Compounds for the treatment of SARS

Abstract

Bisamide inhibitors of SARS-CoV-2 (COVID), pharmaceutical compositions comprising the bisamide inhibitors, and methods of treating severe acute respiratory syndrome are provided.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 008,289, filed Apr. 10, 2020, and U.S. Provisional Patent Application No. 63 / 120,068, filed Dec. 1, 2020, which are hereby incorporated by reference in their entirety.

[0002] Description of U.S. Government Support This invention was made with government support under grant AI150466 awarded by the National Institutes of Health. The government has certain rights in the invention.

Background Art

[0003] Background Coronaviruses (CoVs) are enveloped viruses with positive - sense single - stranded RNA and are associated with various natural hosts. CoVs are divided into the α, β, γ, and δ groups, and the β group further consists of subgroups A, B, C, and D. Among these, six CoVs can infect humans (HCoVs), including HCoV - 229E (229E) and HCoV - NL63 (NL63) in the α group, HCoV - OC43 (OC43) and HCoV - HKU1 (HKU1) in β subgroup A, severe acute respiratory syndrome CoV (SARS - CoV) in β subgroup B, and Middle East respiratory syndrome CoV (MERS - CoV) in β subgroup C.

[0004] In this century, SARS-CoV and MERS-CoV have emerged in humans, causing severe lung diseases with alarmingly high fatality rates. In 2002, SARS-CoV infection first appeared in China and then rapidly spread as a global epidemic across more than 30 countries, with 8,273 infected individuals and 775 deaths (almost a 10% mortality rate). In 2012, MERS-CoV occurred in Saudi Arabia and spread throughout the Middle East. In 2015, a second major outbreak of MERS-CoV occurred in South Korea, resulting in an unusually large number of infection transmissions with third and fourth generation cases. As of August 2018, the World Health Organization reported 2,229 laboratory-confirmed cases of MERS-CoV infection, including 791 deaths in 27 countries (a mortality rate of approximately 35%) (available at who.int / emergencies / mers-cov / en / on the World Wide Web). On the other hand, the remaining common HCoVs such as 229E, OC43, and NL63 usually infect the human upper respiratory tract and cause colds, but they can also cause severe and even fatal diseases in children, the elderly, and immunocompromised patients. These situations suggest that these common HCoVs may also pose a lethal threat to humans. It should be noted that HCoVs mutate rapidly. Continuously identified OC43 isolates with novel genomes have been reported.

[0005] The ongoing major outbreak of coronavirus disease 2019 (COVID-19) originated in China in December 2019 and became a global pandemic by March 2020. COVID-19 is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two other coronaviruses, namely SARS-CoV (2002 - 2003) and Middle East respiratory syndrome coronavirus (MERS-CoV) (2012 - present), have caused global major outbreaks in the past two decades. Currently, there is no treatment for COVID-19. Therefore, the development of drugs that can inhibit SARS-CoV-2 will address an urgent unmet medical need.

Summary of the Invention

[0006] Summary The present disclosure relates to a compound of formula (I): G 1 -L-G 2 or a pharmaceutically acceptable salt thereof, wherein, G 1 is a monocyclic aromatic heterocyclyl group; L is a linker; and G 2 is a bicyclic aromatic heterocyclyl group; wherein the compound is not the compound of formula: TIFF0007711088000001.tif25128.

[0007] The present disclosure also relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds and a pharmaceutically acceptable carrier.

[0008] The present disclosure also relates to a method for treating severe acute respiratory syndrome, the method comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds or a pharmaceutical composition comprising the same. [The present invention 1001] Formula (I): G 1 -L-G 2 is a compound of, wherein, G 1 is a monocyclic aromatic heterocyclyl group; L is a linker; and G 2 is a bicyclic aromatic heterocyclyl group; here, the compound is not a compound of the formula: TIFF0007711088000002.tif25128 the compound, or a pharmaceutically acceptable salt thereof. [The present invention 1002] The compound of formula (I) is a compound of formula (II): or a pharmaceutically acceptable salt thereof, TIFF0007711088000003.tif26128 wherein, is alkyl, acyl, acylalkyl, acylalkenyl, -C(O)O-, -C(O)NR-, or -S(C=NR)alkyl; L 1 are each independently alkyl, acyl, CH, CR, CR X 1 、X 2 、X 3 、X 4 , -alkyl-N(R)-, N, O, -S(O) 2 -, and -alkyl-S(O) x -, where x is 0, 1, or 2; x between and X X 1 and between X 3 and X 2 the bonds can be, if necessary, a single bond or a double bond; 3 R, R , and R 1 are the same or different and are alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocycle, alkoxy, amino, halo, haloalkyl, C(O)NR 2 , or C(O)OR; 2 each R is independently H or alkyl; and each n is independently an integer from 0 to 2, the compound of the present invention 1001. [The present invention 1003] The compound of formula (I) is a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein X TIFF0007711088000004.tif19128 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl, the compound of the present invention 1002. 5 [The present invention 1004] is N, the compound of the present invention 1001. X 4 [The present invention 1005] is N and X X 4 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl, the compound of the present invention 1001. 5 [The present invention 1006] Formula: or a pharmaceutically acceptable salt thereof, the compound of the present invention 1001. TIFF0007711088000005.tif82128 [The present invention 1007] Formula: or a pharmaceutically acceptable salt thereof, the compound of the present invention 1001. TIFF0007711088000006.tif190128 [The present invention 1008] Formula: or a pharmaceutically acceptable salt thereof, the compound of the present invention 1001. TIFF0007711088000007.tif183132TIFF0007711088000008.tif202105TIFF0007711088000009.tif97137 [The present invention 1009] Formula: or a pharmaceutically acceptable salt thereof, the compound of the present invention 1001. TIFF0007711088000010.tif28128 [The present invention 1010] Formula: or a pharmaceutically acceptable salt thereof, the compound of the present invention 1001. TIFF0007711088000011.tif33145 [The present invention 1011] Formula: or a pharmaceutically acceptable salt thereof, the compound of the present invention 1001. TIFF0007711088000012.tif25128 [The present invention 1012] Formula: ​ TIFF0007711088000013.tif19128 The compound of the present invention 1001, or a pharmaceutically acceptable salt thereof. [The present invention 1013] Formula: TIFF0007711088000014.tif22128 The compound of the present invention 1001, or a pharmaceutically acceptable salt thereof. [The present invention 1014] A pharmaceutical composition comprising one or more of the compounds of the present invention 1001 to 1013 in a therapeutically effective amount and at least one pharmaceutically acceptable carrier. [The present invention 1015] A method for treating severe acute respiratory syndrome, comprising the step of administering to a patient in need thereof one or more of the compounds of the present invention 1001 to 1013 in a therapeutically effective amount or the pharmaceutical composition of the present invention 1014, whereby the patient is treated for severe acute respiratory syndrome. [The present invention 1016] The method of the present invention 1015, wherein the severe acute respiratory syndrome is COVID-19.

Brief Description of the Drawings

[0009] [Figure 1] This is a fluorescence micrograph showing that in TMPRSS2-overexpressing Vero-E6 cells, GRL-0920S and remdesivir almost completely block the infectivity and cytotoxic activity of SARS-CoV-2. [Figure 2] This is a micrograph of SARS-CoV-2-infected Vero-E6 cells treated with GRL-0820S and GRL-0920S.

