Compounds for treatment of sars

Abstract

To provide bis-amide inhibitors of SARS-CoV-2 (COVID), pharmaceutical compositions comprising the bis-amide inhibitors, and methods of treating a severe acute respiratory syndrome.SOLUTION: The invention provides a compound of formula (I) or a pharmaceutically acceptable salt, and a pharmaceutical composition for treating a severe acute respiratory syndrome containing the compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 014,501, filed April 23, 2020, and U.S. Provisional Patent Application No. 63 / 120,078, filed December 1, 2020, which are incorporated by reference herein in their entireties.

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

[0003] background Coronaviruses (CoVs) are enveloped viruses with positive-sense single-stranded RNA and are associated with various natural hosts. CoVs are divided into α, β, γ, and δ groups, with the β group further consisting 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 the β subgroup A, severe acute respiratory syndrome CoV (SARS-CoV) in the β subgroup B, and Middle East respiratory syndrome CoV (MERS-CoV) in the β subgroup C.

[0004] In this century, SARS-CoV and MERS-CoV have emerged in humans, causing severe lung disease with alarmingly high mortality rates. SARS-CoV infection first appeared in China in 2002 and rapidly spread as a global pandemic to over 30 countries, infecting 8,273 people and killing 775 (a nearly 10% case fatality rate). In 2012, MERS-CoV emerged in Saudi Arabia and spread throughout the Middle East. In 2015, a second MERS-CoV outbreak occurred in South Korea, resulting in an unusually high number of third- and fourth-generation cases. As of August 2018, the World Health Organization reported 2,229 laboratory-confirmed cases of MERS-CoV infection (a nearly 35% case fatality rate) in 27 countries, including 791 deaths (on the World Wide Web: who[dot]int / emergencies / mers-cov / en / ). On the other hand, the remaining common HCoVs, such as 229E, OC43, and NL63, usually infect the upper respiratory tract in humans, causing the common cold, but they also cause severe and even fatal illnesses 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; OC43 isolates with novel genomes are continually being identified.

[0005] The ongoing 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 a 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 outbreaks over the past 20 years. Currently, there is no cure for COVID-19. Therefore, the development of drugs that can inhibit SARS-CoV-2 would address an urgent unmet medical need. Summary of the Invention

[0006] overview The present disclosure provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig): TIFF2025134881000001.tif113128, or a pharmaceutically acceptable salt thereof, During the ceremony, A is -N(R a )-alkyl, -O-alkyl, heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -N(R a )-alkylene-heterocyclyl, -N(R a )-aryl, -alkylene-N(R a )-C(O)-heterocyclyl, -alkylene-N(R a )-C(O)-O-heterocyclyl, or -alkylene-N(R a )—C(O)-alkylene-O-heterocyclyl; each of which may be substituted with any suitable substituent, including halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R 2 is heterocyclo or cycloalkyl; R 3a is H, alkyl, alkoxy, acyl (e.g., haloalkyl acyl such as fluoroalkyl acyl including C(O)CFH), -N(R b ), amide (e.g., —C(O)NR), aryl, -alkylene-O(R d ), benzthiazole (e.g., halo-substituted benzthiazoles such as fluoro-substituted benzthiazoles, including 5- and 6-fluorobenzthiazole), benzoxazole, benzofuranyl, or indolyl; R 3b is SO3Na or CN; R 4is a natural amino acid side chain (e.g., a hydrophobic natural amino acid side chain such as the side chains of alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan), an unnatural amino acid side chain (e.g., a hydrophobic unnatural amino acid side chain such as the side chains of homoalanine, norvaline, norleucine, and homonorleucine), cycloalkyl, or heterocyclo; R a is H or alkyl; R c is H, alkyl, -C(O)-alkyl, -C(O)-alkylene-N(R a )2; R d is H, -P(O)3(Li)2, -P(O)3(Na)2, or -P(O)(OH)2; X 1 is N or C; X 2 is CH, N, or C(O), where X 1 and X 2 The bond between X may be a single bond, or 1 may be a double bond except when X is N; 1 and X 2 only one of may be N; and n is an integer from 0 to 3; and, The compound Not TIFF2025134881000002.tif25128.

[0007] The present disclosure provides a compound of formula (II): TIFF2025134881000003.tif19128, or a pharmaceutically acceptable salt thereof, During the ceremony, R 2 and R 3a are each defined herein; R 8 and R 9 are independently H or alkyl; or may be taken together with the nitrogen atom to which they are attached to form a heterocyclyl group; and R 10 is alkyl or alkenyl.

[0008] The present disclosure provides compounds of formula (III)-(X): TIFF2025134881000004.tif156128TIFF2025134881000005.tif165128, or a pharmaceutically acceptable salt thereof, During the ceremony, Each R 11 is H, alkyl, or each R 11 together with the nitrogen atom to which it is attached form a heterocyclyl group; R 12 is H, amino, OH or alkoxy; R 13 is H, alkyl, or amino, or two adjacent R 13 groups taken together with the carbon atoms to which they are attached form a 5- or 6-membered aryl or heteroaryl group; Y 2 is O or NR a and; Z is NR a or alkyl; R a is H or alkyl; X 3 is bond, CH2, O, NR a , or S(O) p where p is 0, 1, or 2, and X 3 The group having the formula: TIFF2025134881000006.tif10128; thiazolyl; or benzthiazolyl.

[0009] The present disclosure provides compounds of formula (XI)-(XII): TIFF2025134881000007.tif84128, or a pharmaceutically acceptable salt thereof, During the ceremony, The dashed lines are single or double bonds; T and T 1 are each independently NR aor C(O); and R a is H or alkyl.

[0010] The present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds and a pharmaceutically acceptable carrier.

