

[0042] R 11 , R 12 , and R 13 are each independently a bond, an optionally substituted C1-C4 alkylene, or an optionally substituted C2-C4 alkenylene, where the alkylene or alkenylene optionally has one CH2 group replaced by O, S, or NR3, where R3 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 is aryl,

[0043] In this case, any of R1 and adjacent R 11 may, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring, which may optionally further contain one or two additional heteroatoms independently selected from O, S, and N; Here, R in Structure W-2, Structure W-4, Structure W-5, or Structure W-611 and R 12 or R 11 and R 13 may be optionally connected by an optionally substituted alkylene bridge,

[0044] wherein HA is free of any and is selected from pharma- ceutically acceptable acids, such as hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, bisulfate, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid, provided that the structures are selected to form stable compounds without violating the principles of covalent bonding.

[0045] In some embodiments, the HA is empty and the HPP is a free base. In some embodiments, R is a bond or C1-C6 alkylene. In some embodiments, the transport unit is structure W-1, where R1 and R2 are each hydrogen or C1-C6 alkyl. In some embodiments, the transport unit is Structure W-2, Structure W-3, Structure W-4, Structure W-5, or Structure W-6, where R is a bond or C1-C4 alkylene, R1 is hydrogen or C1-C6 alkyl, and R 11 is C1-C4 alkylene, R 12 and R 13 is independently a bond, CH2, or CH2CH2.

[0046] In some embodiments, the transport unit is a heterocyclyl selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is protonated with hydrochloride, hydrobromide, or acetate. In some embodiments, R 11, R 12 , and R 13 are each independently selected from CH2, CH2CH2, CH=CH, CH2CH2CH2, CH=CHCH2, CH2CH2CH2CH2, CH2CH=CH-CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2, each of which is optionally substituted.

[0047] The present disclosure encompasses all reasonable combinations of the embodiments disclosed herein with respect to the structure of the HPP.

[0048] Linker (L) The linker that covalently connects the functional unit of the HPP to the transport unit comprises a bond that can be cleaved after the HPP has permeated across one or more biological barriers. Cleavable bonds include, for example, covalent bonds such as ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate, or oxime bonds.

[0049] In some embodiments, L1 is selected from a bond, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L3)-, -O-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-; L2 is selected from a bond, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L3)-, -O-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-, -O-L5-, -N-L5-, -S-L5-, and -N(L3)-L5-; L4 is selected from a bond, C=O, C=S,

[0050] Selected from JPEG2025504448000005.jpg37135,

[0051] During the ceremony, L3 at each occurrence is independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, and substituted and unsubstituted alkylamino. In certain embodiments, L3 is independently H or C1-C6 alkyl;

[0052] L5, at each occurrence, is independently selected from a bond, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted and unsubstituted heterocycloalkylene, substituted and unsubstituted arylene, and substituted and unsubstituted heteroarylene. In certain embodiments, L5 is independently selected from a bond, CH2COOL6, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted and unsubstituted 5-10 membered heterocycloalkylene, substituted and unsubstituted C6 ... 10 arylene, and substituted and unsubstituted 5- to 10-membered heteroarylene, where L6 is a bond or substituted or unsubstituted C1-C6 alkylene.

[0053] In some embodiments, the linker (L1, L2, and L4 taken together) is selected from the group consisting of C(=O)-O, C(=O)-S, C(=O)-NH, C(=O)-O-CH(L3)-O, C(=O)-O-CH(L3)-S, C(=O)-O-CH(L3)-NH, C(=O)-S-CH(L3)-O, C(=O)-S-CH(L3)-S, C(=O)-S-CH(L3)-NH, P(=O)(-O-L3)-O, OP(=O)(-O-L3), C(=S)-O, C(=NH)-O, C(=NH)-S, C(=N-OL3)-NH, C(=NH-OL3)-O, C(=NH-OL3)-S, OC(=O), SC(=O), NH-C(= O), O-CH(L3)-OC(=O), S-CH(L3)-OC(=O), O-CH(L3)-SC(=O), S-CH(L3)-SC(=O), O-CH(L3)-NH-C(=O), OC(=S), OC(=N-OL3), SC(=N-OL3), and NH-C(=N-OL3), where L3 at each occurrence is independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, and substituted and unsubstituted alkylamino. In certain embodiments, L3 is independently H or C1-C6 alkyl.

[0054] In some embodiments, HPP is selected from the group consisting of structure LRA-1, structure LRA-2, structure LRA-3, structure LRA-4, structure LRA-5, structure LRA-6, structure ARA-1, structure ARA-2, structure ARA-3, structure ARA-4, structure ARA-5, structure ARA-6, structure ARA-7, structure ARA-8, structure ARA-9, structure ARA-10, structure ARA-11, structure ARA-12, structure ARA-13, structure ARA-14, structure 5-LI-1, structure 5-LI-2, structure 5-LI-3, structure 5-LI-4, structure 5-LI-5, structure 5-LI-6, structure 5-LI-7, structure 5-LI-8, structure 5-LI-9, structure 5-LI-10, structure 5-LI-11, structure 5-LI-12, structure 5-LI-13, structure 5-LI-14, structure 5-LI-15, structure 5-LI-16, structure 5-LI-17, structure 5-LI-18, structure 5-LI-19, structure 5-LI-20, structure 5-LI-21, structure 5-LI-22, structure 5-LI-23, structure 5-LI-24, structure 5-LI-25, structure 5-LI-26, structure 5-LI-27, structure 5-LI-28, structure 5-LI-29, structure 5-LI-30, structure 5-LI-31, structure 5-LI-32, structure 5-LI-33, structure 5-LI-34, structure 5-LI-35, structure 5-LI-36, structure 5-LI-37, structure 5-LI-38, structure 5-LI-39, structure 5-LI-40, structure 5-LI-41, structure 5-LI-42, structure 5- 5, Structure 5-LI-6, Structure 5-LI-7, Structure 5-LI-8, Structure FLAP-1, Structure FLAP-2, Structure FLAP-3, Structure FLAP-4, Structure FLAP-5, Structure FLAP-6, Structure NSAID-1, Structure NSAID-2, Structure NSAID-3, selected from Structure NSAID-4, Structure NSAID-5, Structure NSAID-6, Structure NSAID-7, Structure NSAID-8, Structure NSAID-9, Structure NSAID-10, Structure NSAID-11, Structure NSAID-12, and Structure NSAID-13.

[0055] JPEG2025504448000006.jpg101158

[0056] JPEG2025504448000007.jpg90159JPEG2025504448000008.jpg94162

[0057] JPEG2025504448000009.jpg97153JPEG2025504448000010.jpg102159

[0058] JPEG2025504448000011.jpg102152JPEG2025504448000012.jpg104156

[0059] JPEG2025504448000013.jpg111152JPEG2025504448000014.jpg104152

[0060] JPEG2025504448000015.jpg102156JPEG2025504448000016.jpg111157

[0061] JPEG2025504448000017.jpg102160

[0062] This includes stereoisomers and pharma- ceutically acceptable salts thereof. Here, aryl-(Aryl-) is a functional unit of HPP of an anti-inflammatory drug or anti-inflammatory drug related compound, and examples of aryl include, but are not limited to, the following: aryl-(Aryl-) is aryl-1, aryl-2, aryl-3, aryl-4, aryl-5, aryl-6, aryl-7, aryl-8, aryl-9, aryl-10, aryl-11, aryl-12, aryl-13, aryl-14, aryl-15, aryl-16, aryl-17, aryl-18, aryl-19, aryl-20, aryl-21, aryl-22, aryl-23, aryl-24, aryl-25, aryl-26, aryl-27, aryl-28, aryl-29, aryl-30, aryl-31, aryl-32, aryl-33, aryl-34, aryl-35, aryl-36, aryl-37, aryl-38, aryl-39, aryl-40, aryl-41, aryl-42, aryl-43, aryl-44, aryl-45, aryl-46, aryl-47, aryl-48, aryl-49, aryl-50, aryl-51, aryl-52, aryl-53, aryl-54, aryl-55, aryl-56, aryl-57, aryl-58, aryl-59, aryl-60, aryl-61, aryl-62, aryl-63, aryl-64, aryl-65, aryl-66, aryl-67, aryl-68, aryl-69, aryl-70, aryl-71, aryl-72, aryl-73, aryl-74, aryl-75, aryl-76, aryl-77, aryl Aryl-36, Aryl-37, Aryl-38, Aryl-39, Aryl-40, Aryl-41, Aryl-42, Aryl-43, Aryl-44, Aryl-45, Aryl-46, Aryl-47, Aryl-48, Aryl-49, Aryl-50, Aryl-51, Aryl-52, Aryl-53, Aryl-54, Aryl-55, Aryl-56, Aryl-57, Aryl-58, Aryl-59, Aryl-60, Aryl-61, Aryl-62, Aryl-63, Aryl-64, Aryl-65, Aryl-66, Aryl-67, Aryl-68, Aryl-69, Aryl-70, and Aryl-71:

[0063] JPEG2025504448000018.jpg91155JPEG2025504448000019.jpg80163

[0064] JPEG2025504448000020.jpg101165JPEG2025504448000021.jpg108161

[0065] JPEG2025504448000022.jpg91156JPEG2025504448000023.jpg115146

[0066] JPEG2025504448000024.jpg115150JPEG2025504448000025.jpg91155

[0067] JPEG2025504448000026.jpg98148JPEG2025504448000027.jpg96158

[0068] JPEG2025504448000028.jpg80161JPEG2025504448000029.jpg85163

[0069] Where: T is the transport unit as defined above. L1 is selected from nothing, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L3)-, -O-CH2-O-, -O-CH(L3)-O, and -S-CH(L3)-O-; L4 is C=O, C=S,

[0070] JPEG2025504448000030.jpg37135 or

[0071] L1 and L4 together are C(=O)-O, C(=O)-S, C(=O)-NH, C(=O)-O-CH(L3)-O, C(=O)-O-CH(L3)-S, C(=O)-O-CH(L3)-NH, C(=O)-S- CH(L3)-O, C(=O)-S-CH(L3)-S, C(=O)-S-CH(L3)-NH, P(=O)(-O-L3)-O, OP(=O)(-O-L3), C(=S)-O, C(=NH)-O, C(=NH)-S , C(=N-OL3)-NH, C(=NH-OL3)-O, C(=NH-OL3)-S, OC(=O), SC(=O), NH-C(=O), O-CH(L3)-OC(=O), S-CH(L3)-OC(=O), O-C selected from H(L3)-SC(=O), S-CH(L3)-SC(=O), O-CH(L3)-NH-C(=O), OC(=S), OC(=N-OL3), SC(=N-OL3), and NH-C(=N-OL3).

[0072] L3 at each occurrence is independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, and substituted and unsubstituted alkylamino. In certain embodiments, L3 is independently H or C1-C6 alkyl;

[0073] L5, at each occurrence, is independently selected from a bond, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted and unsubstituted heterocycloalkylene, substituted and unsubstituted arylene, and substituted and unsubstituted heteroarylene. In certain embodiments, L5 is independently selected from a bond, CH2COOL6, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted and unsubstituted 5-10 membered heterocycloalkylene, substituted and unsubstituted C6 ... 10 arylene, and substituted and unsubstituted 5- to 10-membered heteroarylene, where L6 is a bond or substituted or unsubstituted C1-C6 alkylene.

[0074] X5, X6, X7, and X8 are independently selected from bond, C(=O), C(=S), OC(=O), OC(=S), CH2, CH, S, O, and NR5, Y, Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are independently H, OH, OW, OC(=O)W, L1-L4-L2-W, OC(=O)CH3, CH3, C2H5, C3H7, C4H9, R6, SO3R6, CH2OR6, CH2OC(=O)R6, CH2C(=O)OR8, OCH3, OC2H5, OR6, CH3SO2, R6SO2, CH3SO3, R6SO3, NO2, CN, CF3, OCF3, CH2(CH2) n NR5R6, CH2(CH2) n OR6, CH(C(=O)NH2)NHR6, CH2C(=O)NH2, F, Br, I, Cl, CH=CHC(=O)NHCH2C(=O)OW, CH=CHC(=O)NHCH2L1-L4-L2-W, NR8C(=O)R5, SO2NR5R8, C(=O)R5, SR5, R6OOCCH(NHR7)(CH2) n C(=O)NH-, R6OOCCH(NHR7)(CH2) n SC(=O)NH-, CF3SCH2C(=O)NH-, CF3CH2C(=O)NH-, CHF2SCH2C(=O)NH-, CH2FSCH2C(=O)NH-, NH2C(=O)CHFS-CH2C(=O)NH-, R7NHCH(C(=O)OW)CH2SCH2C(=O)NH-, R7NHCH(L1-L4-L2-W)CH2SCH2C(=O)NH-, CNCH2SCH2C(=O)NH-, CH3(CH2) n C(=O)NH-, R7N=CHNR7CH2CH2S-, R7N=C(NHR7)NHC(=O)-, R7N=C(NHR7)NHC(=O)CH2, CH3C(Cl)=CHCH2SCH2C(=O)NH-, (CH3)2C(OR6)-, CNCH2C(=O)NH-, CNCH2CH2S-, R7HN=CH(NR7)CH2CH2S-, CH2=CHCH2SCH2C(=O)NH-, CH3CH(OH)-, CH3CH(OR8)-, CH3CH(Y1)-, (CH3)2CH-, CH3CH2-, CH3(CH2) nCH=CH(CH2) m R5 is independently selected from H, C(=O)NH2, CH2CH2OR6, CH2CH2N(CH3)2, CH2CH2N(CH2CH3)2, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, L1-L4-L2-W, and W;

[0075] R6 is independently selected from substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L1-L4-L2-W, and W;

[0076] R7 is independently selected from H, F, Cl, Br, I, CHNHC(=O)CHCH(NHR8)C(=O), R5N=C(NHR6)NHC(=O)-, C(=O)CH3, C(=O)R6, PO(OR5)OR6, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, L1-L4-L2-W, and C-(=O)-W;

[0077] R8 is independently H, F, Cl, Br, I, CH3, C2H5, CF3, CH2CH2F, CH2CH2Cl, CH2CH2Br, CH2CH2I, CH2CHF2, CH2CF3, CH2F, CH2Cl, CH2Br, CH2I, CH2NR6R7, CH(NHR7)CH2C(=O)NH2, C3H7, C4H9, C5H 11 , R6, C(=O)R6, C(=O)NH2, CH2C(=O)NH2, CH2OC(=O)NH2, PO(OR5)OR6, C(CH3)2C(=O)OR6, CH(CH3)C(=O)OR6, CH2C(=O)OR6, C(=O)-W, and L1-L4-L2-W;

[0078] L2 at each occurrence is independently selected from a bond, O, S, -N(L3)-, -N(L3)-CH2-O, -N(L3)-CH2-N(L3)-, -O-CH2-O-, -O-CH(L3)-O, -S-CH(L3)-O-, -O-L5-, -S-L5-, and -N(L3)-L5-; and

[0079] W is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, and Structure W-6; However, the defined structure of HPP shall form a stable compound without violating the principles of covalent bonding.

[0080] In some embodiments, the present disclosure provides a transdermal pharmaceutical composition for transdermal administration to treat signs, symptoms, and / or complications of viral and / or bacterial and / or protozoal and / or fungal infections and related conditions, comprising 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propanoate hydrochloride, 2-(N,N- ... (RS)-N-[1-(1-benzothien-2-yl)ethyl]-N-(2-N,N-diethylaminoacetyloxy)urea hydrochloride, (pyrrolidin-2-yl)methyl 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetate hydrochloride,

[0081] (Pyrrolidin-2-yl)methyl 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoate hydrochloride, (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·HCl, 2-(Dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate hydrochloride , S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate hydrochloride, 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride, (pyrrolidin-2-yl)methyl 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoate hydrochloride,

[0082] (Pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride, (Pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride, (Pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride, (Pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (Pyrrolidine- 2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride, (pyrrolidin-2-yl)methyl 6-chloro-α-methylcarbazole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride,

[0083] (Pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate·HCl, (Pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl, (Pyrrolidin-2-yl)methyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate acetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(p-isobutylphenyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-acetoxybenzoate hydrochloride,

[0084] (Pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride, (Pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride, (Pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate hydrochloride, (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate salt acid salts, (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 6-chloro-α-methyl-9H-carbazole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazole acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride,

[0085] (Pyrrolidin-2-yl)methyl α-methyl-4-[(2-methyl-2-propen-1-yl)amino]benzeneacetate hydrochloride, (Pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride, (Pyrrolidin-2-yl)methyl 10,11-dihydro-α-methyl-10-oxodibenzo[b,f]thiepin-2-acetate hydrochloride, (Pyrrolidin-2-yl)methyl 2-(8-methyl-5-oxo-6H-benzo[b][1]benzoxepin-3-yl (pyrrolidin-2-yl)methyl 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate hydrochloride, (pyrrolidin-2-yl)methyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 2-chloro-2-(3-chloro-4-cyclohexylphenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride,

[0086] (Pyrrolidin-2-yl)methyl 3-(4-biphenylcarbonyl)propanoate hydrochloride, (Pyrrolidin-2-yl)methyl 6-chloro-5-cyclohexyl-1-indanecarboxylate hydrochloride, (Pyrrolidin-2-yl)methyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate hydrochloride, (Pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride acetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 3-2-(2,4-dichlorophenoxy)benzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 4-acetamidophenylsalicylate hydrochloride,

[0087] The present invention relates to a composition comprising an HPP molecule selected from 2-[(2,3-dimethylphenyl)amino]benzoic acid, (pyrrolidin-2-yl)methyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate hydrochloride, (pyrrolidin-2-yl)methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate hydrochloride, (pyrrolidin-2-yl)methyl salicylsalicylate hydrochloride, (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-[[2-[(2,6-dichlorophenyl)amino]phenyl]acetoxy]acetate hydrochloride, or (pyrrolidin-2-yl)methyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate hydrochloride.