Modes for Carrying Out the Invention

[0010] Description The concepts of the present disclosure are shown and described in detail in the drawings and description herein, but the results in the drawings and their descriptions should be considered illustrative rather than limiting the features; it is understood that only exemplary embodiments are shown and described and that protection is desired for all changes and modifications that fall within the spirit of the present disclosure.

[0011] The present disclosure relates to compounds that inhibit SARS-CoV-2. The compounds are useful for the treatment of severe acute respiratory diseases.

[0012] Compound The present disclosure relates to a compound of formula (I): G 1 -L 1 -G 2 or a pharmaceutically acceptable salt thereof, wherein, G 1 is a monocyclic or bicyclic aromatic heterocyclyl group; L 1 is a linker; and G 2is a bicyclic aromatic heterocyclyl group; The compound is not the compound of TIFF0007711088000015.tif25128.

[0013] Examples of the compound of formula (I) include those in which at least one of G 1 and G 2 contains at least one nitrogen atom. Another example of the compound of formula (I) includes those in which G 1 and G 2 each contain one nitrogen atom. Still another example of the compound of formula (I) includes formula (II), (IIa), and (IIb): the compound of TIFF0007711088000016.tif81128 or a pharmaceutically acceptable salt thereof, wherein L 1 is alkyl, acyl (e.g., acylalkyl or acylalkenyl), -C(O)O-, -C(O)NR-, or -S(C=NR)alkyl; X 1 , X 2 , X 3 , X 4 are each independently alkyl, acyl (e.g., -C(O)- and -alkyl-C(O)-), -CH, CR, CR2, -alkyl-N(R)-, N, O, -S(O) x -, or -alkyl-S(O) x -, where x is 0, 1, or 2; the bond between X 1 and X 3 and the bond between X 2 and X 3 can be a single bond or a double bond as necessary; R, R 1 , and R 2 are the same or different (e.g., R, R 1 , and R 2all may be different or at least two of them may be different), each being any suitable substituent such as alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocycle, alkoxy (e.g., -OCH3 and haloalkoxy, -OCF3), amino (including alkoxyamino), halo, haloalkyl (e.g., CF3), C(O)NR2, or C(O)OR (where each R is independently H or alkyl), or two adjacent R 1 groups together with the carbon atom to which they are attached form an aryl or heterocyclyl group; and each n is independently an integer from 0 to 2.

[0014] In all the examples presented herein, each R 2 is on the aryl ring, on the ring containing X 1 ~X 3 or on both the aryl ring and the ring containing X 1 ~X 3 may be present.

[0015] Examples of the compounds of formula (I) include formulae (III), (IIIa), and (IIIb): TIFF0007711088000017.tif49128 compounds or their pharmaceutically acceptable salts, wherein X 1 ~X 4 , R 1 , R 2 , and n are as defined herein, and X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl (e.g., CHF, CF2, and CHCl). For example, X 4 is N. In another example, X 4 is N and X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl (e.g., CHF, CF2, and CHCl). In all the examples presented herein, the linker -X 5 -C(O)- is shown in the indicated direction or the opposite direction (e.g., -C(O)-X5 - Here, -C(O)- can be attached to a ring having X 4 .

[0016] Examples of the compounds of formula (I) include compounds of the formula: TIFF0007711088000018.tif82128 or their pharmaceutically acceptable salts, wherein X 1 ~X 4 , R 1 , R 2 , and n are each defined herein, and X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl (e.g., CHF, CF2, and CHCl). For example, X 1 is N or NH. For example, X 4 is N or NH. In another example, X 1 is NH, X 4 is N, X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl (e.g., CHF, CF2, and CHCl).

[0017] Examples of the compounds of formula (I) include compounds of the formula: TIFF0007711088000019.tif170131 or their pharmaceutically acceptable salts, wherein X 1 ~X 4 , R 1 , R 2 , and n are each defined herein, and X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl (e.g., CHF, CF2, and CHCl). For example, X 4 is N. In another example, X 4 is N, X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl (e.g., CHF, CF2, and CHCl).

[0018] Examples of the compounds of formula (I) include compounds of the formula: TIFF0007711088000020.tif123130TIFF0007711088000021.tif204133TIFF0007711088000022.tif206132TIFF0007711088000023.tif64128 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0019] Examples of the compounds of formula (I) are of the formula: TIFF0007711088000024.tif28128 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0020] Examples of the compounds of formula (I) are of the formula: TIFF0007711088000025.tif33141 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0021] Examples of the compounds of formula (I) are of the formula: TIFF0007711088000026.tif26128 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0022] Examples of the compounds of formula (I) are of the formula: TIFF0007711088000027.tif20128 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0023] Examples of the compounds of formula (I) are of the formula: TIFF0007711088000028.tif23128 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0024] Other compounds contemplated herein are of the formula: TIFF0007711088000029.tif29128 compounds, for example, of the formula: TIFF0007711088000030.tif30128 also includes the compounds or their pharmaceutically acceptable salts thereof.

[0025] Treatment methods The present disclosure relates to a method for treating severe acute respiratory syndrome, the method comprising administering to a patient in need thereof a therapeutically effective amount of any one of said compounds or a pharmaceutical composition comprising the same.

[0026] Severe acute respiratory syndrome (SARS) is a viral disease caused by the SARS-related coronavirus.

[0027] Severe acute respiratory syndrome can be due to coronavirus infection. The coronavirus can be COVID-19.

[0028] Accordingly, the present disclosure provides a method for treating a disease or disorder associated with SARS-CoV-2, the method comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound or a pharmaceutical composition comprising the same.

[0029] Pharmaceutical composition, route of administration, and dosage A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier is provided. The pharmaceutical composition can comprise a plurality of compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition can comprise a pharmaceutically acceptable salt of the compound.

[0030] The pharmaceutical composition can further comprise at least one additional pharmaceutically active agent. The at least one additional pharmaceutically active agent can be an agent useful for the treatment of ischemia-reperfusion injury.

[0031] The pharmaceutical composition can be prepared by combining one or more compounds with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutically active agents.

[0032] As described above, "effective amount" refers to any amount sufficient to achieve the desired biological effect. In combination with the teachings provided herein, by selecting from among various active compounds and important factors such as potency, relative bioavailability, patient body weight, severity of adverse side effects, and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned that is effective in treating a particular subject without causing substantial undesirable toxicity. The effective amount for any particular use can vary depending on factors such as the disease or condition being treated, the particular compound being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can determine the effective amount of a particular compound and / or other therapeutic substance experimentally without undue experimentation. The maximum dose, i.e., the highest safe dose as determined by some medical judgment, may be used. Multiple doses per day may be contemplated to achieve an appropriate systemic level of the compound. The appropriate systemic level can be determined, for example, by measuring the peak or sustained plasma level of the drug in the patient. "Dose" and "dosage" are used interchangeably herein. As used herein, "dosage unit form" refers to physically discrete units suitable as a single dosage for the mammalian subject being treated, each unit containing a predetermined quantity of the active compound calculated to provide the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for each dosage unit form of the invention is determined by and directly dependent on the unique properties of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in the art of compounding such active compounds for the treatment of sensitivity in individuals. In the therapeutic use for the treatment of conditions in mammals (e.g., humans) in which the compounds of the various aspects described herein or their suitable pharmaceutical compositions are effective, the compounds of the various aspects described herein may be administered in an effective amount. The dosage suitable for the present invention may be the composition, pharmaceutical composition, or any other composition described herein.