[0011] The present disclosure also relates to a method for treating severe acute respiratory syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds or a pharmaceutical composition comprising same. [The present invention 1001] Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig): The compound of TIFF2025134881000008.tif113128, During the ceremony, A is -N(R a )-alkyl, -O-alkyl, heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -N(R a )-alkylene-heterocyclyl, -N(R a )-aryl, -alkylene-N(R a )-C(O)-heterocyclyl, -alkylene-N(R a )-C(O)-O-heterocyclyl, or -alkylene-N(R a )—C(O)-alkylene-O-heterocyclyl; each of which may be substituted with any suitable substituent, including halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R 2 is heterocyclo or cycloalkyl; R 3a is H, alkyl, alkoxy, acyl (e.g., haloalkyl acyl such as fluoroalkyl acyl including C(O)CFH), -N(R b ), amide (e.g., —C(O)NR), aryl, -alkylene-O(R d), benzthiazole (e.g., halo-substituted benzthiazoles such as fluoro-substituted benzthiazoles, including 5- and 6-fluorobenzthiazole), benzoxazole, benzofuranyl, or indolyl; R 3b is SO3Na or CN; R 4 is a natural amino acid side chain (e.g., a hydrophobic natural amino acid side chain such as the side chains of alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan), an unnatural amino acid side chain (e.g., a hydrophobic unnatural amino acid side chain such as the side chains of homoalanine, norvaline, norleucine, and homonorleucine), cycloalkyl, or heterocyclo; R a is H or alkyl; R c is H, alkyl, -C(O)-alkyl, -C(O)-alkylene-N(R a )2; R d is H, -P(O)3(Li)2, -P(O)3(Na)2, or -P(O)(OH)2; X 1 is N or C; X 2 is CH, N, or C(O), where X 1 and X 2 The bond between X may be a single bond, or 1 may be a double bond except when X is N; 1 and X 2 only one of may be N; and n is an integer from 0 to 3; and, The compound The compound, or a pharmaceutically acceptable salt thereof, which is not TIFF2025134881000009.tif25128. [The present invention 1002] The compounds of formula (I), (Ia), (Ib), and (Ic) have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000010.tif68128, or a pharmaceutically acceptable salt thereof. [The present invention 1003] The compounds of formula (I), (Ia), (Ib), and (Ic) have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000011.tif77128, or a pharmaceutically acceptable salt thereof. [The present invention 1004] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000012.tif77128, or a pharmaceutically acceptable salt thereof. [The present invention 1005] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000013.tif77128, or a pharmaceutically acceptable salt thereof. [The present invention 1006] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000014.tif77128, or a pharmaceutically acceptable salt thereof. [The present invention 1007] The compounds of formula (Ib) and (Ic) respectively have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000015.tif67128, or a pharmaceutically acceptable salt thereof. [The present invention 1008] The compounds of formula (Ib) and (Ic) respectively have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000016.tif67128, or a pharmaceutically acceptable salt thereof. [The present invention 1009] The compound of formula (I) has the formula: TIFF2025134881000017.tif27128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: a heterocyclo, such as the heterocyclo group of TIFF2025134881000018.tif10128, 3 is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The compound of claim 1001, wherein the group having the formula: is optionally further substituted, heterocyclo; thiazolyl; or benzthiazolyl. [The present invention 1010] The compound of formula (I) has the formula: TIFF2025134881000019.tif27128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: a heterocyclo, such as the heterocyclo group of TIFF2025134881000020.tif10128, 3 is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The compound of claim 1001, wherein the group having the formula: is optionally further substituted, heterocyclo; thiazolyl; or benzthiazolyl. [The present invention 1011] The compound of formula (Ic) has the formula: TIFF2025134881000021.tif31128, or a pharmaceutically acceptable salt thereof, wherein R 2 is the expression: TIFF2025134881000022.tif11128, wherein X a is the bond, (CH2) d (where d is 1, 2, or 3), O, NR a , or S(O) pwhere R a is H or alkyl, p is 0, 1, or 2, and X a The compound of the present invention, wherein the group having the formula: may be further substituted with OH, alkoxy, amino, or amido. [The present invention 1012] The compounds of formula (I), (Ia), (Ib), and (Ic) have the formula: TIFF2025134881000023.tif115128, or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl, and S(O) p R, wherein R is alkyl or arylalkyl. [The present invention 1013] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: The compound of the present invention 1001 is a compound of TIFF2025134881000024.tif114128, or a pharmaceutically acceptable salt thereof. [The present invention 1014] The compounds of formula (Ib) and (Ic) respectively have the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000025.tif60128, or a pharmaceutically acceptable salt thereof. [The present invention 1015] The compound of formula (I) has the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000026.tif25128, or a pharmaceutically acceptable salt thereof. [The present invention 1016] R 3a 1001. The compound of the present invention or a pharmaceutically acceptable salt thereof, wherein is benzthiazole or benzoxazole. [The present invention 1017] R 3a But the expression: Based on TIFF2025134881000027.tif13128, During the ceremony, R 6is alkyl, alkylamino, cycloalkylamino, cycloalkylheterocycloamino, heterocyclocycloalkylamino, or heterocycloamino; and X 4 is S, O, or NR 7 where R 7 is H, alkyl, cycloalkyl, or alkylaryl; The compound of the present invention or a pharmaceutically acceptable salt thereof. [The present invention 1018] X 4 is S or O, or a pharmaceutically acceptable salt thereof. [The present invention 1019] The compound of formula (I) has the formula: TIFF2025134881000028.tif22128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: a heterocyclo, such as the heterocyclo group of TIFF2025134881000029.tif10128, 3 But bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The compound of claim 1001, wherein the group having the formula: is optionally further substituted, heterocyclo; thiazolyl; or benzthiazolyl. [The present invention 1020] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: Compound 1001 of the present invention is a compound of TIFF2025134881000030.tif49128. [The present invention 1021] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: Compound 1001 of the present invention is a compound of TIFF2025134881000031.tif49128. [The present invention 1022] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: Compound 1001 of the present invention is a compound of TIFF2025134881000032.tif49128. [The present invention 1023] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: Compound 1001 of the present invention is a compound of TIFF2025134881000033.tif72128. [The present invention 1024] formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000034.tif52136, or a pharmaceutically acceptable salt thereof. [The present invention 1025] The respective formulas are: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000035.tif52137, or a pharmaceutically acceptable salt thereof. [The present invention 1026] The respective formulas are: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000036.tif52137, or a pharmaceutically acceptable salt thereof. [The present invention 1027] The respective formulas are: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000037.tif52136, or a pharmaceutically acceptable salt thereof. [The present invention 1028] The respective formulas are: TIFF2025134881000038.tif67128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: 1001. A compound of the present invention, which is a compound of formula (II) TIFF2025134881000039.tif67128, or a pharmaceutically acceptable salt thereof. [The present invention 1029] formula: TIFF2025134881000040.tif31128, or a pharmaceutically acceptable salt thereof, wherein R2 is the expression: TIFF2025134881000041.tif11128, wherein X a is the bond, (CH2) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X a The compound of the present invention, wherein the group having the formula: may be further substituted with substituents such as OH, alkoxy, amino, and amido. [The present invention 1030] formula: TIFF2025134881000042.tif88128, or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl (e.g., C(O)R, where R is defined herein), and S(O) p 1001. The compound of claim 1001, wherein R is R, where R is defined herein. [The present invention 1031] The respective formulas are: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000043.tif89128, or a pharmaceutically acceptable salt thereof. [The present invention 1032] formula: TIFF2025134881000044.tif60128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000045.tif24128, or a pharmaceutically acceptable salt thereof. [The present invention 1033] formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000046.tif103133, or a pharmaceutically acceptable salt thereof. [The present invention 1034] The respective formulas are: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000047.tif50130, or a pharmaceutically acceptable salt thereof. [This invention 1035] The respective formulas are: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000048.tif50130, or a pharmaceutically acceptable salt thereof. [The present invention 1036] Formula (II): The compound of TIFF2025134881000049.tif19128, During the ceremony, R 2 is a heterocyclo; R 3a is alkyl, alkoxy, acyl, amido, aryl, benzthiazole, benzoxazole, benzofuranyl, or indolyl; R 8 and R 9 are independently H or alkyl; or may be taken together with the nitrogen atom to which they are attached to form a heterocyclyl group; and R 10 is alkyl or alkenyl; The compound or a pharmaceutically acceptable salt thereof. [This invention 1037] Formula (III)~(X): TIFF2025134881000050.tif156128TIFF2025134881000051.tif165128, During the ceremony, Each R 11 is H, alkyl, or each R 11 together with the nitrogen atom to which it is attached form a heterocyclyl group; R 12 is H, amino, OH, or alkoxy; R 13 is H, alkyl, amino, or two adjacent R 13groups taken together with the carbon atoms to which they are attached form a 5- or 6-membered aryl or heteroaryl group; Y 2 is O or NR a and; Z is NR a or alkyl; and R a is H or alkyl, The compound or a pharmaceutically acceptable salt thereof. [The present invention 1038] Formulas (XI) to (XII): The compound of TIFF2025134881000052.tif85128, During the ceremony, The dashed lines are single or double bonds; T and T 1 are each independently NR a or C(O); and R a is H or alkyl, The compound or a pharmaceutically acceptable salt thereof. [This invention 1039] formula: Compound 1001 of the present invention is a compound of TIFF2025134881000053.tif38128. [The present invention 1040] formula: TIFF2025134881000054.tif38128, wherein R a is H or alkyl. 1001. A compound of the present invention. [The present invention 1041] formula: 1001. A compound of the present invention, which is a compound of formula TIFF2025134881000055.tif150131, or a pharmaceutically acceptable salt thereof. [The present invention 1042] TIFF2025134881000056.tif193122TIFF2025134881000057.tif171128In the above formula, X 3 is a bond, CH2, O, NR a, or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The group having the formula may be further substituted; may be thiazolyl; or may be benzthiazolyl; TIFF2025134881000058.tif128128In the above formula, Y 1 is CH2, O, or NH and X is OH, OCH3, NH2, or NHCH3; TIFF2025134881000059.tif186128In the above formula, X b is O or NR a and R a is H or alkyl; TIFF2025134881000060.tif193122TIFF2025134881000061.tif20577TIFF2025134881000062.tif41128, or a pharmaceutically acceptable salt thereof. [This invention 1043] TIFF2025134881000063.tif136128TIFF2025134881000064.tif20173TIFF2025134881000065.tif170128TIFF2025134881000066.tif21494, or a pharmaceutically acceptable salt thereof; During the ceremony, R a is H or alkyl; and Each R 1 is independently alkyl or alkoxy; 1001 compounds of the present invention. [This invention 1044] 1001. A compound of the present invention, which is TIFF2025134881000067.tif178133TIFF2025134881000068.tif134133TIFF2025134881000069.tif207133TIFF2025134881000070.tif209133TIFF2025134881000071.tif126134, or a pharmaceutically acceptable salt thereof. [This invention 1045] 1001. A compound of the present invention, which is TIFF2025134881000072.tif127128, or a pharmaceutically acceptable salt thereof. [The present invention 1046] 1001. A compound of the present invention, which is TIFF2025134881000073.tif134133, or a pharmaceutically acceptable salt thereof. [This invention 1047] 1001. A compound of the present invention, which is TIFF2025134881000074.tif182128, or a pharmaceutically acceptable salt thereof. [This invention 1048] 1001. A compound of the present invention, which is TIFF2025134881000075.tif81128TIFF2025134881000076.tif117128, or a pharmaceutically acceptable salt thereof. [This invention 1049] 1001. A compound of the present invention, which is TIFF2025134881000077.tif123128, or a pharmaceutically acceptable salt thereof. [The present invention 1050] 1001. A compound of the present invention, which is TIFF2025134881000078.tif78128, or a pharmaceutically acceptable salt thereof. [This invention 1051] 1001. A compound of the present invention, which is TIFF2025134881000079.tif76128, or a pharmaceutically acceptable salt thereof. [This invention 1052] 1001. A compound of the present invention, which is TIFF2025134881000080.tif46134, or a pharmaceutically acceptable salt thereof. [This invention 1053] 1001. A compound of the present invention, which is TIFF2025134881000081.tif96128TIFF2025134881000082.tif123128, or a pharmaceutically acceptable salt thereof. [This invention 1054] 1001. A compound of the present invention, which is TIFF2025134881000083.tif72128TIFF2025134881000084.tif180128, or a pharmaceutically acceptable salt thereof. [This invention 1055] A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any of 1001 to 1054 of the present invention and at least one pharmaceutically acceptable excipient. [The present invention 1056] 1. A method for treating severe acute respiratory syndrome, comprising: The method comprises administering a therapeutically effective amount of one or more of the compounds of the present invention 1001 to 1054 or the pharmaceutical composition of the present invention 1055 to a patient in need thereof, so that the patient is treated for severe acute respiratory syndrome. [This invention 1057] 1056. The method of claim 1056, wherein the severe acute respiratory syndrome is COVID-19. [Brief explanation of the drawings]

[0012] (Figure 1) Micrographs of SARS-CoV-2-infected Vero-E6 cells treated with GRL-1720S, GRL-2420S, and remdesivir (RDV) show that GRL-1720S and GRL-2420S significantly block the cytotoxic activity (CPE) of SARS-CoV-2. E6 cells were exposed to an IgG fraction (20 μg / ml) derived from Pt-nCoV-03 and then to SARS-CoV-2. Photographs of VeroE6 cells were taken on day 3 after exposure to SARS-CoV-2 in the presence of 20 μg / ml of IgG. The structures of GRL-2420S and GRL-1720S are shown in Fig. 1. The file is TIFF2025134881000085.tif42128. DETAILED DESCRIPTION OF THE INVENTION

[0013] explanation While the concepts of the present disclosure have been shown and described in detail in the drawings and description herein, the results in the drawings and their description are to be considered illustrative and not limiting in character; it being understood that only exemplary embodiments have been shown and described, and that protection of all changes and modifications that come within the spirit of the disclosure is desired.

[0014] The present disclosure relates to compounds that inhibit SARS-CoV-2 and are useful in treating severe acute respiratory syndrome.