[0088] In the method of treatment, the viral infection may be caused by one or more RNA viruses. In the method of treatment, the viral infection may be caused by one or more DNA viruses. In the method of treatment, the viral infection may be caused by one or more influenza viruses selected from influenza virus type A, influenza virus type B, influenza virus type C, and influenza virus type D. In the methods of treatment, the viral infection may be caused by a human influenza virus selected from H1N1, H1N2, H1N7, H2N2, H2N3, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N6, H5N8, H5N9, H6N1, H6N2, H6N5, H7N1, H7N2, H7N3, H7N4, H7N9, H7N7, H8N4, H9N2, H10N7, H10N8, H10N3, H11N2, H11N9, H12N5, H13N6, H17N10, and H18N11.

[0089] In the method of treatment, the viral infection may be caused by an avian influenza A virus selected from H1N1, H1N8, H2N9, H3N8, H3N2, H4N6, H4N3, H5N4, H5N8, H5N9, N5N1, H6N2, H6N1, H6N5, H6N8, H7N1, H8N4, H9N2, H9N2, H9N6, H9N7, H10N8, H11N6, H11N9, H12N5, H13N6, H14N4, and H15N9. In the method of treatment, the viral infection may be caused by one or more swine influenza A viruses selected from H1N1, H1N2, H2N1, H3N2, and H2N3.

[0090] In the method of treatment, the viral infection may be caused by an equine influenza virus selected from H3N8 and H7N7. In the method of treatment, the viral infection may be caused by a canine influenza virus selected from H3N2, H3N8, and H5N1. In the method of treatment, the viral infection may be caused by one or more feline influenza viruses selected from feline herpesvirus, feline calicivirus, Bordetella, bronchiseptica, and Chlamydophila felis. In the method of treatment, the viral infection may be caused by one or more coronaviruses. In the method of treatment, the viral infection may be caused by one or more of Severe Acute Respiratory Syndrome Coronavirus (SARS-Co-V), SARS-CoV-1, SARS-CoV-2 (COVID-19), 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV.

[0091] In the method of treatment, the bacterial infection may be caused by one or more Gram-positive bacteria. In the method of treatment, the bacterial infection may be caused by one or more Gram-negative bacteria. In the method of treatment, the bacterial infection may be caused by one or more pathogenic bacteria. In the method of treatment, the pathogenic bacteria may be selected from tuberculosis, streptococcus, syphilis, staphylococcus, aspergillus, tetanus, vibrio cholerae, salmonella, clostridium botulinum, and Escherichia coli (E. Coli).

[0092] In the methods of treatment, the protozoan infection may be caused by one or more pathogenic protozoa that cause disease in humans or animals. In the treatment method, the pathogenic protozoa may be selected from the group consisting of Entamoeba histolytica (amoebozoa), Acanthamoeba (amoebozoa), Giardia lamblia (metamonas), Trichomonas vaginalis (metamonas), Dientamoeba fragilis (metamonas), Trypanosoma brucei (kinetoplastids), Trypanosoma cruzi (kinetoplastids), Leishmania spp. (kinetoplastids), Balantidium coli (ciliates), Plasmodium spp. spp. (Apicomplexa), Toxoplasma gondii (Apicomplexa), Babesia spp. (Apicomplexa), Cryptosporidium spp. (Apicomplexa), and Cyclospora cayetanensis (Apicomplexa).

[0093] In methods of treatment, signs and symptoms of infection may include one or more of fatigue, loss of appetite, weight loss, fever, night sweats, chills, aches, inflammation, cough, shortness of breath, pain, and runny nose.

[0094] In the method of treatment, complications of infectious diseases can include one or more of pneumonia, acute respiratory distress syndrome, chronic obstructive pulmonary disease, blood clots (clotting), meningitis, encephalitis, cardiovascular disease, stroke, heart attack, sepsis, and inflammation of the brain, lungs, kidneys, liver, pancreas, gastrointestinal (GI) system, blood vessels, and other tissues, caused by viruses and / or bacteria and / or protozoa and / or fungi in humans and animals.

[0095] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe for administration to a subject. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compound of the present invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, the following: These include the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,11-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0096] Certain compounds of the present invention can form pharma- ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review of pharma-ceutically acceptable salts, see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), which is incorporated herein by reference.

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0098] The term "alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon group derived by removing one hydrogen atom from an alkane. In certain embodiments, an alkyl group contains 1-12 carbons. In certain embodiments, an alkyl group contains 1-8 carbons. In certain embodiments, and sometimes preferably, an alkyl group contains 1-6 carbons, and in certain embodiments, and sometimes more preferably, an alkyl group contains 1-4 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, and the like. An alkyl group can be substituted or unsubstituted.

[0099] The term "alkenyl" refers to any monovalent aliphatic hydrocarbon group derived by removing one hydrogen atom from an alkene. In certain embodiments, an alkenyl group contains 2 to 12 carbons. In certain embodiments, an alkenyl group contains 2 to 8 carbons. In certain embodiments, and sometimes preferably, an alkenyl group contains 2 to 6 carbons, and in certain embodiments, and sometimes more preferably, an alkenyl group contains 2 to 4 carbons. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, and the like. An alkenyl group can be substituted or unsubstituted.

[0100] The term "alkynyl" refers to a monovalent aliphatic hydrocarbon group derived by removing one hydrogen atom from an alkyne. In certain embodiments, an alkynyl group contains 2-12 carbons. In certain embodiments, an alkynyl group contains 2-8 carbons. In certain embodiments, and sometimes preferably, an alkynyl group contains 2-6 carbons, and in certain embodiments, and sometimes more preferably, an alkynyl group contains 2-4 carbons. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, and the like. An alkynyl group can be substituted or unsubstituted.

[0101] The term "cycloalkyl" refers to any monovalent group formed by removing one hydrogen atom from a cycloalkane. In certain embodiments, a cycloalkyl group contains 3 to 10 carbons. In certain embodiments, a cycloalkyl group contains 3 to 8 carbons. In certain embodiments, and sometimes preferred, a cycloalkyl group contains 3 to 6 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyls can be optionally substituted or unsubstituted.

[0102] The term "heterocyclyl" refers to a cycloalkyl in which at least one ring atom is a non-carbon atom. Examples of non-carbon ring atoms include, but are not limited to, S, O, and N. Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfomorpholinyl, homopiperazinyl, and the like.

[0103] The term "alkylene" refers to a saturated, straight or branched, divalent aliphatic hydrocarbon group derived from a parent alkane by removing two hydrogen atoms. The straight or branched chain groups contain 1 to 12 carbon atoms (including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms), preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCH-), etc. Alkylene groups can be substituted or unsubstituted.

[0104] The term "alkenylene" refers to a divalent aliphatic hydrocarbon group having at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2~12 Alkenylene, more preferably C 2~8 Alkenylene, sometimes more preferably C 2~6 Alkenylene, sometimes even more preferably C 2~4 Alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, etc. Alkenylene groups can be substituted or unsubstituted.

[0105] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group having a completely conjugated pi-electron system. Preferably, the aryl is 6- to 10-membered, such as phenyl and naphthyl, most preferably phenyl. Aryl groups can be substituted or unsubstituted.

[0106] The term "heteroaryl" refers to a 5-14 membered aromatic system having 1-4 heteroatoms selected from O, S, and N as ring atoms. Preferably, the heteroaryl is 5-10 membered (5-, 6-, 7-, 8-, 9-, and 10-membered, etc.), more preferably 5- or 6-membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. Heteroaryls may be fused with aryl, heterocyclyl, or cycloalkyl rings, where the ring attached to the parent structure is a heteroaryl. Heteroaryl groups may be substituted or unsubstituted.

[0107] The term "alkoxy" refers to -O-(alkyl), for example, methoxy, ethoxy, propoxy, butoxy and the like. The term "cycloalkoxy" refers to -O-(cycloalkyl), for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The term "bond" refers to a covalent bond using the "-" symbol.

[0108] The term "hydroxyl" refers to an --OH group. The term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom. The term "amino" refers to the group --NH. The term "alkylthio" refers to alkyl-S-.

[0109] The term "alkylamino" refers to "alkyl-NH-" or sometimes dialkylamino (-NR a R b ), where R a and R b) may be the same or different. Sometimes preferably, the alkyl group is a C1-C6 alkyl, and sometimes more preferably, the alkyl is a C1-C4 alkyl. Examples of alkylamino include, but are not limited to, CH3-NH-, -N(CH3)2, -N(CH2CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -NH-Bu. t , -N(CH3)(Bu t ) etc.

[0110] The term "cyano" refers to the group -CN. The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, where the halogen atoms can be the same or different. The term "nitro" refers to the group --NO.sub.2. The term "oxo" refers to the group =O. The term "carboxyl" refers to the group -C(O)OH. The term "alkoxycarbonyl" refers to the group -C(O)O(alkyl). The term "alkylcarbonyl" refers to a -C(O)-alkyl group.

[0111] The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes cases where the event or circumstance may or may not occur. For example, "a heterocyclyl group optionally substituted with alkyl" means that an alkyl group may, but does not necessarily, be present, and the description includes cases where the heterocyclyl group is substituted with alkyl and cases where the heterocyclyl group is not substituted with alkyl.

[0112] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, being independently replaced with a corresponding number of substituents. A person skilled in the art can determine whether or not substitution is possible without undue effort through experiment or theory. For example, the combination of an amino group or hydroxyl group having free hydrogen and a carbon atom having an unsaturated bond (such as an olefin) may be unstable.

[0113] The term "covalent bond principle" as used herein refers to the basic rules and principles in the formation of covalent bonds in organic compounds as generally understood by those skilled in the art. For example, carbon atom is tetravalent and can only form four covalent bonds (e.g., four single bonds, or one double bond plus two single bonds, etc.), and oxygen is divalent and can only form two covalent bonds (two single bonds at -O-, or one double bond at =O).

[0114] The term "prodrug" refers to a compound that can be transformed in vivo, such as by hydrolysis in blood, to yield the parent compound that is active under physiological conditions. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. In particular, the present disclosure provides a unique class of prodrugs, so-called "highly permeable prodrugs", as defined in the present disclosure.

[0115] When any group in any HPP structure is indicated as being either "substituted" and / or "unsubstituted," this means that the group may be optionally substituted with one or more, preferably one to five, and sometimes more preferably one to three, substituents independently selected from halogen, cyano, nitro, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, alkylthio, alkylamino, alkylsulfonyl (alkylsulfone), alkylsulfoxyl (alkylsulfoxide), acyloxy, carboxylic acid, carboxylic acid ester, and carboxamide groups, and the like. Alkyl groups can have 1 to 10 carbon atoms, sometimes preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Esters can have C1 to C6 carbon atoms, ... 10 It may be an ester of an alcohol, sometimes preferably a C1 to C6 alcohol, sometimes more preferably a C1 to C4 alcohol.

[0116] In some embodiments, when an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, or the like, or a portion thereof is substituted, the substituent(s) may be substituted at any available point of attachment(s), and the substituents may be selected from the group consisting of a C1-C6 alkyl group, a halogen group, a C1-C6 alkoxy group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, a C1-C6 alkylthio group, a C1-C6 alkylamino group, a di-(C1-C6 alkyl)amino group, a thiol group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a 5-membered to 10-membered heterocyclyl group, a C6-C 10 It may be one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3 groups independently selected from an aryl group, a 5- to 10-membered heteroaryl group, a C3-C6 cycloalkoxy group, a C1-C6 cycloalkylthio group, a 5- to 10-membered heterocyclylthio group, and an oxo group.

[0117] In some embodiments, and sometimes preferably, the substituents are independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, and oxo. In some embodiments, and sometimes more preferably, the substituents are independently selected from C1-C4 alkyl, halogen, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, thiol, hydroxyl, nitro, cyano, and amino. As would be understood by one of ordinary skill in the art, the oxo (=O) group cannot be a substituent at an unsaturated carbon in any other group.

[0118] As used in the specification and claim(s), the words "comprising" (and all forms of "comprising" such as "comprise" and "comprises"), "having" (and all forms of "having" such as "have" and "has"), "including" (and all forms of "including" such as "includes" and "include"), or "containing" (and all forms of "containing" such as "contains" and "contain") are inclusive, i.e., open-ended, and do not exclude further unrecited elements or method steps.

[0119] The terms "a" and "an" and "the" and the like in the context of describing the invention (particularly in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise specified herein or clearly contradicted by context. The use of the word "a" or "an" when used in conjunction with the word "comprising" in the claims and / or specification may mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0120] Where the plural is used for compounds, salts, etc., this is taken to mean also a single compound, salt, etc.

[0121] As used herein, the term "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items. When used in a list of two or more items, the term "and / or" means that any one of the listed items can be used alone, or any combination of two or more of the listed items can be used. For example, if a composition, combination, configuration, arrangement, or group is described as including (or comprising) component A, component B, component C, and / or component D, the composition can include A alone, B alone, C alone, D alone, a combination of A and B, a combination of A and C, a combination of A and D, a combination of B and C, a combination of B and D, a combination of C and D, a combination of A and B and C, a combination of A and B and D, a combination of A and C and D, a combination of B and C and D, or a combination of A and B and C and D.

[0122] Throughout this application, the term "about" or "approximately" is used to indicate that a value includes the inherent variation of error for the device, method used to determine the value, or the variation that exists between study subjects. In one aspect, the term "about" or "approximately" generally means within 10%, particularly within 9%, particularly within 8%, particularly within 7%, particularly within 6%, particularly within 5%, particularly within 4%, particularly within 3%, particularly within 2%, particularly within 1%, and particularly within 0.5% of a given value or range.

[0123] In some embodiments, the term "dose" as used herein refers to the total amount of drug or active ingredient taken by an individual subject at any one time, particularly per site, taken by an individual subject at any one time.

[0124] In some embodiments, the term "dosage form" as used herein refers to a unitary administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.

[0125] In some embodiments, the term "unit dose" or "dosage unit" refers to a dosage form that is configured to deliver a specified amount or dose of a composition or its components. Examples of dosage forms for topical administration include, but are not limited to, transdermal patches, creams, foams, gels, lotions, ointments, pastes, powders, shakes, lotions, solids, sponges, tapes, tinctures, vapors, injections, drops, rinses, sprays, and liquids.

[0126] A "unit dose" or "dosage unit" may be configured to provide a complete unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a dose). The predetermined amount in each unit dose may depend on factors including, but not limited to, the unique characteristics of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in the technology of making and administering such unit doses. For example, a unit dose may be a transdermal patch, a spray, i.e., a single spray in a spray application, a drop in a drop application, a length of tape, a rice or pea-sized ointment, or a scoop or spoonful of ointment. A unit dose measuring device, such as a cup, scoop, syringe, dropper, spoon, or irrigation device, may hold a measured amount of the composition equivalent to a dosage form, e.g., cream, foam, gel, lotion, ointment, paste, powder, shake lotion, and solid, a complete unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a dose). In a single dosage form, there can be a single unit dose or multiple unit doses. The kit can include instructions regarding the size of the unit dose or portion thereof.

[0127] III. Pharmaceutical Compositions Comprising HPP Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one HPP of a parent drug or its related compounds that can be used to treat the signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections, and a pharma- ceutically acceptable carrier.

[0128] A pharmaceutical composition may include two or more HPPs of different parent drugs. The different parent drugs may belong to the same or different categories of drugs used to treat signs, symptoms, and / or complications of viral, bacterial, and / or protozoal, and / or fungal infections. For example, a pharmaceutical composition may include an HPP of a parent drug or its related compounds, where the parent drug is selected from 5-lipoxygenase activating protein (FLAP) inhibitors, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), other anti-inflammatory drugs, and any combination thereof.

[0129] In certain embodiments, the pharmaceutical composition comprises a HPP of a parent drug or a related compound thereof, the parent drug being selected from the group consisting of LRA-1, LRA-2, LRA-3, LRA-4, LRA-5, LRA-6, ARA-1, ARA-2, ARA-3, ARA-4, ARA-5, ARA-6, ARA-7, ARA-8, ARA-9, ARA-10, ARA-11, ARA-12, ARA-13, ARA-14, 5-LI-1, 5-LI-2, 5-LI-3, 5-LI-4, 5-LI-5, 5-LI-6, 5-LI-7, 5-LI-8, 5-LI-9, 5-LI-10, 5-LI-11, 5-LI-12, 5-LI-13, 5-LI-14, 5-LI-15, 5-LI-16, 5-LI-17, 5-LI-18, 5-LI-19, 5-LI-20, 5-LI-21, 5-LI-22, 5-LI-23, 5-LI-24, 5-LI-25, 5-LI-26, 5-LI-27, 5-LI-28, 5-LI-29, 5-LI-30, 5-LI-31, 5-LI-32, 5-LI-33, 5-LI-34, 5-LI-35, 5-LI-36, 5-LI-37, 5-LI-38, 5-LI-39, 5-LI-40, 5-LI-41, 5-LI-42, 5-LI-43, 5-LI-44, 5-LI-45, 5-LI-46, 5-LI-47, 5-LI-48, I-4, Structure 5-LI-5, Structure 5-LI-6, Structure 5-LI-7, Structure 5-LI-8, Structure FLAP-1, Structure FLAP-2, Structure FLAP-3, Structure FLAP-4, Structure FLAP-5, Structure FLAP-6, Structure NSAID-1, Structure NSAID-2, Structure NSAI D-3, selected from compounds of structure NSAID-4, structure NSAID-5, structure NSAID-6, structure NSAID-7, structure NSAID-8, structure NSAID-9, structure NSAID-10, structure NSAID-11, structure NSAID-12, and structure NSAID-13.