[0033] Generally, the oral dosage of the compound for human subjects is about 0.01 milligrams / kg / day to 1000 milligrams / kg / day. For once or multiple administrations per day, an oral dosage in the range of 0.5 to 50 milligrams / kg can result in therapeutic outcomes. The dosage may be appropriately adjusted to achieve the desired local or systemic drug level depending on the administration mode. For example, intravenous administration may vary from one digit to several digits lower in dosage per day. If the response in the subject is insufficient at such dosages, higher dosages (or more effective higher dosages via another more local delivery route) may be employed within the tolerance of the patient. Multiple dosages per day are contemplated to achieve an appropriate systemic level of the compound.

[0034] For any compound, the therapeutically effective amount can first be determined from animal models. The therapeutically effective dosage can also be determined from human data for compounds tested in humans and for compounds known to exhibit similar pharmacological activities such as other related active agents. Higher dosages may be required for parenteral administration. The dosage applied can be adjusted based on the relative bioavailability and potency of the compound administered. As is well known in the art, it is well within the ability of one of ordinary skill in the art to adjust the dosage to achieve maximum efficacy based on the methods described above and other methods.

[0035] For clinical use, any compound can be administered in an amount equal to or corresponding to 0.2 to 2,000 milligrams (mg) of the compound per kilogram (kg) of the subject's body weight per day. The compound can be administered in an amount equal to or corresponding to 2 to 2,000 mg of the compound per kg of the subject's body weight per day. The compound can be administered in an amount equal to or corresponding to 20 to 2,000 mg of the compound per kg of the subject's body weight per day. The compound can be administered in an amount equal to or corresponding to 50 to 2,000 mg of the compound per kg of the subject's body weight per day. The compound can be administered in an amount equal to or corresponding to 100 to 2,000 mg of the compound per kg of the subject's body weight per day. The compound can be administered in an amount equal to or corresponding to 200 to 2,000 mg of the compound per kg of the subject's body weight per day. When administering a precursor or prodrug of the compound, it is administered in an amount corresponding to the above amounts of the compound, i.e., in an amount sufficient to deliver it.

[0036] The formulation of the compound can be administered to a human subject in a therapeutically effective amount. A typical dosage range is from about 0.01 microgram / kg to about 2 mg / kg body weight per day. The dosage of the drug administered may vary depending on variables such as the type and degree of the disorder, the overall health of the particular subject, the specific compound being administered, the excipients used to formulate the compound, and the route of administration. The dosage and frequency of administration of any particular compound may be optimized using routine experimentation.

[0037] The compound can be administered at a concentration in the range of about 0.001 micrograms / kg to more than about 500 mg / kg. For example, the concentration can be 0.001 micrograms / kg, 0.01 micrograms / kg, 0.05 micrograms / kg, 0.1 micrograms / kg, 0.5 micrograms / kg, 1.0 micrograms / kg, 10.0 micrograms / kg, 50.0 micrograms / kg, 100.0 micrograms / kg, 500 micrograms / kg, 1.0 mg / kg, 5.0 mg / kg, 10.0 mg / kg, 15.0 mg / kg, 20.0 mg / kg, 25.0 mg / kg, 30.0 mg / kg, 35.0 mg / kg, 40.0 mg / kg, 45.0 mg / kg, 50.0 mg / kg, 60.0 mg / kg, 70.0 mg / kg, 80.0 mg / kg, 90.0 mg / kg, 100.0 mg / kg, 150.0 mg / kg, 200.0 mg / kg, 250.0 mg / kg, 300.0 mg / kg, 350.0 mg / kg, 400.0 mg / kg, 450.0 mg / kg to more than about 500.0 mg / kg or any incremental value thereof. It should be understood that all values and ranges between these values and ranges are meant to be included.

[0038] The compound can be administered at a dosage in the range of about 0.2 milligrams / kg / day to more than about 100 mg / kg / day. For example, the dosage can be 0.2 mg / kg / day to 100 mg / kg / day, 0.2 mg / kg / day to 50 mg / kg / day, 0.2 mg / kg / day to 25 mg / kg / day, 0.2 mg / kg / day to 10 mg / kg / day, 0.2 mg / kg / day to 7.5 mg / kg / day, 0.2 mg / kg / day to 5 mg / kg / day, 0.25 mg / kg / day to 100 mg / kg / day, 0.25 mg / kg / day to 50 mg / kg / day, 0.25 mg / kg / day to 25 mg / kg / day, 0.25 mg / kg / day to 10 mg / kg / day, 0.25 mg / kg / day to 7.5 mg / kg / day, 0.25 mg / kg / day to 5 mg / kg / day, 0.5 mg / kg / day to 50 mg / kg / day, 0.5 mg / kg / day to 25 mg / kg / day, 0.5 mg / kg / day to 20 mg / kg / day, 0.5 mg / kg / day to 15 mg / kg / day, 0.5 mg / kg / day to 10 mg / kg / day, 0.5 mg / kg / day to 7.5 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, 0.75 mg / kg / day to 50 mg / kg / day, 0.75 mg / kg / day to 25 mg / kg / day, 0.75 mg / kg / day to 20 mg / kg / day, 0.75 mg / kg / day to 15 mg / kg / day, 0.75 mg / kg / day to 10 mg / kg / day, 0.75 mg / kg / day to 7.5 mg / kg / day, 0.75 mg / kg / day to 5 mg / kg / day, 1.0 mg / kg / day to 50 mg / kg / day, 1.0 mg / kg / day to 25 mg / kg / day, 1.0 mg / kg / day to 20 mg / kg / day, 1.0 mg / kg / day to 15 mg / kg / day, 1.0 mg / kg / day to 10 mg / kg / day, 1.0 mg / kg / day to 7.5 mg / kg / day, 1.0 mg / kg / day to 5 mg / kg / day, 2 mg / kg / day to 50 mg / kg / day, 2 mg / kg / day to 25 mg / kg / day, 2 mg / kg / day to 20 mg / kg / day, 2 mg / kg / day to 15 mg / kg / day, 2 mg / kg / day to 10 mg / kg / day, 2 mg / kg / day to 7.5 mg / kg / day, or 2 mg / kg / day to 5 mg / kg / day.

[0039] The compound can be administered at a dosage in the range of about 0.25 milligrams / kg / day to about 25 mg / kg / day. For example, the dosage can be 0.25 mg / kg / day, 0.5 mg / kg / day, 0.75 mg / kg / day, 1.0 mg / kg / day, 1.25 mg / kg / day, 1.5 mg / kg / day, 1.75 mg / kg / day, 2.0 mg / kg / day, 2.25 mg / kg / day, 2.5 mg / kg / day, 2.75 mg / kg / day, 3.0 mg / kg / day, 3.25 mg / kg / day, 3.5 mg / kg / day, 3.75 mg / kg / day, 4.0 mg / kg / day, 4.25 mg / kg / day, 4.5 mg / kg / day, 4.75 mg / kg / day, 5 mg / kg / day, 5.5 mg / kg / day, 6.0 mg / kg / day, 6.5 mg / kg / day, 7.0 mg / kg / day, 7.5 mg / kg / day, 8.0 mg / kg / day, 8.5 mg / kg / day, 9.0 mg / kg / day, 9.5 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, 20 mg / kg / day, 21 mg / kg / day, 22 mg / kg / day, 23 mg / kg / day, 24 mg / kg / day, 25 mg / kg / day, 26 mg / kg / day, 27 mg / kg / day, 28 mg / kg / day, 29 mg / kg / day, 30 mg / kg / day, 31 mg / kg / day, 32 mg / kg / day, 33 mg / kg / day, 34 mg / kg / day, 35 mg / kg / day, 36 mg / kg / day, 37 mg / kg / day, 38 mg / kg / day, 39 mg / kg / day, 40 mg / kg / day, 41 mg / kg / day, 42 mg / kg / day, 43 mg / kg / day, 44 mg / kg / day, 45 mg / kg / day, 46 mg / kg / day, 47 mg / kg / day, 48 mg / kg / day, 49 mg / kg / day, or 50 mg / kg / day.