[0015] compound The present disclosure provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig): TIFF2025134881000086.tif113128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: TIFF2025134881000087.tif56130, or a pharmaceutically acceptable salt thereof, During the ceremony, A is -N(R a )-alkyl, -O-alkyl, heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -N(R a )-alkylene-heterocyclyl, -N(R a )-aryl, -alkylene-N(R a )-C(O)-heterocyclyl, -alkylene-N(R a )-C(O)-O-heterocyclyl, or -alkylene-N(R a )—C(O)-alkylene-O-heterocyclyl; each of which may be substituted with any suitable substituent, including halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R 2 is heterocyclo or cycloalkyl; R 3a is H, alkyl, alkoxy, acyl (e.g., haloalkyl acyl such as fluoroalkyl acyl including C(O)CFH), -N(R b ), amide (e.g., —C(O)NR), aryl, -alkylene-O(R d ), benzthiazole (e.g., halo-substituted benzthiazoles such as fluoro-substituted benzthiazoles, including 5- and 6-fluorobenzthiazole), benzoxazole, benzofuranyl, or indolyl; R 3b is SO3Na or CN; R 4 is a natural amino acid side chain (e.g., a hydrophobic natural amino acid side chain such as the side chains of alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan), an unnatural amino acid side chain (e.g., a hydrophobic unnatural amino acid side chain such as the side chains of homoalanine, norvaline, norleucine, and homonorleucine), cycloalkyl, or heterocyclo; R a is H or alkyl; R c is H, alkyl, -C(O)-alkyl, -C(O)-alkylene-N(R a )2; R d is H, -P(O)3(Li)2, -P(O)3(Na)2, or -P(O)(OH)2; X 1 is N or C; X 2 is CH, N, or C(O), where X 1 and X 2 The bond between X may be a single bond, or 1 may be a double bond except when X is N; 1 and X 2 only one of may be N; and n is an integer from 0 to 3; and, The compound Not TIFF2025134881000088.tif25128.

[0016] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000089.tif54133, or a pharmaceutically acceptable salt thereof.

[0017] The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: TIFF2025134881000090.tif52135, or a pharmaceutically acceptable salt thereof.

[0018] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000091.tif52135, or a pharmaceutically acceptable salt thereof.

[0019] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000092.tif52128, or a pharmaceutically acceptable salt thereof.

[0020] The compounds of formula (Ib) and (Ic) each have the formula: TIFF2025134881000093.tif67128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: TIFF2025134881000094.tif67128, or a pharmaceutically acceptable salt thereof.

[0021] Examples of compounds of formula (I) are compounds of the formula: TIFF2025134881000095.tif27128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: heterocyclyl, such as the heterocyclyl group of TIFF2025134881000096.tif10128, 3is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The group having the formula: is optionally further substituted heterocyclyl; thiazolyl; or benzthiazolyl.

[0022] Examples of compounds of formula (I) are compounds of the formula: TIFF2025134881000097.tif27128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: Heterocyclyl, such as the heterocyclyl group of TIFF2025134881000098.tif10128, wherein X 3 is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The group having the formula: is optionally further substituted heterocyclyl; thiazolyl; or benzthiazolyl.

[0023] Examples of compounds of formula (Ic) are compounds of the formula: TIFF2025134881000099.tif31128, or a pharmaceutically acceptable salt thereof, wherein R 2 is the expression: TIFF2025134881000100.tif11128, wherein X a is the bond, (CH2) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X a Groups having the formula may be further substituted with substituents such as OH, alkoxy, amino, and amido.

[0024] A is TIFF2025134881000101.tif105150, where: X 5 is N or CH; R b is heterocyclyl (e.g., tetrahydrofuranyl or pyrrolidinyl) or alkyl; X 4 is S, O, or NR 7 and; R 7 is H, alkyl, cycloalkyl, or alkylaryl; and, Each R c are independently H or alkyl.

[0025] Thus, for example, the present disclosure provides compounds of the formula: TIFF2025134881000102.tif88128, or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl (e.g., C(O)R, where R is defined herein), and S(O) p R, where R is defined herein.

[0026] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000103.tif89128, or a pharmaceutically acceptable salt thereof.

[0027] Compounds of formula (Ib) and (Ic) have the formula: TIFF2025134881000104.tif60128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: TIFF2025134881000105.tif24128, or a pharmaceutically acceptable salt thereof.

[0028] Examples of compounds of formula (I) are compounds of the formula: TIFF2025134881000106.tif22128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: Heterocyclyl, such as the heterocyclyl group of TIFF2025134881000107.tif10128, wherein X 3 is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The group having the formula: is optionally further substituted heterocyclyl; thiazolyl; or benzthiazolyl.

[0029] A is Also contemplated herein is a compound, the compound being TIFF2025134881000108.tif14128.

[0030] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000109.tif103131, or a pharmaceutically acceptable salt thereof.

[0031] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000110.tif50128, or a pharmaceutically acceptable salt thereof.

[0032] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000111.tif50128, or a pharmaceutically acceptable salt thereof.

[0033] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000112.tif52135, or a pharmaceutically acceptable salt thereof.

[0034] The compounds of formula (Id), (Ie), (If), and (Ig) each have the formula: TIFF2025134881000113.tif52135, or a pharmaceutically acceptable salt thereof.

[0035] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000114.tif52135, or a pharmaceutically acceptable salt thereof.

[0036] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000115.tif52135, or a pharmaceutically acceptable salt thereof.

[0037] The compounds of formula (If) and (Ig) respectively have the formula: TIFF2025134881000116.tif67128, or a pharmaceutically acceptable salt thereof, for example, each represented by the formula: TIFF2025134881000117.tif67128, or a pharmaceutically acceptable salt thereof.

[0038] Examples of compounds of formula (Ic) are compounds of the formula: TIFF2025134881000118.tif31128, or a pharmaceutically acceptable salt thereof, wherein R 2 is the expression: TIFF2025134881000119.tif11128, wherein X a is the bond, (CH2) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X aGroups having the formula may be further substituted with substituents such as OH, alkoxy, amino, and amido.

[0039] For example, the present disclosure provides compounds of the formula: TIFF2025134881000120.tif88128, or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl (e.g., C(O)R, where R is defined herein), and S(O) p R, where R is defined herein.

[0040] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000121.tif89128, or a pharmaceutically acceptable salt thereof.

[0041] Compounds of formula (If) and (Ig) have the formula: TIFF2025134881000122.tif60128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: TIFF2025134881000123.tif24128, or a pharmaceutically acceptable salt thereof.

[0042] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000124.tif104131, or a pharmaceutically acceptable salt thereof.

[0043] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000125.tif50128, or a pharmaceutically acceptable salt thereof.

[0044] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: TIFF2025134881000126.tif50128, or a pharmaceutically acceptable salt thereof.

[0045] Further compounds contemplated herein have the formula (II): TIFF2025134881000127.tif19128, or a pharmaceutically acceptable salt thereof, During the ceremony, R 2 and R 3a are each defined herein; A is -N(R a )-alkyl, -O-alkyl, heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -N(R a )-alkylene-heterocyclyl, -N(R a )-aryl, -alkylene-N(R a )-C(O)-heterocyclyl, -alkylene-N(R a )-C(O)-O-heterocyclyl, or -alkylene-N(R a )-C(O)-alkylene-O-heterocyclyl, each of which is optionally substituted; R 8 and R 9 are independently H or alkyl; or may be taken together with the nitrogen atom to which they are attached to form a heterocyclyl group; and R 10 is alkyl (eg, heterocyclylalkyl such as tetrahydrofuranylalkyl, oxazolylalkyl, or pyrrolidinylalkyl); or alkenyl.

[0046] A is heterocyclyl, for example a group of the formula: TIFF2025134881000128.tif108132 may be a heterocyclyl group.

[0047] A is heterocyclyl, for example a group of the formula: TIFF2025134881000129.tif39132 may be a heterocyclyl group.

[0048] A is, It could be TIFF2025134881000130.tif11128.

[0049] Further compounds have the formula (III)-(X): TIFF2025134881000131.tif156128TIFF2025134881000132.tif165128, or a pharmaceutically acceptable salt thereof, wherein each R 11 are independently H or alkyl, or each R 11 together with the nitrogen atom to which it is attached form a heterocyclyl group; each R 13 are independently H, alkyl, or amino, or two adjacent R 13 groups taken together with the carbon atoms to which they are attached form a 5- or 6-membered aryl or heteroaryl group; Y 2 is O or NR a and Z is NR a or alkyl (e.g., CH), and R a is H or alkyl.

[0050] Further compounds contemplated herein include those represented by the formula: 1 are each independently NR a or C(O) and R a is H or alkyl; TIFF2025134881000133.tif85128, or a pharmaceutically acceptable salt thereof; for example, a compound of the formula: TIFF2025134881000134.tif39128, comprising the compound of formula: TIFF2025134881000135.tif150128, including the compound of formula: TIFF2025134881000136.tif39128, or a pharmaceutically acceptable salt thereof.

[0051] In any of the examples disclosed herein, R 2 teeth, It could be TIFF2025134881000137.tif56128.

[0052] In any of the examples disclosed herein, R 3a is a benzthiazole or benzoxazole: TIFF2025134881000138.tif13128, where R 6 is alkyl (e.g., C1-C6 alkyl), alkylamino (e.g., C1-C6 alkylamino), cycloalkylamino (e.g., C3-C6 cycloalkylamino), cycloalkylheterocyclylamino (e.g., C3-C6 cycloalkyl-C3-C6 heterocyclylamino), heterocyclylcycloalkylamino (e.g., C3-C6 heterocyclyl-C3-C6 cycloalkylamino), or heterocyclylamino (e.g., C3-C6 heterocyclylamino); X 4 is S, O, or NR 7 where R 7 is H, alkyl, cycloalkyl, or alkylaryl. X 4 can be S or O.

[0053] Examples of compounds of formula (I), (Ia), (Ib), and (Ic) are compounds of the formula: TIFF2025134881000139.tif80134TIFF2025134881000140.tif210134TIFF2025134881000141.tif128128In the above formula, Y 1 is CH2, O, or NH and X is OH, OCH3, NH2, or NHCH3; TIFF2025134881000142.tif94133In the above formula, X b is O or NR aand R a is H or alkyl; TIFF2025134881000143.tif47130TIFF2025134881000144.tif212119TIFF2025134881000145.tif119128, or a pharmaceutically acceptable salt thereof.

[0054] Examples of compounds of formula (II) are compounds of the formula: TIFF2025134881000146.tif181128TIFF2025134881000147.tif22273TIFF2025134881000148.tif174128TIFF2025134881000149.tif143128, or a pharmaceutically acceptable salt thereof.

[0055] Examples of compounds of formula (II) are compounds of the formula: TIFF2025134881000150.tif223133TIFF2025134881000151.tif196116TIFF2025134881000152.tif202128TIFF2025134881000153.tif175128, or a pharmaceutically acceptable salt thereof.

[0056] Examples of compounds of formula (II) are compounds of the formula: TIFF2025134881000154.tif87130, or a pharmaceutically acceptable salt thereof.

[0057] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compounds of TIFF2025134881000155.tif104135.

[0058] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compounds of TIFF2025134881000156.tif109135.

[0059] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compounds of TIFF2025134881000157.tif20281.

[0060] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compounds of TIFF2025134881000158.tif122128.