[0130] As used herein, the term "pharmaceutical acceptable carrier" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting HPP from one location, bodily fluid, tissue, organ (internal or external), or part of the body to another location, bodily fluid, tissue, organ, or part of the body.

[0131] Each carrier is "pharmacologically acceptable" in the sense of being compatible with the other ingredients of the formulation, e.g., HPP; suitable for use in contact with the tissues or organs of biological subjects without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication; and commensurate with a reasonable benefit / risk ratio.

[0132] Some examples of materials that can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) additives, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) propylene glycol, and the like. (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohols, such as ethyl alcohol and n-propyl alcohol or isopropyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations, such as acetone.

[0133] Pharmaceutical compositions may contain pharma- ceutically acceptable auxiliary substances such as pH adjusting and buffering agents, toxicity adjusting agents, etc., required to approximate physiological conditions, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.

[0134] In one embodiment, the pharma- ceutically acceptable carrier is an aqueous carrier, such as a buffered saline solution. In certain embodiments, the pharma- ceutically acceptable carrier is a polar solvent, such as acetone and ethyl alcohol. In certain embodiments, the pharma- ceutically acceptable carrier is an aqueous solution containing 10% to 35% ethanol by volume.

[0135] The concentration of HPP in these formulations can vary widely and will be selected primarily based on fluid volume, viscosity, body weight, etc., depending on the particular mode of administration selected and the needs of the biological subject. For example, the concentration can be 0.001% to 50% by weight, 0.01% to 30% by weight, 0.1% to 20% by weight, or 1% to 10% by weight.

[0136] The composition of the present invention can be administered for preventive, therapeutic and / or hygienic purposes. Such administration can be by topical, mucosal, such as oral, nasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic, and other convenient routes. The pharmaceutical composition can be administered in various unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration include powders, tablets, pills, capsules, and lozenges, and unit dosage forms suitable for transdermal administration include solutions, suspensions, and emulsions.

[0137] Typical pharmaceutical compositions for transdermal, oral, and intravenous administration will be from about 0.001 g to about 100 g, from about 0.01 g to about 10 g, or from about 0.1 g to about 1 g per subject per day. Dosages from about 0.00001 mg to about 100 g per subject per day can be used. Actual methods for preparing parenterally administrable compositions are known or apparent to those of skill in the art and are described in more detail in publications such as Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, (2005).

[0138] IV. Application of HPP i) Methods for penetrating biological barriers Another aspect of the present disclosure provides a method of delivering a drug molecule to a site within a biological subject by penetrating one or more biological barriers within the biological subject. The method includes administering HPP or a pharmaceutical composition thereof to the biological subject. In certain embodiments, the HPP exhibits greater than about 20 times, greater than about 50 times, greater than about 100 times, greater than about 200 times, greater than about 300 times, greater than about 500 times, greater than about 10 ...

[0139] The term "biological barrier" as used herein refers to a biological layer that separates an environment, preferably an in vivo environment, into different spatial regions or compartments that allow for regulation (e.g., restriction, confine, enhance, or no) of passage, permeation, or migration of a substance or object from one compartment / region to another. The various spatial regions or compartments referred to herein may have the same or different chemical or biological environment(s). Biological layers referred to herein include, but are not limited to, biological membranes, cell layers, biological structures, the inner surface of a subject, organism, organ, or body cavity, the outer surface of a subject, organism, organ, or body cavity, or any combination or plurality thereof.

[0140] Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., nuclear membranes or organelle membranes such as the membranes or envelopes of the Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosomes, nuclei, chloroplasts, plastids, peroxisomes, or microbodies).

[0141] The lipid bilayer referred to herein is a bilayer of lipid class molecules, including but not limited to phospholipids and cholesterol. In certain embodiments, the lipids for the bilayer are amphipathic molecules consisting of polar head groups and non-polar fatty acid tails. The bilayer is composed of two layers of lipids, which are arranged such that the hydrocarbon tails of the lipids face each other and form an oily core held together by hydrophobic effects, while the charged heads of the lipids face the aqueous solution on both sides of the membrane. In another particular embodiment, the lipid bilayer may contain one or more embedded proteins and / or sugar molecules.

[0142] Examples of cell layers include eukaryotic cell linings (e.g., epithelium, lamina propria, smooth muscle, or muscularis mucosae (in the digestive tract)), prokaryotic cell linings (e.g., surface layer or S-layer, which refers to a two-dimensional monolayer composed of identical proteins or glycoproteins, specifically, S-layer refers to a portion of the cell envelope typically found in bacteria and archaea), biofilms (a community structure of microorganisms encapsulated in a self-developed polymeric matrix and attached to a biological or inert surface), and plant cell layers (e.g., epidermis). The cells may be normal or pathological (e.g., diseased, cancerous).

[0143] Examples of biological structures include structures sealed by tight junctions or tight junctions that provide a barrier against the entry of toxins, bacteria, and viruses, such as the blood-milk barrier and the blood-brain barrier (BBB). In particular, the BBB is composed of an impermeable class of endothelium, which represents a physical barrier via tight junctions adjacent to adjacent endothelial cells, and represents a transport barrier composed of efflux transporters. Biological structures can also include a mixture of cells, proteins, and sugars (e.g., a blood clot).

[0144] Examples of the inner surface of a subject, organism, organ, or body cavity include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa, and endometrium (mucosa of the uterus), the inner layer of the wall of a pollen grain or the inner wall layer of a spore, or a combination or plurality thereof.

[0145] Examples of the exterior of a subject, organism, organ, or cavity include capillaries (e.g., capillaries in cardiac tissue), mucous membranes continuous with the skin (such as, for example, the nostrils, lips, ears, genital area, and anus), organs (e.g., the exterior surfaces of the liver, lungs, stomach, brain, kidneys, heart, ears, eyes, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colorectum, intestines, veins, respiratory system, vascular system, anus rectum and anus), skin, cuticle (e.g., the dead layer of epidermal cells or keratinocytes or the overlapping layer of cells covering the hair shaft of an animal, the outer multi-layered structure of the cuticle of many invertebrates, the cuticle or the polymers cutin and / or cutan of plants, the outer layer of the wall of a pollen grain, or the outer wall layer of a spore), and combinations or multiples thereof.

[0146] Further, biological barriers may include a sugar layer, a protein layer, or any other biological layer, or a combination or plurality thereof. For example, skin is a biological barrier having multiple biological layers. Skin includes an epidermis layer (outer surface), a dermis layer, and a subcutaneous layer. The epidermis layer includes several layers, including a basal cell layer, a spinous cell layer, a granular cell layer, and a stratum corneum layer. The cells in the epidermis are called keratinocytes. The stratum corneum ("horny layer") is the outermost layer of the epidermis, where the cells are flat and scaly ("squamous") in shape. These cells are rich in keratin and are arranged in overlapping layers, giving the surface of the skin its toughness and resistance to oil and water.

[0147] ii) Methods of using HPP and pharmaceutical compositions thereof in the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections and related conditions. Another aspect of the disclosure provides a method of treating signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections and related conditions in a subject by administering to the subject HPP or a pharmaceutical composition thereof.

[0148] The term "treating" as used herein means to cure, alleviate, inhibit, or prevent. The term "treat" as used herein means to cure, alleviate, inhibit, or prevent. The term "treatment" as used herein means to cure, alleviate, inhibit, or prevent.

[0149] As used herein, the term "biological subject" or "subject" refers to an organ, a group of organs that work together to perform a particular task, an organism, or a group of organisms. As used herein, the term "organism" refers to an assemblage of molecules that functions as a more or less stable whole and has the characteristics of life, such as an animal, a plant, a fungus, or a microorganism.

[0150] The term "animal" as used herein refers to eukaryotic organisms characterized by voluntary movement. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, birds, reptiles, amphibians, fish, saccharini, and amphioxus), tunicates (e.g., Thalia, Ophiopodia, Sorbella, and Ascidia), articulates (e.g., Insecta, Myriapoda, Malacostraca, Arachnida, Pycnogonida, Brachystomes, Crustacea, and Annelida), geckos (panarthropoda), and worms (e.g., Rotifera).

[0151] In certain embodiments, a method of treating signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections and related conditions in a subject comprises administering to the subject a therapeutically effective amount of HPP or a pharmaceutical composition thereof.

[0152] HPP or a pharmaceutical composition thereof can be administered to a biological subject by any route of administration known in the art, including, but not limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and / or parenteral administration. In some embodiments, preferably, HPP or a pharmaceutical composition thereof is administered to a subject transdermally or topically. The pharmaceutical composition can be administered in a variety of unit dosage forms depending on the method of administration.

[0153] HPP or a pharmaceutical composition thereof can be administered to a subject in the form of a formulation or preparation suitable for each administration route. The formulation useful in the method of the present invention comprises one or more HPPs, one or more pharma- ceutically acceptable carriers therefor, and optionally other therapeutic ingredients. The formulation is suitably provided in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of HPP that can be combined with a carrier material to produce a pharma- ceutically effective dose will generally be that amount of HPP that produces a therapeutic effect. In general, the amount of HPP will range from about 1 percent to about 99 percent of the HPP by weight, and sometimes preferably from about 1 percent to about 20 percent.

[0154] Methods of preparing these formulations or compositions include the step of bringing into association the HPP with one or more pharma- ceutically acceptable carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the HPP with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0155] Formulations suitable for oral administration may be present in the form of capsules, cachets, pills, tablets, lozenges (using flavored bases, usually sucrose and acacia or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or pastilles (using inert bases, such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, etc., each containing a predetermined amount of HPP as the active ingredient. The compounds may also be administered as a bolus, electuary, or paste.

[0156] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the HPP is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as glycerol; For example, powdered agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) difficult solvents, such as paraffin, (6) absorption enhancers, such as quaternary ammonium compounds, (7) wetting agents, such as acetyl alcohol and glycerol monostearate, (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol solids, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0157] Tablets can be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersing agents. Molded tablets can be manufactured by molding a mixture of powdered HPP and an inert liquid diluent in a suitable device. Tablets, and other solid dosage forms such as dragees, capsules, pills and granules, can be optionally marked or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical compounding. They can also be formulated to provide a slow or controlled release of the HPP therein, for example, using various percentages of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres that provide the desired release profile.

[0158] They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can optionally contain pacifying agents, and can be of a composition that releases the HPP(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of implantable compositions that can be used include polymeric substances and waxes. The HPP can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned additives.

[0159] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to HPP, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, and preservatives.

[0160] Suspensions may contain, in addition to HPP, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, powdered agar and tragacanth, and mixtures thereof.

[0161] Preparations for rectal or vaginal administration can be provided as suppositories. Suppositories can be prepared by mixing one or more HPPs with one or more suitable non-irritating additives or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity to release the active agent. Preparations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays, including carriers as known in the art to be suitable.

[0162] Preparations for topical or transdermal or epidermal or cutaneous administration of the HPP compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. Ointments, pastes, creams, and gels may contain, in addition to the HPP composition, additives such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to the HPP composition, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane. For topical or transdermal administration, the best formulation is a solution, optionally and preferably an aqueous solution, for example an aqueous solution containing ethanol or isopropanol.

[0163] Alternatively, HPP or a pharmaceutical composition thereof can be administered by aerosol. This can be achieved by preparing an aqueous aerosol, liposomal preparation, or solid particles containing HPP. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers can also be used. Aqueous aerosols are made by formulating an aqueous solution or suspension of the agent together with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular compound, but typically include non-ionic surfactants (e.g., Tween®, Pluronic®, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0164] Transdermal patches can also be used to deliver HPP compositions to the target site. Such formulations can be made by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.

[0165] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0166] Formulations suitable for parenteral administration include HPP in combination with one or more pharma- ceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0167] Examples of suitable aqueous and non-aqueous carriers that can be used in formulations suitable for parenteral administration include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0168] Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents in the composition, such as sugars, sodium chloride, and the like. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0169] Injectable depot forms are made by forming microencapsule matrices of HPP or in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of HPP to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping HPP in liposomes or microemulsions that are compatible with body tissues.

[0170] In certain embodiments, HPP or its pharmaceutical composition is delivered to the site of action in a therapeutically effective dose. As is known in the field of pharmacology, the exact amount of the pharmacologic effective dose of HPP that will produce the most effective results in terms of efficacy of treatment in a given patient will depend, for example, on the activity, specific properties, pharmacokinetics, pharmacodynamics, and bioavailability of the specific HPP, the physiological condition of the subject (including race, age, sex, weight, diet, type and stage of disease, general physical condition, responsiveness to a given dosage and type of drug), the properties of the pharmacologic acceptable carrier in the formulation, the route and frequency of administration used, and the severity or disposition of the pathology being treated. However, the above guidelines can be used as a basis for fine-tuning the treatment, for example, to determine the optimal dosage of administration, which merely requires routine experimentation consisting of monitoring the subject and adjusting the dosage (Remington: The Science and Practice of Pharmacy (ed. Gennaro, 20th edition, Williams & Wilkins PA, USA) (2000)).

[0171] iii) Use of HPP and pharmaceutical compositions thereof in the manufacture of a medicament for the treatment of signs, symptoms, and complications of viral and / or bacterial and / or protozoal and / or fungal infections and related pathologies. Another aspect of the disclosure provides the use of HPP and pharmaceutical compositions thereof in the manufacture of a medicament for the treatment of the signs, symptoms, and complications of viral, bacterial, protozoal, and / or fungal infections and related conditions.

[0172] In some embodiments, the present disclosure provides a method for producing a pharmaceutical composition comprising: (1) (Pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (2) 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, (3) 2-(N,N-diethylamino)ethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate hydrochloride, (4) 2-(diethylamino)ethyl acetoxybenzoate hydrochloride, (5) (RS)-N-[1-(1-benzothien-2-yl)ethyl]-N-(2-N,N-diethylaminoacetyloxy)urea hydrochloride, (6) (Pyrrolidin-2-yl)methyl 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetate hydrochloride, (7) (Pyrrolidin-2-yl)methyl 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoate hydrochloride, (8) (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate hydrochloride, (9) 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate hydrochloride, (10) S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate hydrochloride,

[0173] (11) 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride [2-(dipropylamino)ethyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride, (12) (Pyrrolidin-2-yl)methyl 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoate hydrochloride, (13) (Pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride, (14) (Pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride, (15) (Pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride, (16) (Pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (17) (Pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride, (18) (Pyrrolidin-2-yl)methyl 6-chloro-α-methylcarbazole-2-acetate hydrochloride, (19) (Pyrrolidin-2-yl)methyl 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoate hydrochloride,

[0174] (20) (Pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate, (21) (Pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride, (22) (Pyrrolidin-2-yl)methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate hydrochloride, (23) (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, (24) (Pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate hydrochloride, (25) (Pyrrolidin-2-yl)methyl 2-(4-isobutylphenyl)propanoate hydrochloride, (26) (Pyrrolidin-2-yl)methyl 2-acetoxybenzoate hydrochloride, (27) (Pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride, (28) (Pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride, (29) (Pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride,

[0175] (30) (Pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride hydrochloride, (31) (Pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate hydrochloride, (32) (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, (33) (Pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride, (34) (Pyrrolidin-2-yl)methyl 6-chloro-α-methyl-9H-carbazole-2-acetate hydrochloride, (35) (Pyrrolidin-2-yl)methyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazole acetate hydrochloride, (36) (Pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride, (37) (Pyrrolidin-2-yl)methyl α-methyl-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate hydrochloride, (38) (Pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride, (39) (Pyrrolidin-2-yl)methyl α-methyl-4-[(2-methyl-2-propen-1-yl)amino]benzeneacetate hydrochloride,

[0176] (40) (Pyrrolidin-2-yl)methyl 5-benzoyl-α-methyl-2-thiophene acetate hydrochloride, (41) (Pyrrolidin-2-yl)methyl 10,11-dihydro-α-methyl-10-oxodibenzo[b,f]thiepin-2-acetate hydrochloride, (42) (Pyrrolidin-2-yl)methyl 2-(8-methyl-5-oxo-6H-benzo[b][1]benzoxepin-3-yl)propanoate hydrochloride, (43) (Pyrrolidin-2-yl)methyl 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate hydrochloride, (44) (Pyrrolidin-2-yl)methyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate hydrochloride, (45) (Pyrrolidin-2-yl)methyl 2-chloro-2-(3-chloro-4-cyclohexylphenyl)acetate hydrochloride, (46) (Pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride, (47) (Pyrrolidin-2-yl)methyl 3-(4-biphenylcarbonyl)propanoate hydrochloride, (48) (Pyrrolidin-2-yl)methyl 3-[5-(4-chlorophenyl)furan-2-yl]-3-hydroxypropanoate hydrochloride, (49) (Pyrrolidin-2-yl)methyl 6-chloro-5-cyclohexyl-1-indanecarboxylate hydrochloride,

[0177] (50) (Pyrrolidin-2-yl)methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate hydrochloride, (51) (Pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride, (52) (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, (53) (Pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate hydrochloride, (54) (Pyrrolidin-2-yl)methyl 3-2-(2,4-dichlorophenoxy)benzeneacetate hydrochloride, (55) (Pyrrolidin-2-yl)methyl 4-acetamidophenyl salicylate hydrochloride, (56) (Pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride, (57) (Pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride, (58) (Pyrrolidin-2-yl)methyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate hydrochloride, (59) (Pyrrolidin-2-yl)methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate hydrochloride, (60) (Pyrrolidin-2-yl)methyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate hydrochloride. in the manufacture of a medicament for treating the signs, symptoms, and complications of viral, bacterial, protozoal, and / or fungal infections and associated diseases selected from the group consisting of:

[0178] In some embodiments, the present disclosure provides the use of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride in the manufacture of a medicament for the treatment of signs, symptoms, and complications of H1N1 virus and other influenza virus infections. salt, (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH, (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride, (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride, or (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride is provided.