[0040] The compound or its precursor can be administered at a concentration in the range of 0.01 micromoles to 500 micromoles or more. For example, the dosage can be 0.01 micromoles, 0.02 micromoles, 0.05 micromoles, 0.1 micromoles, 0.15 micromoles, 0.2 micromoles, 0.5 micromoles, 0.7 micromoles, 1.0 micromoles, 3.0 micromoles, 5.0 micromoles, 7.0 micromoles, 10.0 micromoles, 15.0 micromoles, 20.0 micromoles, 25.0 micromoles, 30.0 micromoles, 35.0 micromoles, 40.0 micromoles, 45.0 micromoles, 50.0 micromoles, 60.0 micromoles, 70.0 micromoles, 80.0 micromoles, 90.0 micromoles, 100.0 micromoles, 150.0 micromoles, 200.0 micromoles, 250.0 micromoles, 300.0 micromoles, 350.0 micromoles, 400.0 micromoles, 450.0 micromoles to about 500.0 micromoles or more, or any incremental value thereof. It should be understood that all values and ranges between these values and ranges are meant to be included.

[0041] The compound or its precursor can be administered at a concentration in the range of 0.10 micrograms / mL to 500.0 micrograms / mL. For example, the concentration can be 0.10 micrograms / mL, 0.50 micrograms / mL, 1 microgram / mL, 2.0 micrograms / mL, 5.0 micrograms / mL, 10.0 micrograms / mL, 20 micrograms / mL, 25 micrograms / mL, 30 micrograms / mL, 35 micrograms / mL, 40 micrograms / mL, 45 micrograms / mL, 50 micrograms / mL, 60.0 micrograms / mL, 70.0 micrograms / mL, 80.0 micrograms / mL, 90.0 micrograms / mL, 100.0 micrograms / mL, 150.0 micrograms / mL, 200.0 micrograms / mL, 250.0 g / mL, 250.0 micrograms / mL, 300.0 micrograms / mL, 350.0 micrograms / mL, 400.0 micrograms / mL, 450.0 micrograms / mL up to about 500.0 micrograms / mL more or any incremental value thereof. It should be understood that all values and ranges between these values and ranges are meant to be included.

[0042] The formulation can be administered in a pharmaceutically acceptable solution, which may typically contain salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic components at pharmaceutically acceptable concentrations. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administration of the pharmaceutical composition can be achieved by any means known to those skilled in the art. Routes of administration include, without limitation, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into a tumor or abscess), mucosal (e.g., topical to the eye), inhalation, and topical.

[0043] For intravenous and other parenteral routes of administration, the compounds can be formulated as lyophilized preparations, as lyophilized preparations of liposome-incorporated or liposome-encapsulated active compounds, as lipid complexes in aqueous suspensions, or as salt complexes. Lyophilized formulations are generally reconstituted immediately prior to administration in a suitable aqueous solution, such as sterile water or physiological saline.

[0044] For oral administration, the compounds can be readily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compound to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipients, optionally, the resulting mixture is comminuted and, if desired, after adding suitable auxiliaries, the mixture of granules is processed to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). Disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate can be added if desired. Optionally, oral formulations can also be formulated in physiological saline or a buffer, such as EDTA, for neutralizing internal acidic conditions, or administered without using any carriers.

[0045] Oral dosage forms of the compounds are also contemplated. The compounds can be chemically modified such that oral delivery of the derivatives is effective. Generally, the chemical modifications contemplated are the attachment of at least one moiety to the compound itself, where the moiety (a) inhibits acid hydrolysis and (b) allows uptake from the stomach or intestine into the bloodstream. An increase in the overall stability of the compound and an increase in the circulation time in the body are also desirable. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-189 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. As indicated above, polyethylene glycol moieties are preferred for pharmaceutical use.

[0046] The location of compound release may be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. One of ordinary skill in the art has available formulations that do not dissolve in the stomach but release the substance in the duodenum or other locations in the intestine. Release can avoid the deleterious effects of the gastric environment either by protection of the compound or by passing beyond the gastric environment, e.g., by release of the compound in the intestine.

[0047] To ensure sufficient resistance to the stomach, a coating that is impermeable up to at least pH 5.0 is essential. Examples of more common inert ingredients used as enteric coatings are cellulose trimellitate acetate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP50, HPMCP55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as a mixed film.

[0048] The coating or mixture of coatings can also be used for tablets not intended for protection from the stomach. This can include a sugar coating or a coating that makes the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) for the delivery of dry therapeutic agents (e.g., powders); a soft gelatin shell can be used for liquid forms. The shell material of cachets can be thick starch or other edible paper. Moist massing techniques can be used for pills, troches, molded tablets, or pulverized tablets.

[0049] The therapeutic substance can be formulated in the preparation as fine multi-particles in the form of granules or pellets with a particle size of about 1 mm. The formulation of the material for capsule administration can also be as a powder, a lightly compressed plug, or even a tablet. The therapeutic substance can be prepared by compression.

[0050] All coloring agents and flavors may be included. For example, the compound can be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product such as a refrigerated beverage containing coloring agents and flavors.

[0051] The therapeutic substance may be diluted or its amount increased with an inert material. These diluents may include carbohydrates, especially mannitol, α-lactose, lactose anhydrous, cellulose, sucrose, processed dextran, and starch. Certain inorganic salts including calcium phosphate tribasic, magnesium carbonate, and sodium chloride may also be used as fillers. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0052] Disintegrants may be included in the formulation of the therapeutic substance in solid dosage forms. Materials used as disintegrants include, without limitation, starch, including the commercially available starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethyl cellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acidic carboxymethyl cellulose, natural sponge, and bentonite may all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums may be used as both disintegrants and binders and may include powdered gums such as agar, karaya, or tragacanth. Alginate and its sodium salts are also useful as disintegrants.

[0053] Binders may be used to hold the therapeutic substances together to form hard tablets and include materials from natural substances such as acacia, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) may both be used in alcohol solutions to granulate the therapeutic substances.

[0054] A friction reducing agent may be included in the formulation of the therapeutic agent to prevent sticking during the formulation process. Lubricants can be used as a layer between the therapeutic substance and the wall of the mold, and these can include, without limitation, stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and 6000 can also be used.

[0055] Lubricants that can improve the flow properties of the drug during formulation and assist in rearrangement during compression can be added. The lubricants can include starch, talc, calcined silica, and hydrated silicoaluminate.

[0056] Surfactants can be added as wetting agents to assist in the dissolution of the therapeutic substance in an aqueous environment. The surfactants can include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents that can be used include benzalkonium chloride and benzethonium chloride. Possible nonionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glyceryl monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants can be present in the formulation of the compound or its derivative either alone or as a mixture in different ratios.