[0061] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compound of TIFF2025134881000159.tif78128.

[0062] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compounds of TIFF2025134881000160.tif38134.

[0063] Examples of compounds of formula (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, the compound TIFF2025134881000161.tif46132.

[0064] Examples of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, compounds of TIFF2025134881000162.tif96128TIFF2025134881000163.tif123128.

[0065] Examples of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) are compounds of the formula: This includes, but is not limited to, compounds of TIFF2025134881000164.tif72128TIFF2025134881000165.tif180128.

[0066] All diastereomers of compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (II)-(XII) are contemplated herein.

[0067] Treatment method The present disclosure relates to a method for treating severe acute respiratory syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of any one of the above compounds or a pharmaceutical composition comprising same.

[0068] Severe acute respiratory syndrome (SARS) is a viral disease caused by a SARS-related coronavirus.

[0069] Severe acute respiratory syndrome may be due to a coronavirus infection. The coronavirus may be COVID-19.

[0070] Accordingly, the present disclosure provides a method for treating a disease or disorder associated with SARS-CoV-2, comprising administering to a subject suffering therefrom a therapeutically effective amount of a compound or a pharmaceutical composition comprising the same.

[0071] Pharmaceutical Compositions, Routes of Administration, and Dosages Pharmaceutical compositions are provided that include a compound and a pharmaceutically acceptable carrier. The pharmaceutical composition may include multiple compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition may include a pharmaceutically acceptable salt of the compound.

[0072] The pharmaceutical composition may further comprise at least one additional pharmaceutically active agent, which may be an agent useful in the treatment of ischemia-reperfusion injury.

[0073] Pharmaceutical compositions may be prepared by combining one or more compounds with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0074] As stated above, "effective amount" refers to any amount sufficient to achieve a desired biological effect. By selecting from among various active compounds and important factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, combined with the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be designed that is effective for treating a particular subject without causing substantial undesirable toxicity. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the specific compound being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular compound and / or other therapeutic agent without necessitating undue experimentation. A maximum dose, i.e., the highest safe dose according to any medical judgment, may be used. Multiple doses per day may be contemplated to achieve an appropriate systemic level of the compound. An appropriate systemic level may be determined, for example, by measuring the patient's peak or sustained plasma levels of the drug. "Dose" and "administration" are used interchangeably herein. "Dosage unit form" refers to physically discrete units suitable as single dosages for the mammalian subject to be treated, each unit containing a predetermined quantity of active compound calculated to provide the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for each dosage unit form of the invention are determined and directly influenced by the unique properties of the active compound and the particular therapeutic effect to be achieved, as well as the limitations inherent in the technology of formulating such active compounds for the treatment of susceptible individuals. In therapeutic use for the treatment of conditions in mammals (e.g., humans) for which the various embodiments of the compounds described herein, or suitable pharmaceutical compositions thereof, are effective, the various embodiments of the compounds described herein may be administered in an effective amount. Dosages suitable for the present invention may be compositions, pharmaceutical compositions, or any other compositions described herein.

[0075] Generally, the daily oral dose of the compound for a human subject is about 0.01 milligrams / kg / day to 1000 milligrams / kg / day. Oral doses ranging from 0.5 to 50 milligrams / kg can produce therapeutic results, with single or multiple daily administrations. The dosage may be appropriately adjusted to achieve the desired local or systemic drug level, depending on the mode of administration. For example, intravenous administration may vary from one to several orders of magnitude lower daily doses. If the subject's response is inadequate at such doses, even higher doses (or effective higher doses via another, more localized delivery route) may be employed, as tolerated by the patient. Multiple daily doses are contemplated to achieve adequate systemic levels of the compound.

[0076] For any compound, the therapeutically effective amount can be first determined from animal models.The therapeutically effective dose can also be determined from human data for compounds that have been tested in humans and for compounds known to exhibit similar pharmacological activity, such as other related active agents.Higher doses may be required for parenteral administration.Applied doses can be adjusted based on the relative bioavailability and efficacy of the administered compound.As is well known in the art, it is well within the ability of a person skilled in the art to adjust doses to achieve maximum efficacy based on the methods described above and other methods.

[0077] For clinical use, any compound may be administered in an amount equal to or equivalent to 0.2 to 2,000 milligrams (mg) of compound per kilogram (kg) of subject body weight per day. The compound may be administered in an amount equal to or equivalent to 2 to 2,000 mg of compound per kg of subject body weight per day. The compound may be administered in an amount equal to or equivalent to 20 to 2,000 mg of compound per kg of subject body weight per day. The compound may be administered in an amount equal to or equivalent to 50 to 2,000 mg of compound per kg of subject body weight per day. The compound may be administered in an amount equal to or equivalent to 100 to 2,000 mg of compound per kg of subject body weight per day. The compound may be administered in an amount equal to or equivalent to 200 to 2,000 mg of compound per kg of subject body weight per day. When a precursor or prodrug of a compound is administered, it is administered in an amount equivalent to, i.e., sufficient to deliver, the above-mentioned amounts of compound.

[0078] The compound formulations can be administered to human subjects in therapeutically effective amounts. Typical dosage ranges are about 0.01 micrograms / kg to about 2 mg / kg of body weight per day. The administered drug dosage can vary depending on variables such as the type and severity of the disorder, the general health of the particular subject, the specific compound administered, the excipients used to formulate the compound, and its route of administration. Routine experimentation can be used to optimize the dosage and frequency of administration of any particular compound.

[0079] The compounds may be administered at concentrations ranging from about 0.001 micrograms / kg to greater than about 500 mg / kg, for example, concentrations of 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 greater than about 500.0 mg / kg or any increment thereof, it being understood that all values ​​and ranges between these values ​​and ranges are meant to be encompassed.

[0080] The compounds may be administered at dosages ranging from about 0.2 milligrams / kg / day to about greater than 100 mg / kg / day. For example, dosages may range from 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, or 0.25 mg / kg / day to 1 mg / kg / day. 0mg / kg / day, 0.25mg / kg / day~7.5mg / kg / day, 0.25mg / kg / day~5mg / kg / day, 0.5mg / kg / day~50mg / kg / day, 0.5mg / kg / day~25mg / kg / day, 0.5mg / kg / day~20 mg / kg / day, 0.5mg / kg / day ~ 15mg / kg / day, 0.5mg / kg / day ~ 10mg / kg / day, 0.5mg / kg / day ~ 7.5mg / kg / day, 0.5mg / kg / day ~ 5mg / kg / day, 0.75mg / kg / day ~ 50 mg / kg / day, 0.75mg / kg / day~25mg / kg / day, 0.75mg / kg / day~20mg / kg / day, 0.75mg / kg / day~15mg / kg / day, 0.75mg / kg / day~10mg / kg / day, 0.75mg / kg / day~ 7.5mg / kg / day, 0.75mg / kg / day ~ 5mg / kg / day, 1.0mg / kg / day ~ 50mg / kg / day, 1.0mg / kg / day ~ 25mg / kg / day, 1.0mg / kg / day ~ 20mg / kg / day, 1.0mg / kg / day ~ 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.

[0081] The compounds may be administered at dosages ranging from about 0.25 milligrams / kg / day to about 25 mg / kg / day. For example, dosages may 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, 5.0 mg / kg / day, 6.0 mg / kg / day, 7.0 mg / kg / day, 8.0 mg / kg / day, 9.0 mg / kg / day, 10.0 mg / kg / day, 11.0 mg / kg / day, 12.0 mg / kg / day, 13.0 mg / kg / day, 14.0 mg / kg / day, 15.0 mg / kg / day, 16.0 mg / kg / day, 17.0 mg / kg / day, 18.0 mg / kg / day, 19.0 mg / kg / day, 20.0 mg / kg / day, 21.0 mg / kg / day, 22.0 mg / kg / day, 23.0 mg / kg / day, 24.0 mg / kg / day, 25.0 mg / kg / day, 26.0 mg / kg / day, 27.0 mg / kg / day, 28.0 mg / kg / day, 29.0 mg / kg / day, 30.0 mg / kg / day, 31.0 mg / kg / day, 32.0 mg / kg / day g / day, 4.25mg / kg / day, 4.5mg / kg / day, 4.75mg / kg / day, 5mg / kg / day, 5.5mg / kg / day, 6.0mg / kg / day, 6.5mg / kg / day, 7.0mg / kg / day, 7. 5mg / kg / day, 8.0mg / kg / day, 8.5mg / kg / day, 9.0mg / kg / day, 9.5mg / kg / day, 10mg / kg / day, 11mg / kg / day, 12mg / kg / day, 13mg / kg / day, 14 mg / kg / day, 15mg / kg / day, 16mg / kg / day, 17mg / kg / day, 18mg / kg / day, 19mg / kg / day, 20mg / kg / day, 21mg / kg / day, 22mg / kg / day, 23mg / k g / day, 24mg / kg / day, 25mg / kg / day, 26mg / kg / day, 27mg / kg / day, 28mg / kg / day, 29mg / kg / day, 30mg / kg / day, 31mg / kg / day, 32mg / kg / day, 3 It may be 3 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.

[0082] The compound or precursor thereof may be administered at a concentration ranging from 0.01 micromolar to 500 micromolar or more. For example, doses may be 0.01 micromolar, 0.02 micromolar, 0.05 micromolar, 0.1 micromolar, 0.15 micromolar, 0.2 micromolar, 0.5 micromolar, 0.7 micromolar, 1.0 micromolar, 3.0 micromolar, 5.0 micromolar, 7.0 micromolar, 10.0 micromolar, 15.0 micromolar, 20.0 micromolar, 25.0 micromolar, 30.0 micromolar, 35.0 micromolar, 40.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 110.0 micromolar, 120.0 micromolar, 130.0 micromolar, 140.0 micromolar, 150.0 micromolar, 160.0 micromolar, 170.0 micromolar, 180.0 micromolar, 190.0 micromolar, 210.0 micromolar, 220.0 micromolar, 230.0 micromolar, 240.0 micromolar, 250.0 micromolar, 260.0 micromolar, 270.0 micromolar, 280.0 micromolar, 290.0 micromolar, 300.0 micromolar, 310.0 micromolar, 320.0 micromolar, 330.0 micromolar, 340.0 micromolar, 350.0 micromolar, 360.0 micromolar, 370 The range may be from 400.0 micromolar, 45.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 150.0 micromolar, 200.0 micromolar, 250.0 micromolar, 300.0 micromolar, 350.0 micromolar, 400.0 micromolar, 450.0 micromolar to greater than about 500.0 micromolar or any increment therein, and it is understood that all values ​​and ranges therebetween are meant to be encompassed.