[0179] In some embodiments, the disclosure provides for the use of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carbazolyl ester ... In one embodiment, the use of (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride, pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride, or (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride is provided.

[0180] In some embodiments, the present disclosure relates to the use of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate ... The present invention provides the use of (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride, pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride, or (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride.

[0181] In some embodiments, the present disclosure provides an agent for the preparation of a medicament for the treatment of viral, bacterial, protozoal, and fungal infection-induced sepsis, comprising 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, or 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride. In one embodiment, the present invention provides for the use of (pyrrolidin-2-yl)methyl 2-[[2-[(2,6-dichlorophenyl)amino]phenyl]acetoxy]acetate hydrochloride, (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, or (pyrrolidin-2-yl)methyl dichlorophenoxy)benzeneacetate hydrochloride.

[0182] In some embodiments, the disclosure provides for the use of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride, or (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride in the manufacture of a medicament for the treatment of signs, symptoms, and complications of drug-resistant viral, bacterial, fungal, and protozoal infections.

[0183] V. Advantages Aspirin, other NSAIDs, and other anti-inflammatory drugs can cause nausea, dyspepsia, heartburn, vomiting, gastroduodenal bleeding, gastric ulcers, and gastritis. Gastroduodenal bleeding caused by NSAIDs is generally painless but can cause fecal blood loss and can lead to persistent iron deficiency anemia.

[0184] By transdermal administration, highly permeable prodrugs of aspirin, other NSAIDs, and other anti-inflammatory drugs, or compositions thereof, can deliver relatively high tissue concentrations of the drug (maximizing efficacy) while maintaining low plasma concentrations of the drug (minimizing side effects), thereby improving efficacy and reducing adverse effects compared to orally administered NSAIDs and other anti-inflammatory drugs.

[0185] Current NSAIDs and other anti-inflammatory drugs are unable to sufficiently penetrate scar tissue (fibroids) in inflamed lungs, liver, heart, respiratory system, kidneys, stomach, intestines, uterus, and other tissues to reduce inflammation in these organs and tissues. In contrast, the highly permeable prodrugs of aspirin, other NSAIDs, and other anti-inflammatory drugs disclosed herein can penetrate any biological barrier and reduce or stop inflammation in any organ or tissue. EXAMPLES

[0186] VI. Working Examples The following examples are provided to better illustrate the claimed invention and should not be interpreted as limiting the scope of the invention in any way. All specific compositions, materials, and methods described below are entirely or partially within the scope of the present invention. These specific compositions, materials, and methods are merely illustrative of specific embodiments within the scope of the present invention. Based on this disclosure, a person skilled in the art can improve equivalent compositions, materials, and methods without exercising inventive ability and without departing from the scope of the present invention. It will be understood that many variations are possible in the procedures described herein while remaining within the scope of the present invention. All such variations are within the scope of the present invention.

[0187] In certain embodiments, the following structure FC: The parent compound having the structure L-1, including stereoisomers and pharma- ceutically acceptable salts thereof, is

[0188] JPEG2025504448000032.jpg3992, where F, L1, L2, and L4 are defined as above; T is the transport unit of HPP. For example, T is selected from W and R6 as defined above.

[0189] In certain embodiments of the present invention, HPP having structure L-1 can be prepared according to organic synthesis using the structure D: JPEG2025504448000033.jpg3473 and a derivative of the parent compound (e.g., an acid halide, mixed anhydride, etc. of the parent compound) having structure E (Scheme 1): T-L2-H Structure E and Here, W C is selected from OH, halogen, alkoxycarbonyl, and substituted aryloxycarbonyloxy; and F, L1, L2, L4 and T are defined as above.

[0190] JPEG2025504448000034.jpg23162 Scheme 1. Preparation of HPP from parent compound (I)

[0191] In certain embodiments, HPP having structure L-1 is prepared according to Scheme 1 above, where L4 is C=O.

[0192] In certain embodiments, the following structure FN: The parent compound having the following structure G:

[0193] JPEG2025504448000036.jpg3659 to produce a compound having the structure L-1:

[0194] We get the HPP of JPEG2025504448000037.jpg4271, where:

[0195] F, L1, L2, and L4 are defined above; T is the transport unit of HPP. For example, T is selected from W and R6 defined above, M is selected from Na, K, or other metals. N is selected from OH, halogen, alkoxycarbonyl, and substituted aryloxycarbonyloxy (Scheme 2).

[0196] JPEG2025504448000038.jpg4595Scheme 2. Preparation of HPP from parent compound (II)

[0197] In certain embodiments, HPP having the structure of structure L-1 is prepared by organic synthesis, where undesired reactive sites such as -C(=O)OH, -NH2, -OH, or -SH are protected prior to linking the transport and functional units according to one of the synthetic routes described above. In certain embodiments, the resulting protected HPP can be further partially or fully deprotected to give partially protected HPP or unprotected HPP, respectively.

[0198] Example 1. Preparation of (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid (diclofenac, 29.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 20% citric acid (R0089, 50 g in 250 ml water) x 2, and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (85% yield).

[0199] Example 2. Preparation of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride 2-(4-isobutylphenyl)propionyl chloride (22.5 g) was dissolved in chloroform (100 ml). The mixture was cooled to 0° C. Triethylamine (15 ml) and diethylaminoethanol (11.7 g) were added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solid by-product was removed by filtration and washed with chloroform (3×30 ml). 1N HCl in ethyl acetate (100 ml) was added and the solid was collected, washed with ethyl acetate (5×50 ml) and dried in a vacuum oven at 40° C. (92% yield).

[0200] Example 3. Preparation of 2-(N,N-diethylamino)ethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate hydrochloride 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid (montelukast, 58.6 g) and 2-(N,N-diethylamino)ethanol (12 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml), and the ethyl acetate solution was evaporated to dryness. 0.5 N HCl in ethyl acetate (200 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml), and dried in a vacuum oven at 40°C (78% yield).

[0201] Example 4. Preparation of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride Acetylsalicyloyl chloride (1-(chlorocarbonyl)phenylacetate, 19.8 g) was dissolved in chloroform (100 ml). The mixture was cooled to 0° C. Trimethylamine (15 ml) and diethylaminoethanol (11.7 g) were added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solid by-product was removed by filtration and washed with chloroform (3×30 ml). The solid was collected, washed with ethyl acetate (5×50 ml) and dried in a vacuum oven at 40° C. (81% yield).

[0202] Example 5. Preparation of (RS)-N-[1-(1-benzothien-2-yl)ethyl]-N-(2-N,N-diethylaminoacetyloxy)urea hydrochloride 2-(N,N-diethylamino)acetic acid (13.1 g) and (±)-N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)urea (zileuton, 23.6 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 0.5N HCl in ethyl acetate (200 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (76% yield).

[0203] Example 6. Preparation of (pyrrolidin-2-yl)methyl 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetate hydrochloride 2-Cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid (veriflavone, 36.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (78% yield).

[0204] Example 7. Preparation of (pyrrolidin-2-yl)methyl 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoate hydrochloride 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoic acid (verlukast, 51.5 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml), and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml), and dried in a vacuum oven at 40°C (83% yield).

[0205] Example 8. Preparation of (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·AcOH Diethylaminoethanol (11.7 g, 0.1 mol) was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetyl chloride (sulindac chloride, 37.5 g, 0.1 mol) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated off. The residue was suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) was added to the reaction mixture with stirring. The ethyl acetate layer was collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. 6 g of acetic acid was added to the reaction mixture with stirring. The organic solution was evaporated off.

[0206] Example 9. Preparation of 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate hydrochloride 2-(3-phenoxyphenyl)propionyl chloride (26.1 g, 0.1 mol) was dissolved in ethyl acetate (300 ml). The mixture was cooled to 0° C. Dimethylaminoethanol (8.9 g) was added to the reaction mixture. Sodium bicarbonate (30 g) was added to the mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with water (3×200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. HCl gas (5 g) was bubbled into the mixture. The solid was collected by filtration and washed with ethyl acetate.

[0207] Example 10. Preparation of S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate hydrochloride Dimethylaminoethyl mercaptan (10.4 g, 0.1 mol) was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 2-(3-phenoxyphenyl)propionyl chloride (27.3 g, 0.1 mol) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated off. The residue was suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) was added to the reaction mixture with stirring. The ethyl acetate layer was collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. Anhydrous HCl gas (5 g) was bubbled into the reaction mixture with stirring. The solid was collected and washed with ethyl acetate.

[0208] Example 11. Preparation of 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride [2-(dipropylamino)ethyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride] 5-(2,4-Difluorophenyl)acetylsalicyl chloride (31.1 g, 0.1 ml) was dissolved in ethyl acetate (300 ml). The mixture was cooled to 0° C. Diethylaminoethanol (11.7 g, 0.1 mol) was added to the reaction mixture. Sodium bicarbonate (30 g) was then added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. Water (200 ml) was then added to the mixture. The ethyl acetate layer was collected and washed with water (3×). The solution was dried over anhydrous sodium sulfate. Anhydrous HCl gas was bubbled into the reaction mixture with stirring. The solid was collected and washed with ethyl acetate.

[0209] Example 12. Preparation of (pyrrolidin-2-yl)methyl 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoate hydrochloride 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoic acid (59.5 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml), and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml), and dried in a vacuum oven at 40°C (77% yield).

[0210] Example 13. Preparation of (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride 5-Benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid (ketorolac, 25.5 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (77% yield).

[0211] Example 14. Preparation of (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride 1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (Etodolac, 28.7 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (77% yield).

[0212] Example 15. Preparation of (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride 2-(2-Fluorobiphenyl-4-yl)propionic acid (flurbiprofen, 24.4 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (87% yield).

[0213] Example 16. Preparation of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride 2-(6-Methoxy-2-naphthyl)propionic acid (Naproxen, 23.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (91% yield).

[0214] Example 17. Preparation of (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride 2-[(2,3-Dimethylphenyl)amino]benzoic acid (mefenamic acid, 24.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (77% yield).

[0215] Example 18. Preparation of (pyrrolidin-2-yl)methyl 6-chloro-α-methylcarbazole-2-acetate hydrochloride 6-Chloro-α-methylcarbazole-2-acetic acid (Carprofen, 24.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (77% yield).

[0216] Example 19. Preparation of (pyrrolidin-2-yl)methyl 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoate hydrochloride 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutanoic acid (47.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml), and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml), and dried in a vacuum oven at 40°C (81% yield).

[0217] Example 20. Preparation of (pyrrolidin-2-yl)methyl(Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate·HCl (Z)-5-Fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetic acid (29.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (81% yield).

[0218] Example 21. Preparation of (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate·HCl 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (26.8 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (79% yield).

[0219] Example 22. Preparation of (pyrrolidin-2-yl)methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate hydrochloride 1-(4-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (29.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (85% yield).

[0220] Example 23. Preparation of (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (28.2 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (80% yield).

[0221] Example 24. Preparation of (pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate hydrochloride 3-Chloro-4-(2-propenyloxy)benzeneacetic acid (20.8 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (87% yield).

[0222] Example 25. Preparation of (pyrrolidin-2-yl)methyl 2-(4-isobutylphenyl)propanoate hydrochloride 2-(4-isobutylphenyl)propanoic acid (20.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (91% yield).

[0223] Example 26. Preparation of (pyrrolidin-2-yl)methyl 2-acetoxybenzoate hydrochloride 2-Acetoxybenzoic acid (18.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (89% yield).

[0224] Example 27. Preparation of (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride 5-(2,4-Difluorophenyl)salicylic acid (25.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (78% yield).

[0225] Example 28. Preparation of (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride 5-(2,4-Difluorophenyl)acetylsalicylic acid (29.2 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (71% yield).

[0226] Example 29. Preparation of (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride 2-(3-benzoylphenyl)propanoic acid (25.3 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (82% yield).

[0227] Example 30. Preparation of (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride 2-(3-phenoxylphenyl)propanoic acid (24.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (86% yield).

[0228] Example 31. Preparation of (pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate hydrochloride (Z)-5-Fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetic acid (35.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (83% yield).

[0229] Example 32. Preparation of (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (29.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (79% yield).

[0230] Example 33. Preparation of (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride α-Methyl-4-(2-thienylcarbonyl)benzeneacetic acid (26.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (80% yield).

[0231] Example 34. Preparation of (pyrrolidin-2-yl)methyl 6-chloro-α-methyl-9H-carbazole-2-acetate hydrochloride 6-Chloro-α-methyl-9H-carbazole-2-acetic acid (27.4 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (89% yield).

[0232] Example 35. Preparation of (pyrrolidin-2-yl)methyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazole acetate hydrochloride 2-(4-Chlorophenyl)-α-methyl-5-benzoxazole acetic acid (30.2 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (78% yield).

[0233] Example 36. Preparation of (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propionic acid (25.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (78% yield).

[0234] Example 37. Preparation of (pyrrolidin-2-yl)methyl α-methyl-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate hydrochloride α-Methyl-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (33.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (91% yield).

[0235] Example 38. Preparation of (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionic acid (25.5 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (80% yield).

[0236] Example 39. Preparation of (pyrrolidin-2-yl)methyl α-methyl-4-[(2-methyl-2-propen-1-yl)amino]benzeneacetate hydrochloride α-Methyl-4-[(2-methyl-2-propen-1-yl)amino]benzeneacetic acid (21.9 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (84% yield).

[0237] Example 40. Preparation of (pyrrolidin-2-yl)methyl 5-benzoyl-α-methyl-2-thiophene acetate hydrochloride 5-Benzoyl-α-methyl-2-thiopheneacetic acid (26.0 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (77% yield).

[0238] Example 41. Preparation of (pyrrolidin-2-yl)methyl 10,11-dihydro-α-methyl-10-oxodibenzo[b,f]thiepin-2-acetate hydrochloride 10,11-Dihydro-α-methyl-10-oxodibenzo[b,f]thiepin-2-acetic acid (29.8 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (89% yield).

[0239] Example 42. Preparation of (pyrrolidin-2-yl)methyl 2-(8-methyl-5-oxo-6H-benzo[b][1]benzoxepin-3-yl)propanoate hydrochloride 2-(8-Methyl-5-oxo-6H-benzo[b][1]benzoxepin-3-yl)propanoic acid (29.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (93% yield).

[0240] Example 43. Preparation of (pyrrolidin-2-yl)methyl 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate hydrochloride 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propionic acid (24.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (90% yield).

[0241] Example 44. Preparation of (pyrrolidin-2-yl)methyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate hydrochloride 4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetic acid (28.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2×200 ml), 2×20% citric acid (R0089, 50 g in 250 ml water), and water (3×300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (93% yield).

[0242] Example 45. Preparation of (pyrrolidin-2-yl)methyl 2-chloro-2-(3-chloro-4-cyclohexylphenyl)acetate hydrochloride 2-Chloro-2-(3-chloro-4-cyclohexylphenyl)acetic acid (28.7 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (82% yield).

[0243] Example 46. Preparation of (pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride 4,5-Diphenyl-2-oxazolepropanoic acid (29.3 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (87% yield).

[0244] Example 47. Preparation of (pyrrolidin-2-yl)methyl 3-(4-biphenylcarbonyl)propanoate hydrochloride 3-(4-Biphenylcarbonyl)propionic acid (25.4 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (81% yield).

[0245] Example 48. Preparation of (pyrrolidin-2-yl)methyl 3-[5-(4-chlorophenyl)furan-2-yl]-3-hydroxypropanoate hydrochloride 3-[5-(4-chlorophenyl)furan-2-yl]-3-hydroxypropanoic acid (26.7 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (85% yield).

[0246] Example 49. Preparation of (pyrrolidin-2-yl)methyl 6-chloro-5-cyclohexyl-1-indanecarboxylate hydrochloride 6-Chloro-5-cyclohexyl-1-indane carboxylic acid (27.9 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (85% yield).

[0247] Example 50. Preparation of (pyrrolidin-2-yl)methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate hydrochloride 1-(4-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (35.8 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (77% yield).

[0248] Example 51. Preparation of (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (25.7 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (81% yield).

[0249] Example 52. Preparation of (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (29.2 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (79% yield).

[0250] Example 53. Preparation of (pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate hydrochloride 3-Chloro-4-(2-propenyloxy)benzeneacetic acid (22.7 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (79% yield).

[0251] Example 54. Preparation of (pyrrolidin-2-yl)methyl 3-2-(2,4-dichlorophenoxy)benzeneacetate hydrochloride 3-2-(2,4-dichlorophenoxy)benzeneacetic acid (29.7 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (79% yield).

[0252] Example 55. Preparation of (pyrrolidin-2-yl)methyl 4-acetamidophenyl salicylate hydrochloride 4-Acetamidophenylsalicylic acid (27.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (79% yield).

[0253] Example 56. Preparation of (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride 2-[(2,3-Dimethylphenyl)amino]benzoic acid (24.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (81% yield).

[0254] Example 57. Preparation of (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride 2-[(2,3-Dimethylphenyl)amino]benzoic acid (24.1 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (84% yield).

[0255] Example 58. Preparation of (pyrrolidin-2-yl)methyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate hydrochloride 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (41.4 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (84% yield).