[0057] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the case of soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Furthermore, a stabilizer can be added. Microspheres formulated for oral administration can also be used. Such microspheres are clearly defined in the art. All formulations for oral administration should be in dosage amounts suitable for such administration.

[0058] For buccal administration, the composition can take the form of tablets or troches formulated in a conventional manner.

[0059] For topical administration, the compound can be formulated as a solution, gel, ointment, cream, suspension, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0060] For administration by inhalation, the compound can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example, made of gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0061] Lung delivery of the compound (or its salt) is also contemplated. During inhalation, the compound is delivered to the mammalian lung and migrates through the pulmonary epithelial lining into the bloodstream. Other reports of inhaled molecules are Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (a1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins," Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-γ and tumor necrosis factor α) and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). Methods and compositions for the pulmonary delivery of drugs for systemic effects are described in U.S. Patent No. 5,451,569 issued to Wong et al. on September 19, 1995 (specifically incorporated by reference for the disclosure thereof).

[0062] Those contemplated for use include a wide range of mechanical devices designed for the pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, which are well known to those of skill in the art.

[0063] Transnasal delivery of the pharmaceutical composition is also contemplated. Transnasal delivery enables the transfer of the pharmaceutical composition into the bloodstream immediately after administration of the therapeutic product to the nose, without the need for deposition of the product in the lungs. Formulations for transnasal delivery include those using dextran or cyclodextrin.

[0064] When it is desirable to deliver them systemically, the compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations are in unit dosage forms with preservatives and can be provided, for example, in ampoules or multiple-dose containers. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and can contain formulating agents such as suspending, stabilizing and / or dispersing agents.

[0065] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions.

[0066] Alternatively, the active compound can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0067] The compounds can also be formulated in rectal or vaginal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0068] In addition to the formulations described above, the compounds can also be formulated as depot preparations. Such long-acting formulations can be formulated using suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as poorly soluble derivatives, e.g., as poorly soluble salts.

[0069] The pharmaceutical composition can also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, without limitation, polymers such as calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polyethylene glycol.

[0070] Suitable liquid or solid pharmaceutical dosage forms include, for example, aqueous solutions or saline for inhalation, microencapsulated, encapsulated, coated with fine gold particles, contained in liposomes, nebulized, aerosolized, pellets for implantation into the skin, or dried and rubbed onto the skin as a sharp. The pharmaceutical composition includes granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, droplets, or preparations for long-term release of the active compound, in which excipients and additives and / or adjuvants, e.g., disintegrants, binders, coating agents, swelling agents, lubricants, fragrances, sweeteners or solubilizers are customarily used as described above. The pharmaceutical composition is suitable for use in various drug delivery systems. For a concise review of methods for drug delivery, see Langer R, Science 249:1527-1533 (1990).

[0071] The said compound and optionally one or more other therapeutic substances can be administered as such (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt is preferably pharmaceutically acceptable, although pharmaceutically unacceptable salts may conveniently be used to prepare their pharmaceutically acceptable salts. Such salts include, without limitation, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Also, such salts can be prepared as alkali metal or alkaline earth salts such as sodium, potassium or calcium salts of carboxylic acid groups.

[0072] Suitable buffers include acetic acid and salts (1 - 2% w / v); citric acid and salts (1 - 3% w / v); boric acid and salts (0.5 - 2.5% w / v); and phosphoric acid and salts (0.8 - 2% w / v). Suitable preservatives include benzalkonium chloride (0.003 - 0.03% w / v); chlorobutanol (0.3 - 0.9% w / v); parabens (0.01 - 0.25% w / v) and thimerosal (0.004 - 0.02% w / v).

[0073] The pharmaceutical composition contains an effective amount of the compound described herein and optionally one or more therapeutic substances contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" represents natural or synthetic organic or inorganic components with which the active ingredient is combined to facilitate its application. The components of the pharmaceutical composition can also be combined with the compound and with each other in such a way that there is no interaction that would substantially impair the desired pharmaceutical effect.

[0074] The therapeutic substance, including but not limited to the compound, may be provided in particles. As used herein, "particle" means nanoparticles or microparticles (or, in some cases, larger particles) that can be wholly or partially composed of the compounds or other therapeutic substances described herein. The particle may contain the therapeutic substance within a core surrounded by a coating including, but not limited to, an enteric coating. The therapeutic substance may also be dispersed throughout the particle. The therapeutic substance may also be adsorbed to the particle. The particle may be of any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. The particle may contain, in addition to the therapeutic substance, any of the materials routinely used in the pharmaceutical and medical arts, including but not limited to erosive, non-erosive, biodegradable, or non-biodegradable materials or combinations thereof. The particle may be a microcapsule containing a compound in solution or semi-solid state. The particle may be substantially any shape.

[0075] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering a therapeutic substance. Such polymers can be natural or synthetic polymers. The polymer is selected based on the period during which release is desired. Of particular interest are bioadhesive polymers including the bioerodible hydrogels described in Sawhney et al., Macromolecules 26:581-587 (1993), the teachings of which are specifically incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, gluten, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0076] The therapeutic substance may be contained in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the mode and profile of drug release from the formulation are controlled. This refers to both immediate and non-immediate release formulations, and non-immediate release formulations include, without limitation, sustained release and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional meaning to refer to a drug formulation that provides a gradual release of a drug over a long period of time and can result in a substantially constant blood concentration of the drug over a long period of time. The term "delayed release" is used in its conventional meaning to refer to a drug formulation in which there is a time delay between administration of the formulation and release of the drug therefrom. "Delayed release" may or may not be accompanied by a gradual release of the drug over a long period of time, and thus may or may not be "sustained release".

[0077] The use of long-term sustained release implants may be particularly suitable for the treatment of chronic conditions. As used herein, "long-term" release means that the implant is constructed and adjusted to deliver a therapeutically relevant level of the active ingredient for at least 7 days and up to a maximum of 30 - 60 days. Long-term sustained release implants are well known to those skilled in the art and include some of the release systems described above.

[0078] Definitions For convenience, some of the terms employed in the specification, examples, and appended claims are collected here. These definitions are to be read in light of the remainder of the disclosure and are to be understood as being made by one of ordinary skill in the art. 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.

[0079] As used herein, the articles "a" and "an" refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0080] In the specification and in the claims, as used herein, the expression "and / or" is to be understood to mean "either or both" of the elements so conjoined, i.e., elements that may be conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed using "and / or" are likewise to be construed as "one or more" of the elements so conjoined. Other elements may optionally be present whether or not they are related to the specifically recited elements, outside of those specifically identified by the "and / or" clause. Thus, as a non-limiting example, when used in combination with open-ended expressions such as "comprising", a reference to "A and / or B" can refer to only A (optionally including elements other than B); or only B (optionally including elements other than A); or further to both A and B (optionally including other elements).

[0081] In the specification and in the claims, as used herein, "or" is to be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is inclusive, i.e., including at least one of a number of or the elements of the list, but also including more than one and optionally also including additional unlisted elements. Terms that are clearly shown to be contrasting, such as "only one of", "exactly one of", or when used in the claims "consisting of", refer to exactly one of a number of or the elements of the list. Generally, the term "or" as used herein is to be construed to indicate an exclusive alternative (i.e., "either one or the other but not both") only when preceded by exclusive terms such as "either", "one of", "only one of", or "exactly one of". When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0082] In the specification and claims, as used herein, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of all of the specifically listed elements in the list of elements, nor excluding any combinations of elements in the list of elements. This definition also allows that elements other than those specifically recited within the list of elements referred to by the phrase "at least one" may optionally be present, whether or not related to the specifically recited elements. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B" or equivalently "at least one of A and / or B") can mean that there is at least one A, optionally including more than one A, and no B (optionally including elements other than B); or that there is at least one B, optionally including more than one B, and no A (optionally including elements other than A); or further, that there is at least one A, optionally including more than one A, and at least one B, optionally including more than one B (optionally including other elements), and so forth.