[0083] The compound or precursor thereof may be administered at a concentration ranging from 0.10 micrograms / mL to 500.0 micrograms / mL. For example, the concentration may 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 micrograms / mL, 250.0 micrograms / mL, 300.0 micrograms / mL, 350.0 micrograms / mL, 400.0 micrograms / mL, 450.0 micrograms / mL to greater than about 500.0 micrograms / mL, or any increment thereof. It is understood that all values ​​and ranges between these values ​​and ranges are meant to be encompassed.

[0084] The formulation can be administered in a pharmaceutically acceptable solution, which typically contains pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any method that delivers the compound to the desired surface. Administering a pharmaceutical composition can be achieved by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into tumors or abscesses), mucosal (e.g., topically to the eye), inhalation, and topical.

[0085] For intravenous and other parenteral administration routes, the compounds can be formulated as lyophilized preparations, as lyophilized preparations of liposome-intercalated or liposome-encapsulated active compounds, as lipid complexes in aqueous suspension, or as salt complexes. Lyophilized preparations are generally reconstituted in a suitable aqueous solution, such as sterile water or physiological saline, immediately prior to administration.

[0086] For oral administration, compounds can be easily formulated by combining active compounds with pharmaceutically acceptable carriers known in the art.Such carriers allow compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated.Pharmaceutical preparations for oral use can be obtained as solid excipients, and optionally, the resulting mixture is ground, and if desired, the granular mixture is processed after adding suitable excipients 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, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP), etc. If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Optionally, oral preparations may also be formulated in saline or buffers, such as EDTA, to neutralize internal acidic conditions, or may be administered without any carrier.

[0087] Oral dosage forms of the compounds are also contemplated. The compounds can be chemically modified to enable effective oral delivery of the derivatives. Generally, contemplated chemical modifications involve the attachment of at least one moiety to the compound itself, where the moiety (a) inhibits acid hydrolysis and (b) allows uptake into the bloodstream from the stomach or intestine. Increasing the overall stability of the compound and increasing its circulation time in the body are also desirable. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts," In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, 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, for pharmaceutical applications, polyethylene glycol moieties are preferred.

[0088] The location of release of the compound may be the stomach, the small intestine (duodenum, jejunum, or ileum), or the large intestine. Those skilled in the art have available formulations that will not dissolve in the stomach but will release the substance in the duodenum or elsewhere in the intestine. Release may avoid the harmful effects of the stomach environment either by protecting the compound or by releasing the compound beyond the stomach environment, for example, in the intestine.

[0089] To ensure adequate gastric resistance, a coating that is impermeable down to at least pH 5.0 is essential. Examples of more common inactive ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP50, HPMCP55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may also be used as mixed films.

[0090] Coatings or mixtures of coatings may also be used on tablets not intended for gastric protection. This may include sugar coatings or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic agents (e.g., powder); a soft gelatin shell may be used for liquid forms. The shell material for cachets may be thick starch or other edible paper. Moist massing techniques may be used for pills, troches, molded tablets, or crushed tablets.

[0091] The therapeutic agent can be included in the formulation as fine multiparticulates 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, lightly compressed plugs, or even tablets. The therapeutic agent can be prepared by compression.

[0092] Colorants and flavorings may all be included. For example, the compound may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage, that contains colorants and flavorings.

[0093] Therapeutic agents may be diluted or augmented with inert materials. These diluents may include carbohydrates, particularly mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts, including calcium triphosphate, 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.

[0094] Disintegrants may be included in the formulation of solid dosage forms of therapeutic agents. Materials used as disintegrants include, but are not limited to, starch, including the commercially available starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, natural sponge, and bentonite may all be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums may be used as disintegrants and binders, including powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0095] Binders may be used to hold the therapeutic substance together to form a hard tablet and include materials from natural sources such as acacia, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and HPMC may both be used in alcoholic solutions to granulate the therapeutic substance.

[0096] Antifriction agents may be included in the therapeutic agent formulation to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic agent and the mold wall, and may include, but are not limited to, 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, and Carbowax 4000 and 6000 may also be used.

[0097] Lubricants may be added to improve the flow properties of the drug during formulation and to aid rearrangement during compression. Lubricants may include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0098] Surfactants may be added as wetting agents to aid in dissolving the therapeutic substance in the aqueous environment. Surfactants may 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, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present in the formulation of the compound or its derivatives either alone or as a mixture in different ratios.

[0099] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the 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, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well-defined in the art. All formulations intended for oral administration should be in a dosage suitable for such administration.

[0100] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0101] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0102] For administration by inhalation, compound can be conveniently delivered in the form of aerosol spray from pressurized pack or nebulizer, using suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.In the case of pressurized aerosol, dosage unit can be determined by providing a valve to deliver a metered amount.For example, capsules and cartridges of gelatin for use in inhaler or insufflator can be formulated to contain a powder mixture of compound and suitable powder base, for example, lactose or starch.

[0103] Pulmonary delivery of the compound (or salt thereof) is also contemplated. During inhalation, the compound is delivered to the lungs of a mammal and passes through the lung epithelial lining into the bloodstream. Other reports of inhaled molecules include 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) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α1-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 pulmonary delivery of drugs for systemic effect are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al. (specifically incorporated by reference for its disclosure in this regard).

[0104] Contemplated for use are a wide variety of mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and dry powder inhalers, all of which are well known to those skilled in the art.

[0105] Nasal delivery of pharmaceutical compositions is also contemplated. Nasal delivery allows the pharmaceutical composition to enter 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 nasal delivery include formulations using dextran or cyclodextrin.

[0106] When it is desired to deliver the compounds systemically, they can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The injection preparations can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with preservatives added. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.

[0107] Pharmaceutical preparations for parenteral administration include aqueous solutions of water-soluble active compounds.In addition, suspensions of active compounds 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 suspensions, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, suspensions can also contain suitable stabilizers or agents that increase the solubility of compounds, so as to allow the preparation of highly concentrated solutions.

[0108] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0109] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0110] In addition to the formulations described above, the compounds can also be formulated as sustained-release preparations. Such long-acting preparations can be formulated using suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0111] The pharmaceutical compositions may also comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0112] Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous solutions or saline solutions for inhalation, microencapsulated, encapsulated, coated with fine gold particles, contained in liposomes, atomized, aerosolized, pellets for skin implantation, or dried on a sharp object and rubbed onto the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, droplets, or preparations for extended release of active compounds, in which excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are commonly used as described above. Pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-1533 (1990).

[0113] The compound and, optionally, one or more other therapeutic agents may be administered as such (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt should be pharmaceutically acceptable, although pharmaceutically unacceptable salts may be conveniently used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, 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. Such salts may also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0114] Suitable buffering agents 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).

[0115] Pharmaceutical compositions contain an effective amount of the compounds described herein contained in a pharmaceutically acceptable carrier, and optionally one or more therapeutic substances. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents or encapsulating materials suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic component with which active ingredients are combined to facilitate application. The components of pharmaceutical compositions can also be mixed with the compound and with each other in a manner that does not cause any interaction that would substantially impair the desired pharmaceutical effect.

[0116] The therapeutic agent, including but not limited to a compound, may be provided in a particle. "Particle" refers to a nanoparticle or microparticle (or, in some cases, a larger particle) that may be composed entirely or partially of a compound or other therapeutic agent described herein. The particle may contain a therapeutic agent within a core surrounded by a coating, including but not limited to an enteric coating. The therapeutic agent may also be dispersed throughout the particle. The therapeutic agent may also be adsorbed to the particle. The particle may have 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. In addition to the therapeutic agent, the particle may contain any of the materials routinely used in the pharmaceutical and medical arts, including but not limited to erodible, nonerodible, biodegradable, or nonbiodegradable materials, or combinations thereof. The particle may be a microcapsule containing the compound in solution or in a semi-solid state. The particle may be virtually any shape.

[0117] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering therapeutic agents. Such polymers can be natural or synthetic. The polymer is selected based on the desired period of release. Bioadhesive polymers of particular interest include 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).

[0118] 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 manner and profile of drug release from the formulation is controlled. This refers to immediate and non-immediate release formulations, which include, but are not limited to, sustained and delayed release formulations. The term "sustained release" (also called "extended release") is used in its conventional sense to refer to a drug formulation that provides gradual release of drug over an extended period of time and can result in a substantially constant blood concentration of drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of drug therefrom. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and thus may or may not be a "sustained release."

[0119] The use of long-term sustained-release implants may be particularly suitable for treating chronic conditions. "Long-term" release means that the implant is constructed and adapted to deliver therapeutic levels of the active ingredient for at least 7 days, and up to 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.

[0120] definition For convenience, some terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as would be 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 those skilled in the art.

[0121] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0122] The term "and / or" in the specification and claims should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are sometimes conjoined and sometimes separate. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related to the specifically identified elements or not. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" may refer to A only (optionally including elements other than B); or B only (optionally including elements other than A); or even both A and B (optionally including other elements), etc.

[0123] In the specification and claims, "or" should 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" shall be interpreted as being inclusive, i.e., including at least one of the number or list of elements, but also including more than one, and optionally including additional unlisted elements. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one of the number or list of elements. In general, the term "or" shall be interpreted to indicate exclusive alternatives (i.e., "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.

[0124] In the specification and claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This provision also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related to the specifically identified elements or not. Thus, as a non-limiting example, "at least one of A and B" (or, similarly, "at least one of A or B" or, similarly, "at least one of A and / or B") can refer to the presence of at least one A, optionally including more than one A, and no B (optionally including elements other than B); or the presence of at least one B, optionally including more than one B, and no A (optionally including elements other than A); or further, the presence of at least one A, optionally including more than one A, and the presence of at least one B, optionally including more than one B (optionally including other elements), etc.

[0125] It is also understood that in any method claimed herein that includes more than one step or act, unless expressly stated to the contrary, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are described.

[0126] In the claims, as in the foregoing specification, any transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including, but not limited to,

[0127] 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, racemic mixtures thereof, and other mixtures thereof, to be encompassed within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present disclosure.

[0128] For example, if a particular enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with a suitable optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0129] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of hydrogen by deuterium or tritium, or carbon by a C- or C-enriched carbon are within the scope of the disclosure.