[0256] Example 59. Preparation of (pyrrolidin-2-yl)methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate hydrochloride 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid (31.8 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (74% yield).

[0257] Example 60. Preparation of (pyrrolidin-2-yl)methyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate hydrochloride 2-[[2-Methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridine carboxylic acid (29.6 g) and N-Boc-L-prolinol (tert-butoxycarbonyl-2-pyrrolidinemethanol, 20.1 g) were placed in a 1 L round bottom flask and acetone (200 ml) was added to the mixture. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 19.2 g), 4-dimethylaminopyridine (DMAP, 5 g), and 1-hydroxybenzotriazole (HOBt, 15 g) were added to the solution. The mixture was stirred overnight at room temperature. The solution was evaporated to near dryness. Ethyl acetate (500 ml) was added to the mixture. The solution was washed with water (2 x 200 ml), 2 x 20% citric acid (R0089, 50 g in 250 ml water), and water (3 x 300 ml). The solution was dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with ethyl acetate (3 x 50 ml) and the ethyl acetate solution was evaporated to dryness. 3N HCl in ethyl acetate (50 ml) was added and the mixture was stirred for 3 hours. The solid was collected, washed with ethyl acetate (5 x 50 ml) and dried in a vacuum oven at 40°C (74% yield).

[0258] Example 61. Skin permeability of HPP The skin permeation rates of most of the NSAID prodrugs have been reported in previous patents.

[0259] (Pyrrolidin-2-yl)methyl 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutanoate hydrochloride (compound-1), 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutanoic acid (parent drug-1), (Pyrrolidin-2-yl)methyl 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thio pyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoate hydrochloride (compound-2), 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (parent drug-2), (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·AcOH (compound-3), 2-(5-fluoro-2-methyl-1-(4- (Methylsulfinyl)benzylidene)-1H-inden-1-yl)acetic acid (parent drug-3), (pyrrolidin-2-yl)methyl 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoate hydrochloride (compound-4), 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropane Acid (Parent Drug-4), (Pyrrolidin-2-yl)methyl 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetate hydrochloride (Compound-5), 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid (Parent Drug-5), (RS)-N-[1-(1-benzothien-2-yl)ethyl]-N-(2-N,N-diethylaminoacetyloxy)urea hydrochloride (Compound-6), (±)-N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)urea (Parent Drug-6), 2-(N,N-diethylamino)ethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropane-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate hydrochloride (Compound-7), 2-(N,N-diethylamino)ethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropane The permeability of (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride (compound-8), and 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid (parent drug-8) through rabbit skin was measured in vitro by using modified Franz cells isolated from rabbit dorsal skin tissue (300 μm to 350 μm thick). The receptor solution, consisting of 10 ml of pure water, is shown in Table 1. These results suggest that the positive charge of the amino group plays a very important role in drug passage across the membrane and skin barrier.

[0260] Table 1. Cumulative doses of anti-inflammatory drugs over an 8-hour period JPEG2025504448000039.jpg118140

[0261] Example 62. Antipyretic activity Eighty-four Sprague Dawley rats were randomly divided into seven groups (n = 12) and fever was induced by injecting 100 μg / kg LPS (dissolved in saline, 0.2 mg / mL) into the abdomen of each rat, followed 2 h later by injection of 25% ethanol in water (group A, negative control group), ibuprofen (oral, group B, 100 mg / kg; ibuprofen was suspended in 0.5% CMC-Na at a final concentration of 20 mg / mL), 7% ibuprofen in 70% ethanol (topical, group C, 100 mg / kg), 2-(N,N-diethylamino)ethyl 2-(4-isobutyl)propanol in 25% ethanol, or 2-(N,N-diethylamino)ethyl 2-(4-isobutyl)propanol in 25% ethanol. (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)propanoate·HCl (transdermal, group D, 20 mg / kg), (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride (transdermal, group E, 20 mg / kg), (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride (transdermal, group F, 20 mg / kg), and (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride (transdermal, group G, 20 mg / kg) in 7% ethanol in 35% ethanol were administered (topical and transdermal test articles were administered to the back of the rats). The body temperature of the rats was taken 0 minutes (2 hours after challenge), 90 minutes, 180 minutes, and 270 minutes after administration of the test compounds. The results are shown in Table 2.

[0262] Table 2. Antipyretic activity of NSAIDs and related compounds JPEG2025504448000040.jpg112157

[0263] These results revealed that the prodrug exhibited potent antipyretic activity at a dose of 20 mg / kg, better than oral ibuprofen (100 mg / kg), and topical ibuprofen (100 mg / kg) showed no antipyretic activity.

[0264] Example 63. Anti-inflammatory activity Fifty Wistar rats were randomly divided into five groups (n=10). Carrageenan solution was prepared as a 1% (wt / vol) solution in 0.9% saline. Paw edema was induced by subcutaneous injection of 100 μL of carrageenan solution into the right footpad and 2 h later, the rats were administered 25% ethanol in water (G1, negative control group), ibuprofen (oral, G2, 100 mg / kg, ibuprofen suspended in 0.5% CMC-Na at a final concentration of 20 mg / mL), or 7% ibuprofen in 70% ethanol. Buprofen (topical, G3, 100 mg / kg), 7% 2-(N,N-diethylamino)ethyl 2-(4-isobutylphenyl)propanoate·HCl in 25% ethanol (transdermal, G4, 20 mg / kg), and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride (transdermal, G5, 20 mg / kg) were administered (topical and transdermal test articles were administered to the back of the rats). The rats' paw volumes were measured at 0 hours (before carrageenan challenge), 2 hours (before test article treatment), and 6 hours (4 hours after test compound administration). The results are shown in Table 3.

[0265] Table 3. Paw volume (mL) JPEG2025504448000041.jpg41165

[0266] These results revealed that the prodrug exhibited potent anti-inflammatory activity at a dose of 20 mg / kg, better than oral ibuprofen (100 mg / kg), and topical ibuprofen (100 mg / kg) showed no anti-inflammatory activity.

[0267] Example 64. Efficacy of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride and 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in treating signs, symptoms, and / or complications of H1N1 virus infection A total of one hundred and ten (110) mice were used in this study. Four (4) groups of ten (10) mice were used for the virus titration study and seven (7) groups of ten (10) mice were used for the efficacy of mitigating signs and symptoms of viral infection test article study. All mice were challenged by intranasal instillation with a lethal dose of mouse-adapted influenza A PR / 8 / 34 (H1N1) on study day 0. 10 x TCID 50 , 1x TCID per mouse 50 , 0.1 x TCID per mouse 50 or 0.01×TCID per mouse 50 A single dose of virus was administered via the nasal mucosa by pipette. For efficacy studies, mice were anesthetized with isoflurane on day 0, held in the dorsal position, and administered 0.1 × TCID per mouse. 50 of virus was administered by intranasal instillation, and mice received a single dose of various concentrations of test article or vehicle control once daily starting on day 2 post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (25% ethanol). 7% 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in 15% ethanol (low dose: 25.2 mg / kg, group 2, medium dose: 50.4 mg / kg, group 3, and high dose: 100.8 mg / kg, group 4) and 6.25% 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride in 25% ethanol (low dose: 22.5 mg / kg, group 5, medium dose: 45 mg / kg, group 6, and high dose: 90 mg / kg, group 7) and vehicle (25% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the back of the animals for high, medium, or low doses. After viral challenge, the mice were observed for clinical signs of disease, including body weight, health score, morbidity, and mortality.

[0268] mortality rate For efficacy studies, survival of Balb / c mice challenged with a lethal dose of mouse-adapted influenza A PR / 8 / 34 (H1N1) is shown as Kaplan-Meier survival curves in Figure 1. 100.8 mg / kg (high dose, group 4) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided the greatest amount of protection with 100% animal survival. As shown in FIG. 1 and Table 4, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride at both 25.2 mg / kg (low dose, Group 2) and 50.4 mg / kg (medium dose, Group 3) resulted in a 90% survival rate, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 22.5 mg / kg (low dose, Group 5) and 90 mg / kg (high dose, Group 7) resulted in a 90% survival rate, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 45 mg / kg (medium dose, Group 6, 3 deaths) resulted in a 70% survival rate, and vehicle (25% ethanol, Group 1, 5 deaths) resulted in a 50% survival rate.

[0269] Table 4. Effect of drugs on survival rate JPEG2025504448000042.jpg18161

[0270] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 5).

[0271] Table 5. Lung lesions characterized in animals JPEG2025504448000043.jpg18158

[0272] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of viral infection by 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride administered intradermally (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) on the backs of animals in a mouse model of influenza A virus infection. Results demonstrated that administration of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride protected mice from death and lung damage, delayed clinical signs of disease, and reduced its severity.

[0273] Example 65. Efficacy of (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride and (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride in treating signs, symptoms, and / or complications of H1N1 virus infection A total of seventy mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and administered 0.1 × TCID per mouse. 50of virus (fresh batch) was administered by intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 2 post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride in 35% ethanol (low dose: 25.1 mg / kg, Group 2, medium dose: 50.2 mg / kg, Group 3, and high dose: 100.3 mg / kg, Group 4) and 7% (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in 35% ethanol (low dose: 24.6 mg / kg, Group 5, medium dose: 49.2 mg / kg, Group 6, and high dose: 98.4 mg / kg, Group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0274] mortality rate As shown in Table 6, the vehicle (35% ethanol, Group 1, 9 deaths) resulted in a 10% survival rate, 25.1 mg / kg (Group 2, 8 deaths) and 50.2 mg / kg (Group 3, 8 deaths) of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride resulted in a 20% survival rate, 100.3 mg / kg (Group 4, 6 deaths) of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride resulted in a 40% survival rate, and 24.6 mg / kg (Group 5, 3 deaths) of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride resulted in a 50% survival rate. A 70% survival rate was achieved with (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 49.2 mg / kg (group 6, 4 deaths), a 60% survival rate was achieved with (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 49.2 mg / kg (group 6, 4 deaths), and a 50% survival rate was achieved with (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 98.4 mg / kg (group 7, 5 deaths).

[0275] Table 6. Effect of drugs on survival rate JPEG2025504448000044.jpg19161

[0276] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 7).

[0277] Table 7. Lung lesions characterized in animals JPEG2025504448000045.jpg18156

[0278] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of viral infection by intradermal administration (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride on the backs of animals in a mouse model of influenza A virus infection. Results demonstrated that administration of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride protected mice from death and lung damage, delayed clinical signs of disease, and reduced its severity.

[0279] Example 66. Efficacy of (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride and (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH in treating signs, symptoms, and / or complications of H1N1 virus infection A total of seventy mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and administered 0.1 × TCID per mouse. 50100 mg / kg, Group 2; Medium dose: 50.0 mg / kg, Group 3; and High dose: 100.0 mg / kg, Group 4) of 7% (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride in 35% ethanol (low dose: 25.0 mg / kg, Group 2; medium dose: 50.0 mg / kg, Group 3; and high dose: 100.0 mg / kg, Group 4) of 7% (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsuccinimide) in 35% ethanol were administered by intranasal instillation, and mice were given a single dose of various concentrations of the test article or vehicle control once a day starting on day 2 post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). (1H-inden-1-yl)-1H-indenyl (1H-indenyl) benzylidene acetate·ACOH (low dose: 25.5 mg / kg, group 5, medium dose: 50.9 mg / kg, group 6, and high dose: 101.9 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm × 5 cm, 1.5 cm × 3.5 cm, or 1 cm × 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease, including body weight, health score, morbidity, and mortality.

[0280] mortality rate As shown in Table 8, vehicle (group 1, 8 deaths) resulted in a 20% survival rate, (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride at 25.0 mg / kg (group 2, 6 deaths) resulted in a 40% survival rate, (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride at 50.0 mg / kg (group 3, 5 deaths) resulted in a 50% survival rate, (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride at 100.0 mg / kg (group 4, 4 deaths) resulted in a 60% survival rate, and (Z)-2-(N,N-diethylaminoethyl) ethyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride at 25.5 mg / kg (group 5, 4 deaths) resulted in a 50% survival rate. A 60% survival rate was achieved with (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH, a 70% survival rate was achieved with (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH at 50.9 mg / kg (group 6, 3 deaths), and a 50% survival rate was achieved with (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH at 101.9 mg / kg (group 7, 5 deaths).

[0281] Table 8. Effect of drugs on survival rate JPEG2025504448000046.jpg19163

[0282] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 9).

[0283] Table 9. Lung lesions characterized in animals JPEG2025504448000047.jpg19163

[0284] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of influenza A virus infection by intradermal administration (within an area of ​​2 cm × 5 cm, 1.5 cm × 3.5 cm, or 1 cm × 2.5 cm for high, medium, or low doses) of (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride and (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH on the animals' backs in a mouse model of influenza A virus infection. The results demonstrated that administration of (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride and (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH protected mice from death and lung damage, delayed clinical signs of disease, and reduced their severity.

[0285] Example 67. Efficacy of (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride and (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride in treating signs, symptoms, and / or complications of H1N1 viral infection A total of seventy mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and administered 0.1 × TCID per mouse. 50of virus (fresh batch) was administered by intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 2 post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride in 35% ethanol (low dose: 25.0 mg / kg, group 2, medium dose: 50.1 mg / kg, group 3, and high dose: 100.1 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 5, medium dose: 49.8 mg / kg, group 6, and high dose: 99.6 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0286] mortality rate As shown in Table 10, vehicle (group 1, 9 deaths) resulted in 10% survival, (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride at 25.0 mg / kg (group 2, 7 deaths) resulted in 30% survival, (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride at 50.1 mg / kg (group 3, 5 deaths) resulted in 50% survival, and (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride at 100.1 mg / kg (group 4, 5 deaths) resulted in 50% survival. A 50% survival rate was achieved with (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride at 24.9 mg / kg (group 5, 4 deaths), a 60% survival rate was achieved with (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride at 49.8 mg / kg (group 6, 5 deaths), and a 40% survival rate was achieved with (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride at 99.6 mg / kg (group 7, 6 deaths).

[0287] Table 10. Effect of drugs on survival rate JPEG2025504448000048.jpg18164

[0288] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 11).

[0289] Table 11. Lung lesions characterized in animals JPEG2025504448000049.jpg19165

[0290] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of viral infection by percutaneous administration (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) of (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride and (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride on the backs of animals in a mouse model of influenza A virus infection. Results demonstrated that administration of (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride and (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride protected mice from death and lung damage, delayed clinical signs of disease, and reduced its severity.

[0291] Example 68. Efficacy of (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride and (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride in treating signs, symptoms, and / or complications of H1N1 virus infection A total of seventy mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and administered 0.1 × TCID per mouse. 50of virus (fresh batch) was administered by intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 2 post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride in 35% ethanol (low dose: 25.0 mg / kg, group 2, medium dose: 49.9 mg / kg, group 3, and high dose: 99.8 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride in 35% ethanol (low dose: 24.7 mg / kg, group 5, medium dose: 49.4 mg / kg, group 6, and high dose: 98.7 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0292] mortality rate As shown in Table 12, vehicle (group 1, 8 deaths) resulted in a 20% survival rate, (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride at 25.0 mg / kg (group 2, 7 deaths) resulted in a 30% survival rate, (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride at 49.9 mg / kg (group 3, 5 deaths) resulted in a 50% survival rate, (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride at 99.8 mg / kg (group 4, 4 deaths) resulted in a 60% survival rate, and (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride at 24.7 mg / kg (group 5, 6 deaths) resulted in a 70% survival rate. A 40% survival rate was achieved with (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride at 49.4 mg / kg (group 6, 4 deaths), a 60% survival rate was achieved with (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride at 49.4 mg / kg (group 6, 4 deaths), and a 70% survival rate was achieved with (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate·ACOH(pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride at 98.7 mg / kg (group 7, 3 deaths).

[0293] Table 12. Effect of drugs on survival rate JPEG2025504448000050.jpg19163

[0294] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 13).

[0295] Table 13. Lung lesions characterized in animals JPEG2025504448000051.jpg18161

[0296] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of viral infection by percutaneous administration (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) of (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride and (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride on the backs of animals in a mouse model of influenza A virus infection. Results demonstrated that administration of (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride and (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride protected mice from death and lung damage, delayed clinical signs of disease, and reduced its severity.

[0297] Example 69. Efficacy of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in treating signs, symptoms, and / or complications of COVID-19 infection A total of one hundred and ten (110) hACE2 mice were used in this study. Four (4) groups of ten (10) mice were used for the viral titration study and seven (7) groups of ten (10) mice were used for the efficacy of test article study in mitigating signs and symptoms of COVID-19 viral infection. All mice were challenged with a lethal dose of mouse-adapted Covid-19 by intranasal instillation on study day 0. A total of 5.5 x 10 mice per mouse were used in the viral titration study. 4 PFU, 5.5 × 10 per mouse 3 PFU, 5.5 × 10 per mouse 2A single dose of COVID-19 was administered via the nasal mucosa by pipette at 100 PFU or 5.5×10 PFU per mouse. In efficacy studies, mice were anesthetized with isoflurane on day 0, held in dorsal rump position and administered 3×10 PFU per mouse by intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 1 post-challenge through day 15. Group 1 served as the infection control group and was treated with vehicle (25% ethanol). 7% 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in 25% ethanol (low dose: 25.2 mg / kg, group 2, medium dose: 50.4 mg / kg, group 3, and high dose: 100.8 mg / kg, group 4) and 6.25% (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in 25% ethanol (low dose: 22.5 mg / kg, group 5, medium dose: 45 mg / kg, group 6, and high dose: 90 mg / kg, group 7) and vehicle (25% ethanol) were administered intradermally to the animals' backs in an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0298] mortality rate For efficacy studies, the survival rates of hACE2 mice challenged with a lethal dose of mouse-adapted COVID-19 are shown in Table 14. As shown in Table 14, 100.8 mg / kg (high dose, group 4, 1 death) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided the greatest amount of protection with 90% animal survival, 25.2 mg / kg (low dose, group 2, 6 deaths) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided 40% survival, 50.4 mg / kg (medium dose, group 3, 3 deaths) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided 70% survival, and 22.5 mg / kg (low dose, group 5, 3 deaths) of (pyrrolidin-2-yl)benzoate hydrochloride provided 50% survival. (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 45 mg / kg (medium dose, group 6, 4 deaths) resulted in a 70% survival rate, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 45 mg / kg (medium dose, group 6, 4 deaths) resulted in a 60% survival rate, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 90 mg / kg (high dose, group 7, 6 deaths) resulted in a 40% survival rate, and vehicle (25% ethanol, group 1, 9 deaths) resulted in a 10% survival rate.