[0083] It should also be understood that in any method claimed in this specification that includes more than one step or act, unless the contrary is clearly indicated, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0084] As in the specification above, in the claims, transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "composed of", etc. are all open-ended, i.e., they are to be understood to mean including non-limitingly.

[0085] The various compounds contained in the compositions of the present disclosure may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present disclosure may also be optically active. The present disclosure contemplates all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, their racemic mixtures, and other mixtures thereof, that are included within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are intended to be included in the present disclosure.

[0086] For example, if a particular enantiomer of a compound of the present disclosure is desired, this can be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary is cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino or an acidic functional group such as a carboxyl, diastereomeric salts are formed with a suitable optically active acid or base, and subsequently the diastereomers thus formed are resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer.

[0087] The structures illustrated herein also mean that they include compounds that differ only in the presence of atoms containing one or more isotopes. For example, compounds produced by replacement of hydrogen with deuterium or tritium, or carbon with carbon rich in 13C or 14C are within the scope of the present disclosure.

[0088] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material involved in carrying or transporting a subject chemical substance from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not being harmful to the patient, and being substantially nonpyrogenic. Examples of materials that can serve as pharmaceutically 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances employed in pharmaceutical formulations. The pharmaceutical compositions of the present disclosure are nonpyrogenic, i.e., they do not induce a significant increase in temperature when administered to a patient.

[0089] The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the thus formed salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, etc. (see, for example, Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19).

[0090] In another case, the compounds useful in the methods may contain one or more acidic functional groups and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these cases means the relatively non-toxic inorganic and organic base addition salts of the compounds. These salts can also be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, the above Berge et al).

[0091] For use in therapy, the "therapeutically effective amount" (or "effective amount") of a compound, when administered as part of a desired dosing regimen (to a mammal such as a human), is that amount of the compound in a preparation which, according to clinically acceptable criteria for the disorder or condition being treated or for cosmetic purposes, for example, at a reasonable benefit / risk ratio applicable to any medical treatment, alleviates symptoms, improves the condition, or delays the onset of the disease state.

[0092] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration to a patient of one or more compounds of the present disclosure. When administered prior to the clinical appearance of an undesirable condition (e.g., a disease or other undesirable situation in a host animal), the treatment is preventive (i.e., it protects the host from the manifestation of the undesirable condition), while when administered after the appearance of the undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, improve, or stabilize the existing undesirable condition or its side effects).

[0093] The term "patient" or "subject" refers to a mammal suffering from a disease, disorder, or condition. The patient or subject can be a primate, dog, cat, or horse. The patient can be a bird. The bird can be a domesticated bird such as a chicken. The bird can be a poultry. The patient or subject can be a human.

[0094] Fatty chains include the classes of alkyl, alkenyl, and alkynyl defined below. Straight-chain fatty chains are limited to non-branched carbon chain moieties. As used herein, the term "aliphatic group" refers to straight-chain, branched-chain, or cyclic aliphatic hydrocarbon groups, including saturated and unsaturated aliphatic groups such as alkyl groups, alkenyl groups, or alkynyl groups.

[0095] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a defined number of carbon atoms, or up to 30 carbon atoms if not defined. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and moieties that are positional isomers of these moieties. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. A straight-chain or branched-chain alkyl may have up to 30 carbon atoms in its main chain (e.g., C1 - C 30 , and in the case of a branched chain, C3 - C 30 ), or may have up to 20 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0096] The term "alkylene" refers to an alkyl group having a defined number of carbons, e.g., 2 to 12 carbon atoms, and containing two attachment points to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. The alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain moiety and may be substituted with one or more substituents.

[0097] "Cycloalkyl" means a monocyclic or bicyclic, or bridged or spirocyclic, or polycyclic saturated carbon cyclic ring, each having 3 to 12 carbon atoms. In various aspects, cycloalkyl has 3 to 10 carbon atoms in their ring structure, or 3 to 6 carbon atoms in the ring structure. The cycloalkyl group may be substituted or unsubstituted.

[0098] Unless otherwise specified, "lower alkyl" as used herein is an alkyl group as defined above, having 1 to 10 carbons or 1 to 6 carbon atoms in its main chain structure, and means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. A substituent designated as alkyl herein may be lower alkyl.

[0099] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having a specified number of carbon atoms or, when no limitation on the number of carbon atoms is specified, up to 26 carbon atoms and having one or more double bonds in said moiety. Alkenyls having 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl in their various isomeric forms, where the unsaturated bond may be located anywhere in said moiety and may have either the (Z) or (E) configuration around the double bond.

[0100] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but having one or more triple bonds in said moiety.

[0101] The term "alkylthio" refers to an alkyl group as defined above with a sulfur moiety attached. The "alkylthio" moiety can be represented by one of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2)m-R1, where m and R1 are defined below. Representative alkylthio groups include methylthio, ethylthio, and the like. As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined below with an oxygen moiety attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. "Ether" is two hydrocarbons covalently bonded by oxygen. Thus, the alkyl substituent that makes the alkyl into an ether can be an alkoxyl such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2)m-R 10 or an alkoxyl similar thereto, where m and R 10 are described below.

[0102] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, for example, a moiety that can be represented by the formula: TIFF0007711088000031.tif10128, where R 11 and R 12 are each independently hydrogen, alkyl, alkenyl, -(CH2) m -R 10 or R 11 and R 12 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure; R 10 represents alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclic; m is an integer in the range of zero or 1 to 8. In some cases, only one of R 11 or R 12 can be carbonyl, for example, R 11 , R 12 , and nitrogen do not form an imide together. R 11 and R12 each independently represents hydrogen, alkyl, alkenyl, or -(CH2) m -R 10 and can thus represent. Therefore, the term "alkylamine" as used herein means an amine group to which a substituted or unsubstituted alkyl is attached, i.e., R 11 and R 12 wherein at least one of them is an alkyl group. An amino group or an alkylamine is basic, which means having a conjugate acid with a pKa > 7.00, i.e., the protonated form of these functional groups has a pKa exceeding approximately 7.00 with respect to water.

[0103] The term "amide" refers to the group: TIFF0007711088000032.tif15128, where each R 13 independently represents hydrogen or a hydrocarbyl group, or two R 13 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0104] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). In various aspects, the aryl group includes a 5- to 12-membered ring or a 6- to 10-membered ring. The term "aryl" includes polycyclic ring systems having two or more cyclic rings in which at least one of the rings is aromatic and, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl, where two adjacent rings share two or more carbons. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, 5- to 12-membered rings, or 5- to 10-membered rings having a ring structure containing 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. Each instance of an aryl group can be independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent ("substituted aryl"). The aromatic ring can be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, and the like. For example, the aryl group can be unsubstituted C5-C12 aryl or substituted C5-C10 aryl.

[0105] As used herein, the terms "halo", "halide", or "halogen" mean halogen and include, without limitation, fluoro, chloro, bromo, iodo, etc. in both radioactive and non-radioactive forms. Halo may be selected from the group consisting of fluoro, chloro, and bromo.