[0130] The phrase "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, that is involved in carrying or transporting a chemical substance of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. 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, e.g., sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower 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) buffers 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; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations. The pharmaceutical compositions of the present disclosure are non-pyrogenic, i.e., they do not induce a significant temperature increase when administered to a patient.

[0131] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of compounds. These salts can be prepared in situ during the final isolation and purification of the compounds, or separately by reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. 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 (see, e.g., Berge et al. (1977) "Pharmaceutical Salts" J. Pharm. Sci. 66:1-19).

[0132] In other cases, compounds useful in the methods may contain one or more acidic functional groups and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to 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 separately by reacting the purified compounds in their free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0133] A "therapeutically effective amount" (or "effective amount") of a compound, with respect to use in therapy, refers to the amount of compound in a preparation that, when administered (to a mammal such as a human) as part of a desired dosing regimen, alleviates the symptoms, improves the condition, or delays the onset of a disease state in accordance with clinically acceptable criteria for the disorder or condition being treated or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0134] The term "prophylactic or therapeutic" treatment is art-recognized and includes 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 condition in a host animal), the treatment is prophylactic (i.e., protects the host from the development of the undesirable condition), whereas when administered after the appearance of the undesirable condition, the treatment is therapeutic (i.e., is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0135] The term "patient" or "subject" refers to a mammal suffering from a disease, disorder, or condition. The patient or subject may be a primate, dog, cat, or horse. The patient may be a bird. The bird may be a domesticated bird, such as a chicken. The bird may be poultry. The patient or subject may be a human.

[0136] Aliphatic chains include alkyl, alkenyl, and alkynyl groups as defined below. Straight chain aliphatic chains are limited to unbranched carbon chain moieties. The term "aliphatic group" refers to a straight, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0137] "Alkyl" refers to a fully saturated, cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms, or if not specified, up to 30 carbon atoms. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl of 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 has 30 or fewer carbon atoms in its backbone (e.g., C1-C for straight chain). 30 , C3 to C for branched chains 30 ), or up to 20 carbon atoms. Alkyl groups can be substituted or unsubstituted.

[0138] The term "alkylene" refers to an alkyl group having a specified number of carbons, e.g., 2 to 12 carbon atoms, and containing two points of attachment to the remainder of the compound on the longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moieties, and may be substituted with one or more substituents.

[0139] "Cycloalkyl" means mono- or bicyclic, or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. In various aspects, cycloalkyls have from 3 to 10 carbon atoms in their ring structure, or from 3 to 6 carbon atoms in the ring structure. Cycloalkyl groups can be substituted or unsubstituted.

[0140] Unless the number of carbon atoms is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from 1 to 10 carbons, or from 1 to 6 carbon atoms, in its backbone structure, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Substituents designated herein as alkyl may be lower alkyls.

[0141] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having one or more double bonds, having a specified number of carbon atoms, or up to 26 carbon atoms if no limitation to the number of carbon atoms is specified. Alkenyls having 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, 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 the moiety and may have either the (Z) or (E) configuration around the double bond.

[0142] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but which contains one or more triple bonds.

[0143] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur moiety attached thereto. The "alkylthio" moiety can be represented by one of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH)-R, where m and R are defined below. Representative alkylthio groups include methylthio, ethylthio, and the like. The term "alkoxyl" or "alkoxy" refers to an alkyl group, as defined below, having an oxygen moiety attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, substituents of an alkyl that render the alkyl an ether are -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH)R. 10 wherein m and R are or resemble alkoxyl such that they can be represented by one of 10 are listed below.

[0144] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, for example, amines of the formula: TIFF2025134881000166.tif10128, wherein 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 polycyclyl; and m is zero or an integer ranging from 1 to 8. In some cases, R 11 or R 12 Only one of R 11 , R 12 , and nitrogen together do not form an imide. 11 and R 12are each independently hydrogen, alkyl, alkenyl, or -(CH2) m -R 10 Thus, the term "alkylamine" refers to an amine having a substituted or unsubstituted alkyl attached thereto, i.e., R 11 and R 12 where at least one of the groups is an alkyl group. Amino groups or alkylamines are basic, meaning that they have a conjugate acid with a pKa > 7.00, i.e., the protonated forms of these functional groups have a pKa with respect to water of greater than about 7.00.

[0145] The term "amide" refers to the group: TIFF2025134881000167.tif15128, where each R 13 independently represent 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.

[0146] 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, aryl groups include 5- to 12-membered rings or 6- to 10-membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two adjacent rings share two or more carbons, where at least one of the rings is aromatic and the other cyclic ring can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. 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 in which the ring structure contains 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 may 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, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. For example, the aryl group may be unsubstituted C5-C12 aryl or substituted C5-C10 aryl.

[0147] The terms "halo," "halide," or "halogen" mean halogen and include, but are not limited to, fluoro, chloro, bromo, iodo, and the like, in both radioactive and non-radioactive forms. Halo may be selected from the group consisting of fluoro, chloro, and bromo.

[0148] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 12-membered ring structures, 5- to 12-membered rings, or 5- to 10-membered rings whose ring structures contain 1-4 heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocycles 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, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with the substituents described above, such as halogen, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0149] The term "carbonyl" is art-recognized and has the formula: TIFF2025134881000168.tif11128, wherein X' is a bond or represents oxygen, nitrogen, or sulfur; R14 represents hydrogen, an alkyl, alkenyl, -(CH2)m-R10, or a pharmaceutically acceptable salt; and R15 represents hydrogen, an 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 moiety is referred to herein as a carboxyl group, and particularly 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 of the above formula is replaced with sulfur, the formula represents a "thiocarbonyl" group. Where X' is a sulfur and R14 or R15 is not hydrogen, the formula represents a "thioester" group. Where X' is a sulfur and R14 is hydrogen, the formula represents a "thiocarboxylic acid" group. Where X' is a sulfur and R15 is hydrogen, the formula represents a "thioformate" group. On the other hand, where X' is a bond and R14 is not hydrogen, the above formula represents a "ketone" group. Where X' is a bond and R14 is hydrogen, the above formula represents an "aldehyde" group.

[0150] The term "nitro" means -NO2; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO2-; the term "azido" means -N3; ​​the term "cyano" means -CN; the term "isocyanato" means -NCO; the term "thiocyanato" means -SCN; the term "isothiocyanato" means -NCS; and the term "cyanato" means -OCN.

[0151] The definition of each designation, eg, alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0152] The term "substituted" refers to moieties having substituents replacing hydrogen on one or more carbons of the main chain. It is understood that "substituted" or "substituted with" implicitly includes the proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, and the like. 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 nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different, for appropriate organic compounds. Heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. 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, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aryl, or aromatic or heteroaromatic moieties. Substituents on substituted alkyls can be selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. Substituents on substituted alkyls can be selected from fluoro, carbonyl, cyano, or hydroxyl. Those of skill in the art will understand that the substituents themselves can be substituted, where appropriate. Unless specifically described as "unsubstituted," references herein to chemical moieties are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0153] In this disclosure, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, found inside the cover of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0154] All patents, published patent applications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All such publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0155] The inventions illustratively described herein may suitably be practiced in the absence of any element or limitation not specifically disclosed herein. Thus, for example, any occurrence herein 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 type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0156] The terms and expressions employed are used as terms of description and not of limitation. In this regard, if a particular term is defined under "Definitions" and is otherwise defined, explained, or discussed anywhere in the "Detailed Description," all such definitions, explanations, and discussions are intended to be attributable to such terms. Nor is the use of such terms and expressions intended to exclude all equivalents to the features shown and described or portions thereof. Further, while subheadings such as "Definitions" are used in the "Detailed Description," for example, such use is for ease of reference only and is not intended to limit any disclosure provided in one section to only that section; rather, any disclosure provided under one subheading is intended to apply to disclosures under all other subheadings as well.

[0157] It will be appreciated by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the present disclosure contained herein in light of information known to those skilled in the art, and may be made without departing from the scope of the present disclosure. While the present disclosure has been described in detail above, it will be more clearly understood by reference to the following examples, which are for illustrative purposes only and are not intended to be limiting of the disclosure. [Example]

[0158] The present invention may be better understood by reference to the following examples, which are provided by way of illustration and not by way of limitation.

[0159] ((S)-1-(((S)-1-(benzo[d]thiazol-2-yl)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl Step 1: To a stirred solution of bis-THF carbonate (60 mg, 0.20 mmol) in acetonitrile (3 mL) at 280 °C was added (S)-leucine methyl ester (55 mg, 0.30 mmol) and DIPEA (0.19 mL, 1.01 mmol). The reaction mixture was stirred at 23 °C for 24 h. The solvent was removed, and the residue was purified by flash chromatography to give the methyl ester (40.2 mg, 65%) as a solid. The above ester was treated with 1 M aqueous LiOH solution at 0 °C. After 6 h, the mixture was acidified to pH 3, extracted with ethyl acetate, dried over NaSO, and concentrated under reduced pressure. The crude acid was used in the next coupling reaction without further purification.