[0299] Table 14. Effect of drugs on survival rate JPEG2025504448000052.jpg18163

[0300] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 15).

[0301] Table 15. Lung lesions characterized in animals JPEG2025504448000053.jpg22159

[0302] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of COVID-19 infection by 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride administered intradermally (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) on the backs of animals in a mouse model of COVID-19 infection. Results demonstrated that administration of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride protected mice from death and lung damage, delayed clinical signs of disease, and reduced its severity.

[0303] Example 70. Efficacy of 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride in treating signs, symptoms, and / or complications of COVID-19 infection A total of seventy hACE2 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in dorsal position, and challenged with 3x10 PFU of COVID-19 per mouse via intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 1 postchallenge through day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride in 35% ethanol (low dose: 25.1 mg / kg, Group 2, medium dose: 50.2 mg / kg, Group 3, and high dose: 100.3 mg / kg, Group 4) and 7% 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride in 35% ethanol (low dose: 24.6 mg / kg, Group 5, medium dose: 49.2 mg / kg, Group 6, and high dose: 98.4 mg / kg, Group 7) and vehicle (35% ethanol) were administered intradermally to the animals within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on their backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0304] mortality rate As shown in Table 16, vehicle (35% ethanol, Group 1, 9 deaths) resulted in 10% survival, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride at 25.1 mg / kg (Group 2, 7 deaths) resulted in 30% survival, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride at 50.2 mg / kg (Group 3, 5 deaths) resulted in 50% survival, and (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride at 100.3 mg / kg (Group 4, 5 deaths) resulted in 50% survival. A 50% survival rate was achieved with 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, a 60% survival rate was achieved with 24.6 mg / kg (group 5, 4 deaths), a 50% survival rate was achieved with 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 49.2 mg / kg (group 6, 5 deaths), and a 50% survival rate was achieved with 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 98.4 mg / kg (group 7, 2 deaths due to signs and symptoms of ARDS).

[0305] Table 16. Effect of drugs on survival rate JPEG2025504448000054.jpg19163

[0306] Characterization of pulmonary infection Pulmonary lesions and peribronchiolitis were characterized in all dead and surviving animals (Table 17).

[0307] Table 17. Lung lesions characterized in animals JPEG2025504448000055.jpg19158

[0308] conclusion The aim of this study was to evaluate the mitigation of signs, symptoms, and / or complications of COVID-19 infection by (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride administered intradermally (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) on the backs of animals in a mouse model of COVID-19 infection. The results demonstrated that administration of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride protected hACE2 mice from death and lung damage, delayed clinical signs of disease, and reduced its severity.

[0309] Example 71. Efficacy of (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride and (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride in treating signs, symptoms, and / or complications of COVID-19 infection A total of seventy hACE2 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in dorsal position, and challenged with 3x10 PFU of COVID-19 per mouse via intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 1 postchallenge through day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2; medium dose: 49.9 mg / kg, group 3; and high dose: 99.7 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydro-1H-pyrrolidine-1-carboxylate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2; medium dose: 49.9 mg / kg, group 3; and high dose: 99.7 mg / kg, group 4). Lahydropyrano[3,4-b]indole-1-acetate hydrochloride (low dose: 24.7 mg / kg, group 5, medium dose: 49.4 mg / kg, group 6, and high dose: 98.9 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally to animals within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on their backs at high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease, including weight, health score, morbidity, and mortality.

[0310] Example 72. Efficacy of (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride in treating signs, symptoms, and / or complications of COVID-19 infection A total of seventy hACE2 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in dorsal position, and challenged with 3x10 PFU of COVID-19 per mouse via intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 1 postchallenge through day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2; medium dose: 49.9 mg / kg, group 3; and high dose: 99.8 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyranoyl)propanoate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2; medium dose: 49.9 mg / kg, group 3; and high dose: 99.8 mg / kg, group 4). [2,3-b]pyridin-7-yl)propionate hydrochloride (low dose: 24.9 mg / kg, group 5, medium dose: 49.8 mg / kg, group 6, and high dose: 99.7 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the back of the animals at high, medium, or low doses. After viral challenge, the mice were observed for clinical signs of disease, including body weight, health score, morbidity, and mortality.

[0311] Example 73. Efficacy of (pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride in treating signs, symptoms, and / or complications of COVID-19 infection A total of seventy hACE2 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in dorsal position, and challenged with 3x10 PFU of COVID-19 per mouse via intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting on day 1 postchallenge through day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride in 35% ethanol (low dose: 24.7 mg / kg, group 2, medium dose: 49.4 mg / kg, group 3, and high dose: 98.7 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 5, medium dose: 49.9 mg / kg, group 6, and high dose: 99.7 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0312] Example 74. Efficacy of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in cecal slurry-induced sepsis A total of one hundred (100) C57 / BL6 mice were used in this study. Five (5) groups of six (6) mice were used for the cecal slurry titration study and seven (7) groups of ten (10) mice were used for the efficacy of alleviating signs and symptoms of cecal slurry-induced sepsis test article study. All mice were challenged with cecal slurry by intraperitoneal (IP) injection on study day 0. In the titration study, each mouse received an intraperitoneal (IP) injection with cecal slurry at a dose of 5 mg per mouse, 7.5 mg per mouse, 10 mg per mouse, 12.5 mg per mouse, or 15 mg per mouse. In the efficacy study, mice were anesthetized with isoflurane on day 0, held in the dorsal position and administered 10 mg of cecal slurry per mouse via intraperitoneal (IP) injection, and were given a single dose of various concentrations of test article or vehicle control once daily starting 2 hours post-challenge through day 15. Group 1 served as the infection control group and was treated with vehicle (25% ethanol). 7% 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in 25% ethanol (low dose: 25.2 mg / kg, group 2, medium dose: 50.4 mg / kg, group 3, and high dose: 100.8 mg / kg, group 4) and 6.25% (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in 25% ethanol (low dose: 22.5 mg / kg, group 5, medium dose: 45 mg / kg, group 6, and high dose: 90 mg / kg, group 7) and vehicle (25% ethanol) were administered intradermally to the animals' backs in an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0313] mortality rate Survival rates of C57 / BL6 mice challenged with cecal slurry for efficacy studies. As shown in Table 18, 100.8 mg / kg (high dose, group 4) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided the greatest amount of protection with 80% animal survival, 25.2 mg / kg (low dose, group 2) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided 40% survival, 50.4 mg / kg (medium dose, group 3) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided 60% survival, and 22.5 mg / kg (low dose, group 5) of (pyrrolidinediamine) hydrochloride provided 50% survival. (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 45 mg / kg (medium dose, group 6) and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 45 mg / kg (medium dose, group 6) resulted in a 70% survival rate, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 90 mg / kg (high dose, group 7) resulted in a 50% survival rate, and vehicle (25% ethanol, group 1) resulted in a 0% survival rate.

[0314] Table 18. Effect of drugs on survival rate JPEG2025504448000056.jpg18164

[0315] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of cecal slurry-induced sepsis by 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride administered percutaneously (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) on the backs of animals in a mouse model of cecal slurry-induced sepsis. Results demonstrated that administration of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride protected mice from death and delayed and reduced the severity of clinical signs of disease.

[0316] Example 75. Efficacy of (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride in cecal slurry-induced sepsis A total of seventy C57 / BL6 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane and held in the dorsal breech position and administered 10 mg of cecal slurry per mouse via intraperitoneal (IP) injection, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting 2 hours post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride in 35% ethanol (low dose: 25.1 mg / kg, group 2, medium dose: 50.2 mg / kg, group 3, and high dose: 100.3 mg / kg, group 4) and 7% 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride in 35% ethanol (low dose: 24.6 mg / kg, group 5, medium dose: 49.2 mg / kg, group 6, and high dose: 98.4 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally to the animals within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on their backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0317] mortality rate As shown in Table 19, vehicle (35% ethanol, Group 1) resulted in 0% survival, (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride at 25.1 mg / kg (Group 2) resulted in 10% survival, (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride at 50.2 mg / kg (Group 3) resulted in 30% survival, and (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride at 100.3 mg / kg (Group 4) resulted in 20% survival. propionate hydrochloride resulted in a 40% survival rate, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 24.6 mg / kg (group 5) resulted in a 50% survival rate, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 49.2 mg / kg (group 6) resulted in a 50% survival rate, and 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propanoate hydrochloride at 98.4 mg / kg (group 7) resulted in a 40% survival rate.

[0318] Table 19. Effect of drugs on survival rate JPEG2025504448000057.jpg18165

[0319] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of cecal slurry-induced sepsis by percutaneous administration (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) of (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride and 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propanoate hydrochloride on the backs of animals in a mouse model of cecal slurry-induced sepsis. Results demonstrated that administration of (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride and 2-(diethylamino)ethyl 2-(p-isobutylphenyl)propanoate hydrochloride protected C57 / BL6 mice from death and delayed and reduced the severity of clinical signs of disease.

[0320] Example 76. Efficacy of (pyrrolidin-2-yl)methyl 2-[[2-[(2,6-dichlorophenyl)amino]phenyl]acetoxy]acetate hydrochloride and (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride in cecal slurry-induced sepsis A total of seventy C57 / BL6 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and administered 10 mg of cecal slurry per mouse by intranasal instillation, and mice were given a single dose of various concentrations of test article or vehicle control once daily starting 2 hours post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-[[2-[(2,6-dichlorophenyl)amino]phenyl]acetoxy]acetate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2, medium dose: 49.9 mg / kg, group 3, and high dose: 99.7 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride in 35% ethanol (low dose: 24.7 mg / kg, group 5, medium dose: 49.4 mg / kg, group 6, and high dose: 98.9 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0321] Example 77. Efficacy of (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride and (pyrrolidin-2-yl)methyl dichlorophenoxy)benzeneacetate hydrochloride in cecal slurry-induced sepsis A total of seventy C57 / BL6 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position and administered 1 gm / kg of cecal slurry by intranasal instillation, and given a single dose of various concentrations of test article or vehicle control once daily starting 2 hours post-challenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2, medium dose: 49.9 mg / kg, group 3, and high dose: 99.7 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl dichlorophenoxy)benzene acetate hydrochloride in 35% ethanol (low dose: 24.7 mg / kg, group 5, medium dose: 49.4 mg / kg, group 6, and high dose: 98.9 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on the animals' backs for high, medium, or low doses. After viral challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0322] Example 78. Efficacy of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in a sepsis model of MRSA infection A total of one hundred (100) C57 / BL6 mice were used in this study. Six (6) groups of five (5) mice were used for the Methicillin-Resistant S. aureus strain NRS71 (Sangar 252) titration study, and seven (7) groups of ten (10) mice were used for the efficacy of test article study in alleviating signs and symptoms of a sepsis model of MRSA infection. All mice were challenged with the Methicillin-Resistant S. aureus strain NRS71 (Sangar 252) by intraperitoneal (IP) injection on study day 0. In the titration study, 4 x 10 6CFU of S. aureus, 2 × 10 7 CFU of S. aureus, 1 × 10 8 CFU of S. aureus, 5 × 10 8 CFU of S. aureus, 1 × 10 9 CFU of S. aureus, and 2 × 10 9 Each mouse was given an intraperitoneal (IP) injection of 2 × 10 CFU of S. aureus. For efficacy studies, on day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and injected with 2 × 10 7 CFU of S. aureus were administered by intraperitoneal (IP) injection, and mice received a single dose of various concentrations of test article or vehicle control once daily starting 2 hours postchallenge until day 15. Group 1 served as the infection control group and was treated with vehicle (25% ethanol). 7% 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in 25% ethanol (low dose: 25.2 mg / kg, group 2, medium dose: 50.4 mg / kg, group 3, and high dose: 100.8 mg / kg, group 4) and 6.25% (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride in 25% ethanol (low dose: 22.5 mg / kg, group 5, medium dose: 45 mg / kg, group 6, and high dose: 90 mg / kg, group 7) and vehicle (25% ethanol) were administered intradermally to the animals' backs in an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses. After MRSA challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0323] mortality rate For efficacy studies, survival rates of MRSA-challenged C57 / BL6 mice are shown in Table 20. As shown in Table 20, 100.8 mg / kg (high dose, group 4) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided the greatest amount of protection with 50% of animals survival, 25.2 mg / kg (low dose, group 2) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided 20% survival, 50.4 mg / kg (medium dose, group 3) of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride provided 30% survival, and 22.5 mg / kg (low dose, group 5) of (pyrrolidin-2-yl)methyl benzoate hydrochloride provided 40% survival. methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 45 mg / kg (medium dose, group 6) resulted in a 40% survival rate, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 45 mg / kg (medium dose, group 6) resulted in a 60% survival rate, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride at 90 mg / kg (high dose, group 7) resulted in a 50% survival rate, and vehicle (25% ethanol, group 1) resulted in a 0% survival rate.

[0324] Table 20. Effect of drugs on survival rate JPEG2025504448000058.jpg18164

[0325] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of MRSA-induced sepsis by 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride administered percutaneously (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) on the backs of animals in a mouse model of MRSA-induced sepsis. Results demonstrated that administration of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride and (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride protected mice from death and delayed and reduced the severity of clinical signs of disease.

[0326] Example 79. Efficacy of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride in a sepsis model of MRSA infection A total of seventy C57 / BL6 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and injected with 2 × 10 7CFU of S. aureus were administered by intraperitoneal (IP) injection, and mice received a single dose of various concentrations of test article or vehicle control once daily starting 2 hours postchallenge until day 15. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride in 35% ethanol (low dose: 25.1 mg / kg, Group 2, medium dose: 50.2 mg / kg, Group 3, and high dose: 100.3 mg / kg, Group 4) and 7% 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride in 35% ethanol (low dose: 24.6 mg / kg, Group 5, medium dose: 49.2 mg / kg, Group 6, and high dose: 98.4 mg / kg, Group 7) and vehicle (35% ethanol) were administered intradermally to the animals within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on their backs for high, medium, or low doses. After MRSA challenge, mice were observed for clinical signs of disease including body weight, health score, morbidity, and mortality.

[0327] mortality rate As shown in Table 21, vehicle (35% ethanol, Group 1) resulted in 0% survival, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride at 25.1 mg / kg (Group 2) resulted in 20% survival, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride at 50.2 mg / kg (Group 3) resulted in 30% survival, and (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride at 100.3 mg / kg (Group 4) resulted in 30% survival. 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 24.6 mg / kg (group 5) resulted in a 40% survival rate, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 49.2 mg / kg (group 6) resulted in a 60% survival rate, and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride at 98.4 mg / kg (group 7) resulted in a 50% survival rate.

[0328] Table 21. Effect of drugs on survival rate JPEG2025504448000059.jpg18165

[0329] conclusion The objective of this study was to evaluate the mitigation of signs, symptoms, and / or complications of MRSA-induced sepsis by percutaneous administration of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride on the backs of animals (within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm for high, medium, or low doses) in a mouse model of MRSA-induced sepsis. Results demonstrated that administration of (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride protected C57 / BL6 mice from death and delayed and reduced the severity of clinical signs of disease.

[0330] Example 80. Efficacy of (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride and (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride in a sepsis model of MRSA infection A total of seventy C57 / BL6 mice (seven groups, 10 per group) were used in this study. On day 0, mice were anesthetized with isoflurane, held in the dorsal breech position, and injected with 2 × 10 7 CFU of S. aureus were administered by intranasal instillation, and mice were given a single dose of various concentrations of the test article or vehicle control once daily starting 2 hours post-challenge until day 15, starting at 2 hours post-challenge. Group 1 served as the infection control group and was treated with vehicle (35% ethanol). 7% (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2; medium dose: 49.9 mg / kg, group 3; and high dose: 99.7 mg / kg, group 4) and 7% (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydro-1H-pyrrolidine-1-carboxylate hydrochloride in 35% ethanol (low dose: 24.9 mg / kg, group 2; medium dose: 49.9 mg / kg, group 3; and high dose: 99.7 mg / kg, group 4) were administered. Lahydropyrano[3,4-b]indole-1-acetate hydrochloride (low dose: 24.7 mg / kg, group 5, medium dose: 49.4 mg / kg, group 6, and high dose: 98.9 mg / kg, group 7) and vehicle (35% ethanol) were administered intradermally to animals within an area of ​​2 cm x 5 cm, 1.5 cm x 3.5 cm, or 1 cm x 2.5 cm on their backs at high, medium, or low doses. After MRSA challenge, mice were observed for clinical signs of disease, including weight, health score, morbidity, and mortality.