[0106] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, a 5- to 12-membered ring, or a 5- to 10-membered ring in which the ring structure contains 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. The heterocycle can be saturated or unsaturated. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, phrazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, for example, azetidinone and pyrrolidinone, sultam, sultone, etc. The heterocyclic ring can be substituted at one or more positions with the substituents described above, for example, halogen, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, etc.

[0107] The term "carbonyl" is recognized in the art and has the formula: It includes a part that can be represented by TIFF0007711088000033.tif11128, where X' is a bond or represents oxygen, nitrogen, or sulfur, R14 represents hydrogen, alkyl, alkenyl, -(CH2)m-R10, or a pharmaceutically acceptable salt, R15 represents hydrogen, alkyl, alkenyl, or -(CH2)m-R10, where m and R10 are as defined above. When X' is oxygen and R14 or R15 is not hydrogen, the formula represents an "ester". When X' is oxygen and R14 is as defined above, the said part is called a carboxyl group in this specification, and especially when R14 is hydrogen, the formula represents a "carboxylic acid". When X' is oxygen and R15 is hydrogen, the formula represents a "formate". Generally, when the oxygen atom in the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. When X' is sulfur and R14 or R15 is not hydrogen, the formula represents a "thioester" group. When X' is sulfur and R14 is hydrogen, the formula represents a "thiocarboxylic acid" group. When X' is sulfur and R15 is hydrogen, the formula represents a "thioformate" group. On the other hand, when X' is a bond and R14 is not hydrogen, the above formula represents a "ketone" group. When X' is a bond and R14 is hydrogen, the above formula represents an "aldehyde" group.

[0108] The term "nitro" means -NO2; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO2-; the term "azide" means -N3; the term "cyano" means -CN; the term "isocyanato" means -NCO; the term "thiocyanato" means -SCN; the term "isothiocyanato" means -NCS; the term "cyanato" means -OCN.

[0109] It is intended that the definition of each notation, for example, alkyl, m, n, etc., when it appears multiple times in any structure, is independent of its definition at other places in the same structure.

[0110] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of the main chain. "Substituted" or "substituted with" is understood to implicitly include the condition that such substitution follows the valences of the substituted atoms and substituents and that the substitution results in a stable compound that does not spontaneously undergo conversions such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents can be one or more and can be the same or different for a suitable organic compound. A heteroatom such as nitrogen can have any permissible substituent of the organic compounds described herein that satisfies the valences of the hydrogen substituents and / or the heteroatom. Substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aryl, or aromatic or heteroaromatic moieties. Substituents on a substituted alkyl can be selected from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. Substituents on a substituted alkyl can be selected from fluoro, carbonyl, cyano, or hydroxyl. One of ordinary skill in the art will understand that, where appropriate, the substituent itself may be substituted. Unless otherwise specifically noted as "unsubstituted", references herein to chemical moieties are understood to include substituted variants. For example, a reference to a group or moiety "aryl" implicitly includes both substituted and unsubstituted variants.

[0111] Chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inside front cover of the Handbook of Chemistry and Physics, 67th Ed., 1986 - 87.

[0112] All patents, patent application publications, journal articles, textbooks, and other publications referred to in the specification are indicative of the level of skill of those of ordinary skill in the art to which the present disclosure pertains. All such publications are hereby incorporated by reference into this specification to the same extent as if each individual publication had been specifically and individually indicated to be incorporated by reference.

[0113] The inventions exemplified herein may be suitably practiced in the absence of any element or limitation not specifically disclosed herein. Thus, for example, in any instance in this invention, any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms. Similarly, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods and / or steps of the kind described herein and / or apparent to one of ordinary skill in the art upon reading the present disclosure.

[0114] The terms and expressions employed are used as terms of description and not of limitation. In this regard, to the extent that a particular term is defined "below" and separately defined, explained, or discussed anywhere in the "Detailed Description", all such definitions, explanations, and discussions are intended to apply to such terms. Also, in the use of such terms and expressions, it is not intended to exclude any equivalents to the features shown and described or portions thereof. Further, for example, in the "Detailed Description", subheadings such as "Definition" are used, but such use is for the sole purpose of making reference easier and is not intended to limit any disclosure provided in one item to that item alone; rather, any disclosure provided under one subheading is intended to apply to the disclosure under any other subheading as well.

[0115] Other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent to those of ordinary skill in the art from the description of the present disclosure contained herein in view of the information known to them, and may be made without departing from the scope of the present disclosure, as will be understood by those of ordinary skill in the relevant art. Although the present disclosure has been described in detail heretofore, this has been for purposes of illustration only and is not intended to limit the present disclosure, which will be more clearly understood by reference to the following examples.

Examples

[0116] The present invention can be better understood by reference to the following examples provided by way of illustration. The present invention is not limited to the examples provided herein.

[0117] An efficient approach to drug discovery against etiological agents involves the investigation of existing compounds known to be active against the relevant pathogens and subsequent optimization of the identified lead compounds. SARS-CoV-2, which causes COVID-19, belongs to the β-coronavirus genus, including SARS-CoV and MERS-CoV. The genome of SARS-CoV-2 has approximately 80% nucleotide identity with the genome of SARS-CoV as a whole, but the main proteases (Mpro) of both SARS-CoV-2 and SARS-CoV have substantially the same structure.

[0118] This disclosure relates to two anti-Mpro compounds, GRL-0820S and GRL-0920S, which exhibit potent activity against SARS-CoV-2 with IC 50 values of 15 ± 18 and 2.8 ± 0.3 μM, respectively, in assays based on Vero-E6 cells or TMPRSS2-overexpressing Vero-E6 cells using two SARS-CoV-2 strains, JPN / TY / WK-521 and NCGM-nCoV-05-2N, as confirmed by a quantitative RNA-qPCR assay with cell culture supernatants, and are known to be effective against SARS-CoV. The results of the RNA-qPCR assay were confirmed by the results of a cytotoxicity effect inhibition assay. Compounds GRL-0820S and GRL-0920S have chemical formulas: TIFF0007711088000034.tif32128, respectively.

[0119] Remdesivir showed significant activity against SARS-CoV-2 in the assay (IC 50showed (=2.6±0.7 μM), but none of the seven test compounds containing favipiravir, hydroxychloroquine, lopinavir, nelfinavir, nafamostat, nitazoxanide, or ribavirin showed a significant effect. When Vero-E6 and TMPRSS2-overexpressing Vero-E6 cells were exposed to SARS-CoV-2, cultured for 3 days in the presence of 100 μM, and examined by immunostaining, GRL-0920S completely blocked the infectivity, replication, and cytotoxic effects of SARS-CoV-2 without significant toxicity. GRL-0820S and remdesivir significantly blocked the infectivity and replication of SARS-CoV-2, but viral breakthrough occurred. None of the seven compounds showed significant activity. Therefore, GRL-0920S is considered a therapeutic substance for COVID-19 and plays a role as a lead compound in the development of more potent anti-SARS-CoV-2 compounds. The findings presented herein suggest that compounds active against SARS-CoV show potent activity against SARS-CoV-2, strongly suggesting that future new waves of SARS-CoV infection will be controlled by anti-Mpro inhibitors.