[0160] Step 2: TIFF2025134881000170.tif30146 To a stirred solution of acid (15 mg) and amine (18 mg) in dry DMF was added HBTU (24 mg) and DIPEA (0.1 mL) at 0 °C, and the resulting mixture was stirred at 23 °C for 24 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, dried over Na2SO4, and concentrated. The crude material was purified by column chromatography using MeOH-DCM as the eluent to give the title compound (10 mg, 35% yield) as an off-white solid. TIFF2025134881000171.tif58128

[0161] Aspects The present invention provides the following exemplary aspects, the numbering of which should not be construed as defining an order of importance. Embodiment 1 is a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig): TIFF2025134881000172.tif113131, or a pharmaceutically acceptable salt thereof, During the ceremony, A is -N(R a )-alkyl, -O-alkyl, heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -N(Ra )-alkylene-heterocyclyl, -N(R a )-aryl, -alkylene-N(R a )-C(O)-heterocyclyl, -alkylene-N(R a )-C(O)-O-heterocyclyl, or -alkylene-N(R a )—C(O)-alkylene-O-heterocyclyl; each of which may be substituted with any suitable substituent, including halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R 2 is heterocyclo or cycloalkyl; R 3a is H, alkyl, alkoxy, acyl (e.g., haloalkyl acyl such as fluoroalkyl acyl including C(O)CFH), -N(R b ), amide (e.g., —C(O)NR), aryl, -alkylene-O(R d ), benzthiazole (e.g., halo-substituted benzthiazoles such as fluoro-substituted benzthiazoles, including 5- and 6-fluorobenzthiazole), benzoxazole, benzofuranyl, or indolyl; R 3b is SO3Na or CN; R 4 is a natural amino acid side chain (e.g., a hydrophobic natural amino acid side chain such as the side chains of alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan), an unnatural amino acid side chain (e.g., a hydrophobic unnatural amino acid side chain such as the side chains of homoalanine, norvaline, norleucine, and homonorleucine), cycloalkyl, or heterocyclo; R a is H or alkyl; R c is H, alkyl, -C(O)-alkyl, -C(O)-alkylene-N(R a )2; R d is H, -P(O)3(Li)2, -P(O)3(Na)2, or -P(O)(OH)2; X 1is N or C; X 2 is CH, N, or C(O), where X 1 and X 2 The bond between X may be a single bond, or 1 may be a double bond except when X is N; 1 and X 2 only one of may be N; and n is an integer from 0 to 3; and, The compound Not TIFF2025134881000173.tif25128. Aspect 2 is directed to compounds of formula (I), (Ia), (Ib), and (Ic) having the formula: TIFF2025134881000174.tif69128, or a pharmaceutically acceptable salt thereof. Aspect 3 is where the compounds of Formulas (I), (Ia), (Ib), and (Ic) have the formula: TIFF2025134881000175.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 4 is where the compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: TIFF2025134881000176.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 5 is where the compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula: TIFF2025134881000177.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 6 is directed to compounds of formula (I), (Ia), (Ib), and (Ic), each of which has the formula: TIFF2025134881000178.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 7 is where the compounds of formula (Ib) and (Ic) each have the formula: TIFF2025134881000179.tif67128, or a pharmaceutically acceptable salt thereof. Aspect 8 is wherein the compounds of formula (Ib) and (Ic) each have the formula: TIFF2025134881000180.tif67128, or a pharmaceutically acceptable salt thereof. Aspect 9 is the compound of formula (I) having the formula: TIFF2025134881000181.tif27128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: a heterocyclo, such as the heterocyclo group of TIFF2025134881000182.tif10128, 3 is bond, CH2, O, NR a , or S(O) p where p is 0, 1, or 2, and X 3 is optionally further substituted heterocyclo; thiazolyl; or benzthiazolyl. Aspect 10 is the compound of formula (I) having the formula: TIFF2025134881000183.tif27128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: a heterocyclo, such as the heterocyclo group of TIFF2025134881000184.tif10128, 3 is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 is optionally further substituted heterocyclo; thiazolyl; or benzthiazolyl. Aspect 11 is wherein the compound of Formula (Ic) has the formula: TIFF2025134881000185.tif31128, or a pharmaceutically acceptable salt thereof, wherein R 2 is the expression: TIFF2025134881000186.tif11128, wherein X a is the bond, (CH2) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X a The group having the formula: may be further substituted with substituents such as OH, alkoxy, amino, and amido. Aspect 12 is directed to compounds of Formulas (I), (Ia), (Ib), and (Ic) having the formula: TIFF2025134881000187.tif88128, or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl, and S(O) p R, where R is alkyl or arylalkyl. Aspect 13 is directed to compounds of Formulas (I), (Ia), (Ib), and (Ic), each of which has the formula: 13. The compound of claim 1, 2, and 12, wherein the compound is a compound of formula TIFF2025134881000188.tif89128, or a pharmaceutically acceptable salt thereof. Aspect 14 is wherein the compounds of Formula (Ib) and (Ic) each have the formula: 14. The compound of claim 1, 2, 12, and 13, wherein the compound is a compound of formula TIFF2025134881000189.tif60128, or a pharmaceutically acceptable salt thereof. Aspect 15 is wherein the compound of Formula (I) has the formula: TIFF2025134881000190.tif24128, or a pharmaceutically acceptable salt thereof. Aspect 16 is R 3a16. The compound of any one of embodiments 12 to 15, or a pharmaceutically acceptable salt thereof, wherein is benzthiazole or benzoxazole. Embodiment 17 relates to a compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein R 3a But the expression: Based on TIFF2025134881000191.tif13128, During the ceremony, R 6 is alkyl, alkylamino, cycloalkylamino, cycloalkylheterocycloamino, heterocyclocycloalkylamino, or heterocycloamino; and X 4 is S, O, or NR 7 where R 7 is H, alkyl, cycloalkyl, or alkylaryl. Aspect 18 is X 4 is S or O; or a pharmaceutically acceptable salt thereof. Aspect 19 is directed to compounds of formula (I) having the formula: TIFF2025134881000192.tif22128, or a pharmaceutically acceptable salt thereof, wherein R 5 is the expression: a heterocyclo, such as the heterocyclo group of TIFF2025134881000193.tif10128, 3 is bond, CH2, O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 is optionally further substituted heterocyclo; thiazolyl; or benzthiazolyl. Aspect 20 is directed to compounds of Formulas (I), (Ia), (Ib), and (Ic), each of which has the formula: TIFF2025134881000194.tif103128 or a pharmaceutically acceptable salt thereof. Aspect 21 is directed to compounds of Formulas (I), (Ia), (Ib), and (Ic), each of which has the formula: TIFF2025134881000195.tif50128 or a pharmaceutically acceptable salt thereof. Aspect 22 is directed to compounds of Formulas (I), (Ia), (Ib), and (Ic), each of which has the formula: TIFF2025134881000196.tif50128 or a pharmaceutically acceptable salt thereof. Aspect 23 is directed to compounds of Formulas (I), (Ia), (Ib), and (Ic), each of which has the formula: TIFF2025134881000197.tif50128 or a pharmaceutically acceptable salt thereof. Aspect 24 is a compound of formula (II): TIFF2025134881000198.tif19128, or a pharmaceutically acceptable salt thereof, During the ceremony, R 2 and R 3a are each defined herein; R 8 and R 9 are independently H or alkyl; or may be taken together with the nitrogen atom to which they are attached to form a heterocyclyl group; and R 10 is alkyl or alkenyl. Aspect 25 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig) having the formula: TIFF2025134881000199.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 26 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig), each of which has the formula: TIFF2025134881000200.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 27 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig), each of which has the formula: TIFF2025134881000201.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 28 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig), each of which has the formula: TIFF2025134881000202.tif52135, or a pharmaceutically acceptable salt thereof. Aspect 29 is directed to compounds of formula (If) and (Ig), each of which has the formula: TIFF2025134881000203.tif67128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: TIFF2025134881000204.tif67128, or a pharmaceutically acceptable salt thereof. Aspect 30 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig) having the formula: TIFF2025134881000205.tif31128, or a pharmaceutically acceptable salt thereof, wherein R 2 is the expression: TIFF2025134881000206.tif11128, wherein X a is the bond, (CH2) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X a The group having the formula: relates to compounds of embodiment 1, which may be further substituted with substituents such as OH, alkoxy, amino, and amido. Aspect 31 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig) having the formula: TIFF2025134881000207.tif88128, or a pharmaceutically acceptable salt thereof, wherein R dis H, alkyl, acyl (e.g., C(O)R, where R is defined herein), and S(O) p R, where R is defined herein. Aspect 32 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig), each of which has the formula: TIFF2025134881000208.tif89128, or a pharmaceutically acceptable salt thereof. Aspect 33 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig) having the formula: TIFF2025134881000209.tif60128, or a pharmaceutically acceptable salt thereof, for example, a compound of the formula: TIFF2025134881000210.tif24128, or a pharmaceutically acceptable salt thereof. Aspect 34 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig) having the formula: TIFF2025134881000211.tif103131, or a pharmaceutically acceptable salt thereof. Aspect 35 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig), each of which has the formula: TIFF2025134881000212.tif50128, or a pharmaceutically acceptable salt thereof. Aspect 36 is directed to compounds of Formulas (Id), (Ie), (If), and (Ig), each of which has the formula: TIFF2025134881000213.tif50128, or a pharmaceutically acceptable salt thereof. Aspect 37 is a compound of Formulas (III)-(X): TIFF2025134881000214.tif156128TIFF2025134881000215.tif165128, or a pharmaceutically acceptable salt thereof, During the ceremony, Each R 11is H, alkyl, or each R 11 together with the nitrogen atom to which they are attached form a heterocyclyl group; R 12 is H, amino, OH, or alkoxy; R 13 is H, alkyl, amino, or two adjacent R 13 groups taken together with the carbon atoms to which they are attached form a 5- or 6-membered aryl or heteroaryl group; Y 2 is O or NR a and; Z is NR a or alkyl; and R a is H or alkyl. Aspect 38 is a compound of formula (XI)-(XII): TIFF2025134881000216.tif84128 or a pharmaceutically acceptable salt thereof, During the ceremony, The dashed lines are single or double bonds; T and T 1 are each independently NR a or C(O); and R a is H or alkyl. Aspect 39 is a compound of the formula: The compound of embodiment 1 is the compound of TIFF2025134881000217.tif38128. Aspect 40 is a compound of the formula: The compound of embodiment 1 is the compound of TIFF2025134881000218.tif38128. Aspect 41 is a compound of the formula: TIFF2025134881000219.tif150128, or a pharmaceutically acceptable salt thereof. Aspect 42 is a compound of the formula: TIFF2025134881000220.tif193114TIFF2025134881000221.tif21073TIFF2025134881000222.tif90128In the above formula, Y 1 is CH2, O, or NH and X is OH, OCH3, NH2, or NHCH3; TIFF2025134881000223.tif94128In the above formula, X b is O or NR a and R a is H or alkyl; TIFF2025134881000224.tif191130TIFF2025134881000225.tif20477, or a pharmaceutically acceptable salt thereof. Aspect 43 is a compound of the formula: TIFF2025134881000226.tif181128TIFF2025134881000227.tif22273TIFF2025134881000228.tif174128TIFF2025134881000229.tif143128, or a pharmaceutically acceptable salt thereof. Aspect 44 is a compound of the formula: TIFF2025134881000230.tif221133TIFF2025134881000231.tif223132TIFF2025134881000232.tif224128TIFF2025134881000233.tif83128, or a pharmaceutically acceptable salt thereof. Aspect 45 is a compound of the formula: TIFF2025134881000234.tif86129, or a pharmaceutically acceptable salt thereof. Aspect 46 is a compound of the formula: TIFF2025134881000235.tif103135, or a pharmaceutically acceptable salt thereof. Aspect 47 is a compound of the formula: TIFF2025134881000236.tif113137, or a pharmaceutically acceptable salt thereof. Aspect 48 is a compound of the formula: TIFF2025134881000237.tif20383, or a pharmaceutically acceptable salt thereof. Aspect 49 is a compound of the formula: TIFF2025134881000238.tif119128, or a pharmaceutically acceptable salt thereof. Embodiment 50 is a compound having the formula: TIFF2025134881000239.tif78128, or a pharmaceutically acceptable salt thereof. Aspect 51 is a compound of the formula: TIFF2025134881000240.tif38135, or a pharmaceutically acceptable salt thereof. Aspect 52 is a compound of the formula: TIFF2025134881000241.tif46134, or a pharmaceutically acceptable salt thereof. Aspect 53 is a compound of the formula: TIFF2025134881000242.tif186128TIFF2025134881000243.tif33128, or a pharmaceutically acceptable salt thereof. Aspect 54 is a compound of the formula: TIFF2025134881000244.tif166128TIFF2025134881000245.tif87128, or a pharmaceutically acceptable salt thereof. Embodiment 55 relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of embodiments 1-54 and at least one pharmaceutically acceptable excipient. Embodiment 56 relates to a method for treating severe acute respiratory syndrome, comprising administering a therapeutically effective amount of one or more of the compounds of embodiments 1-54 or the pharmaceutical composition of embodiment 55 to a patient in need thereof. Embodiment 57 relates to the method of embodiment 56, wherein the severe acute respiratory syndrome is COVID-19.