[0331] Example 81. Efficacy of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study in the treatment of COVID-19 infection in hospitalized adults Patients cannot be enrolled or randomized until all eligibility criteria (including laboratory results) have been confirmed.

[0332] Inclusion Criteria: 1. Hospitalized with pulmonary symptoms of active COVID-19. 2. The patient (or legally authorized representative) has provided informed consent prior to initiating any study procedures. 3. The patient (or legally authorized representative) understands and agrees to comply with the planned study procedures. 4. Males aged 18 years or older or non-pregnant adult females at the time of enrollment.

[0333] 5. Laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (COVID-19) infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (not serology) in any specimen, as documented by any of the following: a. Laboratory-confirmed COVID-19 infection by a method defined above in a sample collected within 72 hours prior to randomization; or b. Laboratory-confirmed COVID-19 infection by the methods defined above in a sample collected ≥72 hours prior to randomization that has documented inability to obtain a repeat sample (e.g., due to a shortage of testing supplies, limited testing capacity, results taking >24 hours, etc.) AND progressive illness suggestive of ongoing COVID-19 infection.

[0334] 6. Room air SpO2 < 93% with an ordinal scale score of 4 (hospitalization, oxygen by mask or nasal cannula) or room air SpO2 < 93% with an ordinal scale score of 5 (hospitalization, noninvasive ventilation or high-flow oxygen) or an ordinal scale score of 6 (hospitalization, intubation and mechanical ventilation). The ordinal scale scores are as follows: 0) Not infected, no clinical or virological evidence of infection 1) Ambulatory (undiagnosed), no activity limitations 2) Ambulatory (undiagnosed), activity limited and / or requiring home oxygen 3) Diagnosed (mild illness), not requiring supplemental oxygen 4) Diagnosed (moderate illness), requiring supplemental oxygen (via mask or nasal cannula), and requiring ongoing medical care (COVID-19 related or otherwise) 5) Diagnosed (severe disease), non-invasive ventilation or high-flow oxygen 6) Diagnosed (severe illness), intubated and mechanically ventilated 7) Diagnosed (severe disease), ventilation + additional organ support - vasopressors, RRT, or extracorporeal membrane oxygenation (ECMO) 8) Death.

[0335] 7. Women and men of childbearing potential must agree to either abstain from sex from the time of screening until day 37 or use at least one primary form of contraception that does not involve hormonal contraception (e.g., double barrier methods (use of condoms, sponges, diaphragms, spermicidal jelly or cream), same-sex partners, and surgically sterilized patients / partners (≥6 months post-sterilization) are acceptable). 8. Agree not to participate in any new interventional clinical studies until Day 60 (or 30 days after the last dose of investigational drug). However, antivirals or other drugs approved or authorized by the U.S. Food and Drug Administration (FDA) may be permitted, and this should be determined by the patient's physician.

[0336] Exclusion criteria: 1. Any condition or reason, including the presence of any significant medical or neuropsychiatric condition, including the presence of laboratory abnormalities, including local or regional requirements for eligibility for clinical research, that in the Investigator's judgment would place the patient at unacceptable risk if he or she were to participate in the study, violate local or regional laws / requirements, or impair the ability to interpret data from the study, including but not limited to the following: A platelet count of 50 x 10 per liter 9Less than one. b. Not meeting local or regional requirements for eligibility to participate in clinical research.

[0337] 2. Requirement of extracorporeal membrane oxygenation at baseline. 3. Stage 4 or greater chronic kidney disease or end-stage renal disease (ESRD). 4. High risk of hemorrhagic events (e.g., recent cerebral hemorrhage, gastrointestinal hemorrhage, severe trauma, recent surgery, or organ biopsy). 5. Currently using antiplatelet agents (e.g., aspirin). 6. Pregnant (patient has a positive pregnancy test at screening) or breastfeeding. 7. Patients are expected to be discharged or transferred to a hospital other than the research site. 8. Allergy to any investigational drug or known allergy to nonsteroidal anti-inflammatory drugs, including aspirin. 9. To be eligible to participate in the PK substudy, patients must agree to refrain from taking oral aspirin or any orally administered acetylsalicylic acid medications until PK sampling is complete.

[0338] Efficacy Endpoints: Primary Efficacy Endpoints: Difference in length of hospital stay between the study arm and the control arm. Key Secondary Endpoints: The amount of time a patient can maintain a peripheral capillary oxygen saturation (SpO2) greater than 93% without supplemental oxygen. Other secondary endpoints: 1. The time it takes to improve one category using a 9-point ordinal scale. 2.Time to improve two categories using a 9-point ordinal scale.

[0339] Dosage regimen: A 7% solution of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride in 15% ethanol was used as the drug of the invention, and the vehicle (15% ethanol) was used as placebo. Each patient or their caregiver should administer medication as directed by study personnel. For patients not in prone position, administration on either the front or back of the patient is acceptable. The administration site should be documented in each patient's source documents and eCRF. If administering medication on the back, instructions for prone patients will be followed. If administering IP on the front, instructions for non-prone patients will be followed.

[0340] For a prone patient, the drug would be administered as follows: Low-dose group: 1 spray to the skin at the back of the neck, 1 spray to the skin on the left side of the neck, 1 spray to the skin on the right side of the neck, and 9 sprays to the skin on the back around the lungs (12 sprays total, 84 mg) applied twice daily for 28 days for a total of 24 sprays (168 mg) per day. High dose group: 2 sprays to the skin at the back of the neck, 1 spray to the skin on the left side of the neck, 1 spray to the skin on the right side of the neck, and 20 sprays to the skin on the back (total of 24 sprays, 168 mg) applied twice daily for 28 days for a total of 48 sprays (336 mg) per day.

[0341] For patients not in the prone position, the drug would be administered as follows: Low-dose group: 1 spray to the skin on the front of the neck, 1 spray to the skin on the left side of the neck, 1 spray to the skin on the right side of the neck, and 9 sprays to the skin on the chest around the lungs (12 sprays total, 84 mg) applied twice daily for 28 days for a total of 24 sprays (168 mg) per day. High dose group: 2 sprays applied to the skin on the front of the neck, 1 spray to the skin on the left side of the neck, 1 spray to the skin on the right side of the neck, and 20 sprays to the skin on the chest (total of 24 sprays, 168 mg) twice daily for 28 days for a total of 48 sprays (336 mg) per day.

[0342] Efficacy Results: Patients treated with the drug of the present invention had a mean hospital stay of about 4 days and a mean age of 65.5 years. Patients treated with placebo had a mean hospital stay of about 8 days and a mean age of 64.1 years. Some patients treated with placebo were unable to meet the discharge criteria on the 29th day.

[0343] Patients treated with the drug of the present invention took an average of about 3 days to maintain a peripheral capillary oxygen saturation (SpO2) above 93% without supplemental oxygen. Patients treated with placebo took an average of about 8 days to maintain a peripheral capillary oxygen saturation (SpO2) above 93% without supplemental oxygen. Some patients treated with placebo still required supplemental oxygen on the 29th day.

[0344] Patients treated with the drug of the invention took an average of about 3 days to achieve a 2-category improvement using a 9-point ordinal scale, while patients treated with a placebo took an average of about 8 days to achieve a 2-category improvement using a 9-point ordinal scale.

Claims

1. 1. A compound of structure L-1, capable of penetrating one or more biological barriers for the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections, or related pathologies: 【Chemistry 1】 (In the formula, F as a functional unit is a molecular portion of an active pharmaceutical ingredient (i.e., a parent drug molecule) selected from a 5-lipoxygenase-activating protein (FLAP) inhibitor, a 5-lipoxygenase inhibitor, a leukotriene receptor antagonist, and an anti-inflammatory agent; T as a transport unit is a basic group containing a protonatable nitrogen, L １ , L ２ , and L ４ together form a linker, such that the compound of structure L-1 can be hydrolyzed or metabolized under physiological conditions to release functional unit F and form the active pharmaceutical ingredient (i.e., the parent drug molecule) or a biologically active metabolite thereof. or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. L １ is a bond, O, S, -N(L ３ ) -, -N(L ３ )-CH ２ -O, -N(L ３ )-CH ２ -N(L ３ ) -, -O-CH ２ -O-, -O-CH(L ３ )-O, -S-CH(L ３ )-O-; L ２ is a bond, O, S, -N(L ３ ) -, -N(L ３ )-CH ２ -O, -N(L ３ )-CH ２ -N(L ３ ) -, -O-CH ２ -O-, -O-CH(L ３ )-O, -S-CH(L ３ ) -O-, -O-L ５ -, -N-L ５ -, -SL ５ -, and -N(L ３ )-L ５ - is selected from, L ４ is a bond, C=O, C=S, 【Chemistry 2】 is selected from Each L ３ are independently H or C １ ~C ６ is alkyl, Each L ５ are independently a bond, CH ２ COOL ６ , substituted or unsubstituted C １ ~C ６ Alkylene, substituted or unsubstituted C ３ ~C ６ Cycloalkylene, substituted and unsubstituted 5- to 10-membered heterocycloalkylene, substituted and unsubstituted C ６ ~C １０ arylene, and substituted and unsubstituted 5- to 10-membered heteroarylene, wherein L ６ is a bond or a substituted or unsubstituted C １ ~C ６ is alkylene, 2. The therapeutic HPP or its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein said structure L-1 forms a stable compound without violating the principle of covalent bonding.

3. The linker L １ -L ４ -L ２ - is jointly -O-X-X ５ -, -NH-X-X ５ -, -S-X-X ５ -, -OC(=O)-X ５ -, -NH-C(=O)-X ５ -, -S-C(=O)-X-X ５ -, -C(=O)-O-X-X ５ -, -C(=O)-SX, -C(=O)-NH-X-, -XX ５ -C(=O), -C(=O)X ５ -X-, -X ５ -C(=O), and C(=O)-X ５ - is selected from, X is a bond, C(=O), or C １ ~C ４ alkylene, and X ５ is a bond, C(=O), C １ ~C ４ Alkylene, S, O, and NR ５ and R ５ is H or C １ ~C ６ 2. The therapeutic HPP of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

4. The linker (L １ , L ２ , and L ４ (jointly) are C(=O)-O, C(=O)-S, C(=O)-NH, C(=O)-O-CH(L ５ )-O, C(=O)-O-CH(L ５ )-S, C(=O)-O-CH(L ５ )-NH, C(=O)-S-CH(L ５ )-O, C(=O)-S-CH(L ５ )-S, C(=O)-S-CH(L ５ )-NH, P(=O)(-OL ５ )-O, O-P(=O)(-OL ５ ), C(=S)-O, C(=NH)-O, C(=NH)-S, C(=N-OL ３ )-NH, C(=NH-OL ３ )-O, C(=NH-OL ３ )-S, O-C(=O), S-C(=O), NH-C(=O), O-CH(L ５ )-OC(=O), S-CH(L ５ )-OC(=O), O-CH(L ５ )-S-C(=O), S-CH(L ５ )-S-C(=O), O-CH(L ５ )-NH-C(=O), OC(=S), OC(=N-OL ３ ), S-C (=N-OL ３ ), and NH-C(=N-OL ３ ), wherein L ３ and L ５ is independently selected at each occurrence from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, and substituted and unsubstituted alkylamino, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. 2. The therapeutic HPP of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein T is a substituted or unsubstituted primary amine, a substituted or unsubstituted secondary amine, a substituted or unsubstituted tertiary amine, or a heterocyclyl group containing a protonatable nitrogen in the ring.

6. T is structure W-1, structure W-2, structure W-3, structure W-4, structure W-5, and structure W-6: 【Transformation 3】 is selected from R, at each occurrence, is independently selected from a bond, substituted and unsubstituted alkylene, substituted and unsubstituted cycloalkylene, and substituted and unsubstituted heterocyclylene; R １ and R ２ are independently H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocyclyl, or alternatively, R １ and R ２ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, optionally further containing one or two additional heteroatoms independently selected from O, S, and N; R １１ , R １２ , and R １３ each independently represents a bond, an optionally substituted C １ ~C ４ alkylene, or optionally substituted C ２ ~C ４ alkenylene, wherein said alkylene and said alkenylene are optionally O, S, or NR ３ One CH replaced by ２ having a group, Here, the R in Structure W-2, Structure W-3, or Structure W-5 １ Any of the adjacent R １１ can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring, which can optionally further contain one or two additional heteroatoms independently selected from O, S, and N; Here, the R in Structure W-2, Structure W-4, Structure W-5, or Structure W-6 １１ and the above R １２ Or the R １１ and the above R １３ can be optionally connected by an optionally substituted alkylene bridge; wherein HA is either empty or a pharmaceutically acceptable acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid; 2. The therapeutic HPP or its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein said structure L-1 forms a stable compound without violating the principle of covalent bonding.

7. R is a bond or C １ ~C ６ 7. The therapeutic HPP of claim 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is alkylene.

8. R １１ , R １２ , and R １３ are each independently CH ２ , C.H. ２ CH ２ , CH=CH, CH ２ CH ２ CH ２ , CH=CHCH ２ , C.H. ２ CH ２ CH ２ CH ２ , C.H. ２ CH=CH-CH ２ , C.H. ２ CH ２ CH ２ CH ２ CH ２ , C.H. ２ CH ２ CH ２ CH ２ CH ２ CH ２ 7. The therapeutic HPP of claim 6, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from:

9. The transport unit T is of structure W-1, where R １ and R ２ are hydrogen or C １ ~C ６ 7. The therapeutic HPP of claim 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

10. The transport unit T is Structure W-2, Structure W-3, Structure W-4, Structure W-5, or Structure W-6, where R is a bond or C １ ~C ４ alkylene, and R １ is hydrogen or C １ ~C ６ alkyl, and R １１ is C １ ~C ４ alkylene, and R １２ and R １３ are independently a bond, CH ２ , or CH ２ CH ２ 7. The therapeutic HPP of claim 6, wherein:

11. 2. The therapeutic HPP or its stereoisomer or pharmaceutically acceptable salt thereof of claim 1, wherein the transport unit T is a heterocyclyl selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is protonated with hydrochloride, hydrobromide, or acetic acid.