[0120] Figure 1 is a fluorescence micrograph showing that GRL-0920S and remdesivir almost completely block the infectivity and cytotoxic activity of SARS-CoV-2 in TMPRSS2-overexpressing Vero-E6 cells. VeroE6 / TMPRSS2 cells (2×104 cells / well in a 96-well plate) were exposed to the JPN / TY / WK-521 strain of SARS-CoV-2 at a multiplicity of infection (MOI) of 0.1 in the presence of each of the compounds at 1, 10, and 100 μM. After 3 days, the cells were fixed with 4% paraformaldehyde and subjected to immunofluorescence staining using a mouse monoclonal anti-spike antibody. The SARS-CoV-2 spike (S) antigen, F-actin, and nuclei are shown in green, red, and blue, respectively.

[0121] Figure 2 is a micrograph of SARS-CoV-2-infected Vero-E6 cells treated with GRL-0820S and GRL-0920S, showing that both compounds significantly block the cytopathic activity of SARS-CoV-2. E6 cells were exposed to the IgG fraction (20 μg / ml) derived from Pt-nCoV-03 and then to SARS-CoV-2. Photographs of Vero E6 cells were taken on the third day after exposure to SARS CoV-2 in the presence of 20 μg / ml of IgG.

[0122] 1H-Indole-4-carboxylic acid 5-chloropyridin-3-yl: TIFF0007711088000035.tif20128A suspension of 1H-indole-4-carboxylic acid (100 mg, 0.62 mmol) and 5-chloropyridin-3-ol (96.5 mg, 0.74 mmol) in anhydrous CH2Cl2 (5 ml) was added with 4-dimethylaminopyridine (37.8 mg, 0.31 mmol) at 23 °C and stirred for 5 minutes. To the suspension was added N,N'-dicyclohexylcarbodiimide (191.9 mg, 0.93 mmol), and the mixture was stirred for 24 hours. The reaction mixture was quenched with an aqueous NaHCO3 solution and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give the inhibitor (140 mg, 83%) as an amorphous solid, R f = 0.4 (40% EtOAc / hexane). TIFF0007711088000036.tif38128

[0123] 1-Allyl-1H-indole-4-carboxylic acid 5-chloropyridin-3-yl TIFF0007711088000037.tif A stirred solution of 1-allyl-1H-indole-4-carboxylic acid (40 mg, 0.20 mmol, 1.0 eq) and 5-chloropyridin-3-ol (31 mg, 0.23 mmol, 1.2 eq) in CH2Cl2 (2 mL) was treated with DCC (62 mg, 0.3 mmol, 1.5 eq) and DMAP (12 mg, 0.1 mmol, 0.5 eq). The resulting reaction mixture was stirred at room temperature for 12 h. After this period, the reaction mixture was concentrated under reduced pressure to give a residue. Saturated aqueous NaHCO3 (5 mL) was added to the residue and the resulting mixture was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (20% ethyl acetate / hexane) to give the title compound (50 mg, 80% yield). TIFF0007711088000038.tif18128

[0124] Numbered embodiments Embodiment 1 relates to a compound of formula (I): G 1 -L-G 2 or a pharmaceutically acceptable salt thereof, wherein, G 1 is a monocyclic aromatic heterocyclyl group; L is a linker; and G 2 is a bicyclic aromatic heterocyclyl group; wherein the compound is not of the formula: TIFF0007711088000039.tif25128 Embodiment 2 relates to the compound of Embodiment 1, wherein the compound of formula (I) is a compound of formula (II): TIFF0007711088000040.tif26128 or a pharmaceutically acceptable salt thereof, wherein, L 1 is alkyl, acyl (e.g., acylalkyl or acylalkenyl), -C(O)O-, -C(O)NR-, or -S(C=NR)alkyl; X 1 、 X 2 、 X 3 、 X 4 are each independently alkyl, acyl, CH, CR, CR2, -alkyl-N(R)-, N, O, -S(O) x -, and -alkyl-S(O) x -, where x is 0, 1, or 2; X 1 and X 3 and between X 2 and X 3 The bond between can optionally be a single bond or a double bond; R, R 1 , and R 2 are the same or different and are alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocycle, alkoxy, amino, halo, haloalkyl, C(O)NR2, or C(O)OR; Each R is independently H or alkyl; and Each n is independently an integer from 0 to 2. Embodiment 3 relates to a compound of Embodiment 1 or 2, wherein the compound of formula (I) is a compound of formula (III): TIFF0007711088000041.tif19128 or a pharmaceutically acceptable salt thereof, wherein X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl. Embodiment 4 relates to a compound of any of Embodiments 1 - 3, wherein X 4 is N. Embodiment 5 relates to a compound of any of Embodiments 1 - 4, wherein X 4 is N and X 5 is alkyl, alkenyl, -O-, -N(R)-, -C(O)-, or haloalkyl. Embodiment 6 relates to a compound of any of Embodiments 1 - 5 having the formula: TIFF0007711088000042.tif82128 or a pharmaceutically acceptable salt thereof. Embodiment 7 relates to a compound of the formula: Relates to a compound of any one of embodiments 1 to 6 having TIFF0007711088000043.tif212120 or a pharmaceutically acceptable salt thereof. Embodiment 8 is of the formula: Relates to a compound of any one of embodiments 1 to 7 having TIFF0007711088000044.tif183132, TIFF0007711088000045.tif207130, TIFF0007711088000046.tif63136 or a pharmaceutically acceptable salt thereof. Embodiment 9 is of the formula: Relates to a compound of any one of embodiments 1 to 7 having TIFF0007711088000047.tif28128 or a pharmaceutically acceptable salt thereof. Embodiment 10 is of the formula: Relates to a compound of any one of embodiments 1 to 7 having TIFF0007711088000048.tif33144 or a pharmaceutically acceptable salt thereof. Embodiment 11 is of the formula: Relates to a compound of any one of embodiments 1 to 7 having TIFF0007711088000049.tif26128 or a pharmaceutically acceptable salt thereof. Embodiment 12 is of the formula: Relates to a compound of any one of embodiments 1 to 7 having TIFF0007711088000050.tif20128 or a pharmaceutically acceptable salt thereof. Embodiment 13 is of the formula: Relates to a compound of any one of embodiments 1 to 7 having TIFF0007711088000051.tif23128 or a pharmaceutically acceptable salt thereof. Embodiment 14 relates to a pharmaceutical composition comprising one or more of any one of embodiments 1 to 13 in a therapeutically effective amount and at least one pharmaceutically acceptable excipient. Embodiment 15 is a method for treating severe acute respiratory syndrome (a method for treating severe acute respiratory syndrome), comprising the step of administering to a patient in need thereof one or more of any one of embodiments 1 to 13 in a therapeutically effective amount or the pharmaceutical composition of embodiment 14 and relates to a method. Aspect 16 relates to the method of Aspect 15, wherein the severe acute respiratory syndrome is COVID-19.

Claims

**Claim 1** A compound having the formula: or a pharmaceutically acceptable salt thereof. **Claim 2** A compound having the formula: or a pharmaceutically acceptable salt thereof. **Claim 3** A compound having the formula: or a pharmaceutically acceptable salt thereof. **Claim 4** A pharmaceutical composition comprising one or more of the compounds according to any one of claims 1 to 3 in a therapeutically effective amount and at least one pharmaceutically acceptable carrier. **Claim 5** A pharmaceutical composition for treating severe acute respiratory syndrome in a patient, comprising one or more of the compounds according to any one of claims 1 to 3 in a therapeutically effective amount. **Claim 6** The pharmaceutical composition according to claim 5, wherein the severe acute respiratory syndrome is COVID-19.

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