Claims

1. Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig): A compound of the formula: During the ceremony, A is -N(R a )-alkyl, -O-alkyl, heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -N(R a )-alkylene-heterocyclyl, -N(R a )-aryl, -alkylene-N(R a )-C(O)-heterocyclyl, -alkylene-N(R a )-C(O)-O-heterocyclyl, or -alkylene-N(R a )—C(O)-alkylene-O-heterocyclyl; each of which may be substituted with any suitable substituent, including halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R 2 is heterocyclo or cycloalkyl; R 3a is H, alkyl, alkoxy, acyl (e.g., C(O)CF 2 haloalkyl acyl such as fluoroalkyl acyl containing -N(R b ), amides (e.g., -C(O)NR 2 ), aryl, -alkylene-O(R d ), benzthiazole (e.g., halo-substituted benzthiazoles such as fluoro-substituted benzthiazoles, including 5- and 6-fluorobenzthiazole), benzoxazole, benzofuranyl, or indolyl; R 3b SO 3 Na or CN; R 4 is a natural amino acid side chain (e.g., a hydrophobic natural amino acid side chain such as the side chains of alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, and tryptophan), an unnatural amino acid side chain (e.g., a hydrophobic unnatural amino acid side chain such as the side chains of homoalanine, norvaline, norleucine, and homonorleucine), cycloalkyl, or heterocyclo; R a is H or alkyl; R c is H, alkyl, -C(O)-alkyl, -C(O)-alkylene-N(R a ) 2 and R d is H, -P(O) 3 (Li) 2 , -P(O) 3 (Na) 2 , or -P(O)(OH) 2 and X 1 is N or C; X 2 is CH, N, or C(O), where X 1 and X 2 The bond between X may be a single bond, or 1 may be a double bond except when X is N; 1 and X 2 only one of may be N; and n is an integer from 0 to 3; and, The compound or a pharmaceutically acceptable salt thereof, which is not

2. The compounds of formula (I), (Ia), (Ib), and (Ic) have the formula:

2. The compound of claim 1, wherein the compound is:

3. The compounds of formula (I), (Ia), (Ib), and (Ic) have the formula:

2. The compound of claim 1, wherein the compound is:

4. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is:

5. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is:

6. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is:

7. The compounds of formula (Ib) and (Ic) respectively have the formula:

2. The compound of claim 1, wherein the compound is:

8. The compounds of formula (Ib) and (Ic) respectively have the formula:

2. The compound of claim 1, wherein the compound is:

9. The compound of formula (I) has the formula: or a pharmaceutically acceptable salt thereof, wherein R 5 is the formula: and a heterocyclo such as a heterocyclo group of the formula: 3 is bond, CH 2 , O, N.R. a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 2. The compound of claim 1, wherein the group having the formula: is optionally further substituted heterocyclo; thiazolyl; or benzthiazolyl.

10. The compound of formula (I) has the formula: or a pharmaceutically acceptable salt thereof, wherein R 5 is the formula: and a heterocyclo such as a heterocyclo group of the formula: 3 is bond, CH 2 , O, N.R. a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 2. The compound of claim 1, wherein the group having the formula: is optionally further substituted heterocyclo; thiazolyl; or benzthiazolyl.

11. The compound of formula (Ic) has the formula: or a pharmaceutically acceptable salt thereof, wherein R 2 is the formula: where X a is a bond, (CH 2 ) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X a 2. The compound of claim 1, wherein the group having the formula: is optionally further substituted with OH, alkoxy, amino, or amido.

12. The compounds of formula (I), (Ia), (Ib), and (Ic) have the formula: or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl, and S(O) p 2. The compound of claim 1, wherein R is alkyl or arylalkyl.

13. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is:

14. The compounds of formula (Ib) and (Ic) respectively have the formula:

2. The compound of claim 1, wherein the compound is:

15. The compound of formula (I) has the formula:

2. The compound of claim 1, wherein the compound is:

16. R 3a 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is benzthiazole or benzoxazole.

17. R 3a But the formula: is the basis of During the ceremony, R 6 is alkyl, alkylamino, cycloalkylamino, cycloalkylheterocycloamino, heterocyclocycloalkylamino, or heterocycloamino; and X 4 is S, O, or NR 7 where R 7 is H, alkyl, cycloalkyl, or alkylaryl; 17. The compound of claim 16 or a pharmaceutically acceptable salt thereof.

18. X 4 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is S or O.

19. The compound of formula (I) has the formula: or a pharmaceutically acceptable salt thereof, wherein R 5 is the formula: and a heterocyclo such as a heterocyclo group of the formula: 3 But the bond, CH 2 , O, N.R. a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 2. The compound of claim 1, wherein the group having the formula: is optionally further substituted heterocyclo; thiazolyl; or benzthiazolyl.

20. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is

21. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is

22. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is

23. The compounds of formula (I), (Ia), (Ib), and (Ic) each have the formula:

2. The compound of claim 1, wherein the compound is

24. formula:

2. The compound of claim 1, wherein the compound is:

25. Each formula:

2. The compound of claim 1, wherein the compound is:

26. Each formula:

2. The compound of claim 1, wherein the compound is:

27. Each formula:

2. The compound of claim 1, wherein the compound is:

28. Each formula: or a pharmaceutically acceptable salt thereof, for example, a compound of the formula:

2. The compound of claim 1, wherein the compound is:

29. formula: or a pharmaceutically acceptable salt thereof, wherein R 2 is the formula: where X a is a bond, (CH 2 ) d (where d is 1, 2, or 3), O, NR a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X a 2. The compound of claim 1, wherein the group having the formula: may be further substituted with substituents such as OH, alkoxy, amino, and amido.

30. formula: or a pharmaceutically acceptable salt thereof, wherein R d is H, alkyl, acyl (e.g., C(O)R, where R is defined herein), and S(O) p 2. The compound of claim 1, wherein R is R, where R is defined herein.

31. Each formula:

2. The compound of claim 1, wherein the compound is:

32. formula: or a pharmaceutically acceptable salt thereof, for example, a compound of the formula:

2. The compound of claim 1, wherein the compound is:

33. formula:

2. The compound of claim 1, wherein the compound is:

34. Each formula:

2. The compound of claim 1, wherein the compound is:

35. Each formula:

2. The compound of claim 1, wherein the compound is:

36. Formula (II): A compound of the formula: During the ceremony, R 2 is a heterocyclo; R 3a is alkyl, alkoxy, acyl, amido, aryl, benzthiazole, benzoxazole, benzofuranyl, or indolyl; R 8 and R 9 are independently H or alkyl; or may be taken together with the nitrogen atom to which they are attached to form a heterocyclyl group; and R 10 is alkyl or alkenyl; The compound or a pharmaceutically acceptable salt thereof.

37. Formulas (III) to (X): A compound of the formula: During the ceremony, Each R 11 is H, alkyl, or each R 11 together with the nitrogen atom to which it is attached form a heterocyclyl group; R 12 is H, amino, OH, or alkoxy; R 13 is H, alkyl, amino, or two adjacent R 13 groups taken together with the carbon atoms to which they are attached form a 5- or 6-membered aryl or heteroaryl group; Y 2 is O or NR a and Z is NR a or alkyl; and R a is H or alkyl, The compound or a pharmaceutically acceptable salt thereof.

38. Formulas (XI) to (XII): A compound of the formula: During the ceremony, The dashed lines are single or double bonds; T and T 1 are each independently NR a or C(O); and R a is H or alkyl, The compound or a pharmaceutically acceptable salt thereof.

39. formula:

2. The compound of claim 1, wherein the compound is

40. formula: wherein R a is H or alkyl.

41. formula:

2. The compound of claim 1, wherein the compound is:

42. In the above formula, X 3 is a bond, CH 2 , O, N.R. a , or S(O) p where R a is H or alkyl, p is 0, 1, or 2, and X 3 The group having the formula may be further substituted; may be thiazolyl; or may be benzthiazolyl; In the above formula, Y 1 is CH 2 , O, or NH, and X is OH, OCH 3 , N.H. 2 , or NHCH 3 is; In the above formula, X b is O or NR a and R a is H or alkyl; 10. The compound of claim 1, which is:

43. , or a pharmaceutically acceptable salt thereof, During the ceremony, R a is H or alkyl; and Each R 1 is independently alkyl or alkoxy; The compound of claim 1.

44. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

46. ​​The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

50. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

52. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

53. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

55. 55. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any one of claims 1-54 and at least one pharmaceutically acceptable excipient.

56. 1. A method for treating severe acute respiratory syndrome, comprising:

56. The method comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of any one of claims 1-54 or the pharmaceutical composition of claim 55, such that the patient is treated for severe acute respiratory syndrome.

57. 57. The method of claim 56, wherein the severe acute respiratory syndrome is COVID-19.

Images