12. The HPPs include those having the following structures: Structure LRA-1, Structure LRA-2, Structure LRA-3, Structure LRA-4, Structure LRA-5, Structure LRA-6, Structure ARA-1, Structure ARA-2, Structure ARA-3, Structure ARA-4, Structure ARA-5, Structure ARA-6, Structure ARA-7, Structure ARA-8, Structure ARA-9, Structure ARA-10, Structure ARA-11, Structure ARA-12, Structure ARA-13, Structure ARA-14, Structure 5-LI-1, Structure 5-LI-2, Structure 5-LI-3, Structure 5-LI-4, Structure 5-LI-5, Structure 5-LI-6, Structure 5-LI-7, Structure 5-LI-8, Structure FLAP-1, Structure FLAP-2, Structure FLAP-3, Structure FLAP-4, Structure FLAP-5, Structure FLAP-6, Structure NSAID-1, Structure NSAID-2, Structure NSAID -3, Structure NSAID-4, Structure NSAID-5, Structure NSAID-6, Structure NSAID-7, Structure NSAID-8, Structure NSAID-9, Structure NSAID-10, Structure NSAID-11, Structure NSAID-12, and Structure NSAID-13: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 and stereoisomers thereof and pharmaceutically acceptable salts thereof; Here, aryl- means aryl-1, aryl-2, aryl-3, aryl-4, aryl-5, aryl-6, aryl-7, aryl-8, aryl-9, aryl-10, aryl-11, aryl-12, aryl-13, aryl-14, aryl-15, aryl-16, aryl-17, aryl-18, aryl-19, aryl-20, aryl-21, aryl-22, aryl-23, aryl-24, aryl-25, aryl-26, aryl-27, aryl-28, aryl-29, aryl-30, aryl-31, aryl-32, aryl-33, aryl-34, aryl-35, aryl -36, aryl-37, aryl-38, aryl-39, aryl-40, aryl-41, aryl-42, aryl-43, aryl-44, aryl-45, aryl-46, aryl-47, aryl-48, aryl-49, aryl-50, aryl-51, aryl-52, aryl-53, aryl-54, aryl-55, aryl-56, aryl-57, aryl-58, aryl-59, aryl-60, aryl-61, aryl-62, aryl-63, aryl-64, aryl-65, aryl-66, aryl-67, aryl-68, aryl-69, aryl-70, and aryl-71: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 a molecular moiety of an anti-inflammatory drug or anti-inflammatory drug-related compound selected from where: L １ is a bond, O, S, -N(L ３ ) -, -N(L ３ )-CH ２ -O, -N(L ３ )-CH ２ -N(L ５ ) -, -O-CH ２ -O-, -O-CH(L ３ )—O, and —S—CH(L ３ )-O-; L ４ is C=O, C=S, 【Chemistry 28】 or L １ and L ４ together represent C(=O)-O, C(=O)-S, C(=O)-NH, C(=O)-O-CH(L ３ )-O, C(=O)-O-CH(L ３ )-S, C(=O)-O-CH(L ３ )-NH, C(=O)-S-CH(L ３ )-O, C(=O)-S-CH(L ３ )-S, C(=O)-S-CH(L ３ )-NH, P(=O)(-O-L ３ )-O, O-P(=O)(-O-L ３ ), C(=S)-O, C(=NH)-O, C(=NH)-S, C(=N-OL ３ )-NH, C(=NH-OL ３ )-O, C(=NH-OL ３ )-S, O-C(=O), S-C(=O), NH-C(=O), O-CH(L ３ )-O-C(=O), S-CH(L ３ )-O-C(=O), O-CH(L ３ )-S-C(=O), S-CH(L ３ )-S-C(=O), O-CH(L ３ )-NH-C(=O), O-C(=S), O-C(=N-OL ３ ), S-C(=N-OL ３ ), and NH-C(=N-OL ３ ) and are selected from Here, each L ３ are independently H or C １ ~C ６ alkyl, and Each L ５ are independently a bond, CH ２ COOL ６ , substituted or unsubstituted C １ ~C ６ Alkylene, substituted or unsubstituted C ３ ~C ６ Cycloalkylene, substituted and unsubstituted 5- to 10-membered heterocycloalkylene, substituted and unsubstituted C ６ ~C １０ arylene, and substituted and unsubstituted 5- to 10-membered heteroarylene, wherein L ６ is a bond or a substituted or unsubstituted C １ ~C ６ is alkylene, T is structure W-1, structure W-2, structure W-3, structure W-4, structure W-5, and structure W-6: 【Chemistry 29】 is selected from R, at each occurrence, is independently selected from a bond, substituted and unsubstituted alkylene, substituted and unsubstituted cycloalkylene, and substituted and unsubstituted heterocyclylene; R １ and R ２ are independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocyclyl, or alternatively, R １ and R ２ taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl, which optionally further contains one or two additional heteroatoms independently selected from O, S, and N; R １１ , R １２ , and R １３ each independently represents a bond, an optionally substituted C １ ~C ４ alkylene, or optionally substituted C ２ ~C ４ alkenylene, wherein the alkylene and the alkenylene are O, S, or NR ３ one CH optionally replaced by ２ having a group, Here, the R in Structure W-2, Structure W-3, or Structure W-5 １ Any of the adjacent R １１ can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring, which can optionally further contain one or two additional heteroatoms independently selected from O, S, and N; Here, the R in Structure W-2, Structure W-4, Structure W-5, or Structure W-6 １１ and the above R １２ Or the R １１ and the above R １３ can be optionally connected by an optionally substituted alkylene bridge; wherein HA is either empty or a pharmaceutically acceptable acid, optionally selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid; X ５ , X ６ , X ７ , and X ８ are independently a bond, C(=O), C(=S), OC(=O), OC(=S), CH ２ , CH, S, O, and NR ５ is selected from Y, Y １ 、Y ２ 、Y ３ 、Y ４ 、Y ５ 、Y ６ 、Y ７ 、及びY ８ は、独立して、H、OH、OW、OC(=O)W、L １ -L ４ -L ２ -W、OC(=O)CH ３ 、CH ３ 、C ２ H ５ 、C ３ H ７ 、C ４ H ９ 、R ６ 、SO ３ R ６ 、CH ２ OR ６ 、CH ２ OC(=O)R ６ 、CH ２ C(=O)OR ８ 、OCH ３ 、OC ２ H ５ 、OR ６ 、CH ３ SO ２ 、R ６ SO ２ 、CH ３ SO ３ 、R ６ SO ３ 、NO ２ 、CN、CF ３ 、OCF ３ 、CH ２ (CH ２ ) ｎ NHR ５ R ６ 、CH ２ (CH ２ ) ｎ OR ６ 、CH(C(=O)NH ２ )NHR ６ 、CH ２ C(=O)NH ２ 、F、Br、I、Cl、CH=CHC(=O)NHCH ２ C(=O)OW、CH=CHC(=O)NHCH ２ L １ -L ４ -L ２ -W, NR ８ C(=0)R ５ SO ２ NR ５ R ８ 、C(=O)R ５ SR ５ R ６ OOCH(NHR) ７ (CH) ２ ) ｎ C(=O)NH-、R ６ OOCH(NHR) ７ (CH) ２ ) ｎ SC(=O)NH-、CF ３ SCH ２ C(=O)NH-、CF ３ CH ２ C(=0)NH-, CHF ２ SCH ２ C(=0)NH-,CH ２ FSC ２ C(=0)NH-,NH ２ C(=O)CHFS-CH ２ C(=O)NH-、R ７ NHCH(C(=O)OW)CH ２ SCH ２ C(=O)NH-、R ７ NHCH(L) １ -L ４ -L ２ -W)CH ２ SCH ２ C(=0)NH-, CNCH ２ SCH ２ C(=0)NH-,CH ３ (CH) ２ ) ｎ C(=O)NH-、R ７ N&CHNR ７ CH ２ CH ２ S-R ７ N=C(NHR) ７ )NHC(=O)-、R ７ N=C(NHR) ７ )NHCC(=O)CH ２ CH ３ C(Cl)=CHCH ２ SCH ２ C(=O)NH-, (CH ３ ) ２ C (OR ６ ) -, CNCH ２ C(=O)NH-, CNCH ２ CH ２ S-, R ７ HN=CH(NR ７ ) CH ２ CH ２ S-, CH ２ =CHCH ２ SCH ２ C(=O)NH-, CH ３ CH(OH)-, CH ３ CH (OR ８ ) -, CH ３ CH (Y １ ) -, (CH ３ ) ２ CH-, CH ３ CH ２ -, CH ３ (CH ２ ) ｎ CH=CH(CH ２ ) ｍ C(═O)NH—, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, and substituted and unsubstituted alkylcarbonyl; R ５ are independently H, C(=O)NH ２ , C.H. ２ CH ２ OR ６ , C.H. ２ CH ２ N (CH ３ ) ２ , C.H. ２ CH ２ N (CH ２ CH ３ ) ２ , Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, -C(=O)-W, L １ -L ４ -L ２ -W and W, R ６ are independently substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted cycloalkyloxyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, -C(=O)-W, -L １ -L ４ -L ２ -W and W, R ７ are independently H, F, Cl, Br, I, CH ３ NHC(=O)CH ２ CH (NHR ８ ) C(=O), R ５ N=C(NHR ６ )NHC(=O)-,C(=O)CH ３ , C(=O)R ６ , PO(OR ５ ) OR ６ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted alkylamino, L １ -L ４ -L ２ -W, and C-(=O)-W; R ８ is independently H, F, Cl, Br, I, CH ３ , C ２ H ５ , CF ３ , CH ２ CH ２ , CH ２ CH ２ , CH ２ CH ２ , CH ２ CH ２ , CH ２ , CHF ２ , CH ２ , CF ３ , CH ２ , F, CH ２ , Cl, CH ２ , Br, CH ２ , I, CH ２ , NR ６ R ７ , CH(NHR ７ ), CH ２ , C(=O)NH ２ , C ３ H ７ , C ４ H ９ , C ５ H １１ , R ６ , C(=O)R ６ , C(=O)NH ２ , CH ２ , C(=O)NH ２ , CH ２ , OC(=O)NH ２ , PO(OR ５ ), OR ６ , C(CH ３ ), ２ , C(=O)OR ６ , CH(CH ３ ), C(=O)OR ６ , CH ２ , C(=O)OR ６ , C(=O)-W, and L １ -L ４ -L ２ selected from -W, L ２ are independently a bond, O, S, -N(L ３ ) -, -N(L ３ )-CH ２ -O, -N(L ３ )-CH ２ -N(L ３ ) -, -O-CH ２ -O-, -O-CH(L ３ )-O, -S-CH(L ３ ) -O-, -O-L ５ -, -SL ５ -, and -N(L ３ )-L ５ - selected from, and W is selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5, and Structure W-6; 2. The therapeutic HPP of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the defined HPP forms a stable compound without violating any principles of covalent bonding.

13. The HPP is (1) (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate, (2) 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate, (3) 2-(N,N-diethylamino)ethyl 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate, (4) 2-(diethylamino)ethyl acetoxybenzoate, (5) (RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-N,N-diethylaminoacetyloxy)urea, (6) (pyrrolidin-2-yl)methyl 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetate, (7) (pyrrolidin-2-yl)methyl 3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoate, (8) (Z)-2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate, (9) 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propionate, (10) S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl)propanethioate, (11) 2-(dipropylamino)ethyl 4-acetoxy-2',4'-difluoro-[1,1'-biphenyl]-3-carboxylate hydrochloride [2-(dipropylamino)ethyl 5-(2,4-difluorophenyl)acetylsalicylate, (12) (pyrrolidin-2-yl)methyl 3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoate, (13) (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate, (14) (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate, (15) (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate, (16) (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate, (17) (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate, (18) (pyrrolidin-2-yl)methyl 6-chloro-α-methylcarbazole-2-acetate, (19) (pyrrolidin-2-yl)methyl 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoate, (20) (pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate, (21) (Pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate, (22) (pyrrolidin-2-yl)methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate, (23) (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate, (24) (pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate, (25) (pyrrolidin-2-yl)methyl 2-(4-isobutylphenyl)propanoate, (26) (pyrrolidin-2-yl)methyl 2-acetoxybenzoate, (27) (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate, (28) (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate, (29) (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate, (30) (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride, (31) (pyrrolidin-2-yl)methyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate, (32) (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate, (33) (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate, (34) (pyrrolidin-2-yl)methyl 6-chloro-α-methyl-9H-carbazole-2-acetate, (35) (pyrrolidin-2-yl)methyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazole acetate, (36) (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate, (37) (Pyrrolidin-2-yl)methyl α-methyl-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate, (38) (Pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate, (39) (pyrrolidin-2-yl)methyl α-methyl-4-[(2-methyl-2-propen-1-yl)amino]benzeneacetate, (40) (pyrrolidin-2-yl)methyl 5-benzoyl-α-methyl-2-thiophene acetate, (41) (pyrrolidin-2-yl)methyl 10,11-dihydro-α-methyl-10-oxodibenzo[b,f]thiepine-2-acetate, (42) (pyrrolidin-2-yl)methyl 2-(8-methyl-5-oxo-6H-benzo[b][1]benzoxepin-3-yl)propanoate, (43) (pyrrolidin-2-yl)methyl 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate, (44) (Pyrrolidin-2-yl)methyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate, (45) (pyrrolidin-2-yl)methyl 2-chloro-2-(3-chloro-4-cyclohexylphenyl)acetate, (46) (pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate, (47) (pyrrolidin-2-yl)methyl 3-(4-biphenylcarbonyl)propanoate, (48) (pyrrolidin-2-yl)methyl 3-[5-(4-chlorophenyl)furan-2-yl]-3-hydroxypropanoate, (49) (pyrrolidin-2-yl)methyl 6-chloro-5-cyclohexyl-1-indancarboxylate hydrochloride, (50) (Pyrrolidin-2-yl)methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate, (51) (Pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate, (52) (Pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate, (53) (pyrrolidin-2-yl)methyl 3-chloro-4-(2-propenyloxy)benzeneacetate, (54) (pyrrolidin-2-yl)methyl 3-2-(2,4-dichlorophenoxy)benzeneacetate, (55) (pyrrolidin-2-yl)methyl 4-acetamidophenyl salicylate, (56) (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate, (57) (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate, (58) (Pyrrolidin-2-yl)methyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate, (59) (pyrrolidin-2-yl)methyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate, (60) (Pyrrolidin-2-yl)methyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate, and stereoisomers and pharmaceutically acceptable salts thereof, 2. The therapeutic HPP of claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from:

14. 14. The use of HPP or its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein HA is hydrochloric acid (HCl).

15. 14. A pharmaceutical composition comprising the highly permeable prodrug (HPP) of any one of claims 1 to 13, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections, or related pathologies.

16. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable carrier is selected from alcohol, acetone, esters, cellulose, mannitol, croscarmellose sodium, vegetable oils, hydroxypropyl methylcellulose, water, and aqueous solutions, and the pharmaceutical composition is a transdermal composition.

17. (1) The viral infection is caused by an influenza virus, including an RNA virus, a DNA virus, influenza virus type A, influenza virus type B, influenza virus type C, and influenza virus type D, or a coronavirus, wherein the influenza virus is (a) H1N1, H1N2, H1N7, H2N2, H2N3, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N6, H5N8, H (b) a human influenza virus selected from H1N1, H1N8, H2N9, H3N8, H3N2, H4N6, H4N3, H5N4, H5N8, H5N9, H5N1, H6N2, H6N1, H6N5, H7N1, H7N2, H7N3, H7N4, H7N9, H7N7, H8N4, H9N2, H10N7, H10N8, H10N3, H11N2, H11N9, H12N5, H13N6, H17N10, and H18N11; (b) avian influenza A viruses selected from H1N1, H1N2, H2N1, H3N2, and H2N3; (c) swine influenza A viruses selected from H1N1, H1N2, H2N1, H3N2, and H2N3; (d) equine influenza viruses selected from H3N8 and H7N7; and (e) canine influenza viruses selected from H3N2, H3N8, and H5N1. Influenza virus, or (f) a feline influenza virus selected from feline herpesvirus, feline calicivirus, Bordetella bronchiseptica, and Chlamydophila felis, wherein the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-1, SARS-CoV-2 (Covid-19), 229E, NL63, OC43, HKU1, MERS-CoV, and original SARS-CoV; (2) The bacterial infection is caused by a gram-positive bacterium, a gram-negative bacterium, or a pathogenic bacterium, wherein the pathogenic bacterium is selected from tuberculosis, streptococcus, syphilis, staphylococcus, aspergillus, tetanus, vibrio cholerae, salmonella, clostridium botulinum, and escherichia coli; (3) The protozoan infection is caused by a pathogenic protozoan that causes disease in humans or animals, and the pathogenic protozoan is selected from the group consisting of Entamoeba histolytica (Amoebozoa), Acanthamoeba (Amoebozoa), Giardia lamblia (Metamonas), Trichomonas vaginalis (Metamonas), Dientamoeba fragilis (Metamonas), Trypanosoma brucei (Kinetoplastidae), and Trichomonas erythrorhizae. selected from Panosoma cruzi (Kinetoplastida), Leishmania species (Kinetoplastida), Balantidium coli (Ciliata), Plasmodium species (Apicomplexida), Toxoplasma gondii (Apicomplexida), Babesia species (Apicomplexida), Cryptosporidium species (Apicomplexida), and Cyclospora caetanensis (Apicomplexida); (4) the signs or symptoms are selected from fatigue, loss of appetite, weight loss, fever, night sweats, chills, aches, inflammation, cough, shortness of breath, pain, runny nose, and combinations thereof; and (5) The pharmaceutical composition of claim 15, wherein the complication is selected from pneumonia, acute respiratory distress syndrome, chronic obstructive pulmonary disease, blood clots (clotting), meningitis, encephalitis, cardiovascular disease, stroke, heart attack, sepsis, and inflammation of the brain, lungs, kidneys, liver, pancreas, digestive system, blood vessels, and other tissues, and combinations thereof.

18. 19. A method for treating signs, symptoms, and / or complications of a viral, bacterial, protozoan, and / or fungal infection, or related condition, comprising administering to a subject in need thereof a therapeutically effective amount of the highly permeable prodrug of any one of claims 1 to 13, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, wherein the subject does not include a human.

19. 14. Use of HPP or its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of signs, symptoms, and / or complications of viral, bacterial, protozoal, and / or fungal infections.

20. (1) 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-fluorobiphenyl-4-yl)propanoate hydrochloride, (Z) -2-(N,N-diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate.ACOH, (pyrrolidin-2-yl)methyl 2-[(2,3-dimethylphenyl)amino]benzoate hydrochloride, (pyrrolidin-2-yl)methyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)salicylate hydrochloride, or (pyrrolidin-2-yl)methyl 5-(2,4-difluorophenyl)acetylsalicylate hydrochloride, (2) 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride, in the manufacture of a medicament for the treatment of signs, symptoms, and complications of COVID-19 infection and other coronavirus infections. use of (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propanoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride, pyrrolidin-2-yl)methyl 4,5-diphenyl-2-oxazolepropanoate hydrochloride, or (pyrrolidin-2-yl)methyl 2-(3-benzoylphenyl)propionate hydrochloride; (3) In the manufacture of a medicament for the treatment of sepsis induced by viral infection, bacterial infection, protozoan infection, and / or fungal infection, 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride, (pyrrolidin-2-yl)methyl salicylsalicylate hydrochloride, (pyrrolidin-2-yl)methyl salicylsalicylate hydrochloride, use of (pyrrolidin-2-yl)methyl 2-[[2-[(2,6-dichlorophenyl)amino]phenyl]acetoxy]acetate hydrochloride, (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, or (pyrrolidin-2-yl)methyl dichlorophenoxy)benzeneacetate hydrochloride; (4) 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(3-phenoxyphenyl)propionate hydrochloride, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate hydrochloride in the manufacture of a medicament for the treatment of sepsis induced by a drug-resistant viral infection, a drug-resistant bacterial infection, a drug-resistant protozoan infection, and / or a drug-resistant fungal infection. panoate hydrochloride, (pyrrolidin-2-yl)methyl 2-[[2-[(2,6-dichlorophenyl)amino]phenyl]acetoxy]acetate hydrochloride, (pyrrolidin-2-yl)methyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate hydrochloride, (pyrrolidin-2-yl)methyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate hydrochloride, or (pyrrolidin-2-yl)methyldichlorophenoxy)benzeneacetate hydrochloride, and (5) Use of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride, (pyrrolidin-2-yl)methyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate hydrochloride, (pyrrolidin-2-yl)methyl 2-(6-methoxy-2-naphthyl)propanoate hydrochloride, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propanoate hydrochloride, (pyrrolidin-2-yl)methyl 5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylate hydrochloride, or (pyrrolidin-2-yl)methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetate hydrochloride in the manufacture of a medicament for treating the signs, symptoms, and complications of methicillin-resistant Staphylococcus aureus (MRSA) infection.

20. The use according to claim 19, wherein the compound is selected from the group consisting of:

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