MASP-2 inhibitors and methods of use

Abstract

To provide compounds, compositions, and methods of making and using the same, suitable for administration / treatment of a subject suffering from MASP-2 complement pathway related diseases and disorders.SOLUTION: There is provided a compound having the following structure (I), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing Description The sequence listing associated with this application is provided in text format in lieu of hard copy and is hereby incorporated by reference. The text file name containing the sequence listing is 700128_423WO_SEQUENCE_LISTING.txt. The text file is 6.0 KB, was created on December 3, 2020, and has been submitted electronically via EFS-Web.

[0002] Technical Field The present disclosure is generally directed to compositions and methods useful in the medical field. More specifically, the disclosure provides synthetic inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including inhibitors that selectively inhibit MASP-2 relative to thrombin, compositions thereof, and methods for their production and use. [Background technology]

[0003] background The complement system is involved in inflammatory responses and is activated by tissue injury or microbial infection. Complement activation must be tightly regulated to ensure selective targeting of invading microorganisms and avoid self-damage (Ricklin et al., Nat. Immunol. 11:785-797, 2010). It is now widely recognized that the complement system can be activated through three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is typically triggered by a complex composed of a host antibody bound to a foreign substance (i.e., an antigen) and typically requires prior exposure to the antigen for the generation of a specific antibody response. Because activation of the classical pathway depends on a prior adaptive immune response by the host, the classical pathway is part of the adaptive immune system. In contrast, both the lectin and alternative pathways are independent of adaptive immunity and are part of the innate immune system.

[0004] Mannan-binding lectin-associated serine protease-2 (MASP-2) has been shown to be required for the function of the lectin pathway, one of the major complement activation pathways (Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000; Ambrus et al., J. Immunol. 170: 1374-1382, 2003; Schwaeble et al., PNAS 108:7523-7528, 2011). Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, a key component of the adaptive immune response to infection. As described in U.S. Patent No. 9,011,860 (assigned to Omeros Corporation), which is incorporated herein by reference, fully humanized monoclonal antibodies targeting human MASP-2 have been produced that bind to human MASP-2 with high affinity and block lectin pathway complement activity, and are therefore useful for treating various lectin complement pathway-related diseases and disorders.

[0005] MASP-2-dependent complement activation has been implicated in the pathogenesis of numerous acute and chronic disease states. Thus, there is a need for compounds suitable for administration / treatment of subjects suffering from MASP-2 complement pathway-associated diseases and disorders, including diseases that are not adequately or effectively treated with large molecule biological inhibitors. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 9,011,860 [Non-patent literature]

[0007] [Non-Patent Document 1] Ricklin et al., Nat. Immunol. 11 :785-797, 2010 [Non-patent document 2] Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000 [Non-patent document 3] Ambrus et al., J Immunol. 170: 1374-1382, 2003 [Non-patent document 4] Schwaeble et al., PNAS 108:7523-7528, 2011 Summary of the Invention

[0008] overview One embodiment provides a compound having the following structure (I): TIFF2025131710000001.tif39128 formula, TIFF2025131710000002.tif2128, R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , and n is as defined herein.

[0009] A further aspect of the present disclosure provides a pharmaceutical composition comprising a compound of structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0010] Compounds of structure (I) are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. Accordingly, another aspect of the disclosure provides a method for treating MASP-2-associated diseases and disorders, comprising administering to a patient a therapeutically effective amount of a compound of structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0011] [The present invention 1001] A compound having the following structure (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF2025131710000003.tif39128In formula, TIFF2025131710000004.tif2128 represents, independently at each occurrence, a double bond or a single bond; R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or cycloalkyl; R 3 is hydrogen, alkyl, haloalkyl, or cycloalkyl, or R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl; R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH2) m C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , (CH2) m NR 6 S(O)2R 7 , or C(=O)NR 6 R 7 and; R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; L 1 is a direct bond, -CR 8a R 8b -, -S(O) t -, NR 8c , or -O-; R 8a and R 8b are each independently hydrogen, alkyl, or R 8a and R 8b together with the carbons to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl; R 8c is hydrogen, alkyl, haloalkyl, (C=O)alkyl, (C=O)Oalkyl, (C=O)cycloalkyl, (C=O)Ocycloalkyl, (C=O)aryl, (C=O)Oaryl, (C=O)heteroaryl, (C=O)Oheteroaryl, (C=O)heterocyclyl, (C=O)Oheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heterocyclylalkyl; n is 1 or 2; m is 1, 2, 3, 4, 5, or 6; and t is 0, 1, or 2; However, the compound of structure (I) does not have the structure in Table A. [The present invention 1002] R 1 is substituted or unsubstituted aryl. [The present invention 1003] R 1 Substituted or unsubstituted C6-C 10 The compound of the present invention 1001 or 1002, which is aryl. [The present invention 1004] R 1 The compound of any one of claims 1001 to 1003, wherein is substituted or unsubstituted phenyl. [The present invention 1005] R 1 The compound of any one of 1001 to 1004 of the present invention, wherein is substituted phenyl. [The present invention 1006] R 1 But R1a , R 1b , R 1c , R 1d , or R 1e and wherein R is a phenyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 )NH2, C(=NOH)NH2, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12, S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; Any of compounds 1001 to 1005 of the present invention. [The present invention 1007] R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b, R 1c , R 1d , or R 1e But, Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1006 of the present invention. [The present invention 1008] R 1 Halo, haloalkyl, C(=NR 9 )NR 10 R 11 , C(=NR 9 )NR 10 C(O)OR 11 and phenyl substituted with at least one substituent selected from the group consisting of 5- to 10-membered heteroaryl. [The present invention 1009] R 1 -C(=NH)NH2, chloro, fluoro, -CHF2, and 1008 compounds of the present invention, substituted with at least one substituent selected from the group consisting of TIFF2025131710000005.tif14128. [The present invention 1010] R 1 However, the following structure: Any of compounds 1007 to 1009 of the present invention having one of TIFF2025131710000006.tif179146. [The present invention 1011] R 1 But the following structure: Any of compounds 1001 to 1010 of the present invention having one of TIFF2025131710000007.tif106142. [The present invention 1012] R 1 has the following structure: The compound of the present invention 1007 has one of the following: TIFF2025131710000008.tif58128. [The present invention 1013] R 9 But C 1~6 Alkyl or C 1~6 The compound of the present invention 1012, which is haloalkyl. [The present invention 1014] R 9 The compound of the present invention 1013, wherein is methyl. [The present invention 1015] R 9The compound of the present invention 1013, wherein is trifluoromethyl. [The present invention 1016] R 1 The compound of any one of 1001 to 1004 of the present invention, wherein is unsubstituted phenyl. [The present invention 1017] R 1 is a substituted or unsubstituted heteroaryl. [The present invention 1018] R 1 is a substituted or unsubstituted 5- to 10-membered heteroaryl. [The present invention 1019] R 1 is a substituted or unsubstituted pyridinyl, a substituted or unsubstituted pyrrolopyridinyl, a substituted or unsubstituted imidazopyridinyl, a substituted or unsubstituted thienopyridinyl, a substituted or unsubstituted benzimidazolyl, a substituted or unsubstituted isoindolinyl, or a substituted or unsubstituted benzothiazolyl. [The present invention 1020] R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e and heteroaryl substituted with one or more of the following: 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; The compound of the present invention is any one of compounds 1001 and 1017 to 1019. [The present invention 1021] R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14, S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1020 of the present invention. [The present invention 1022] R 1 But the following structure: Compound 1001 or any one of compounds 1017 to 1021 of the present invention, having one of TIFF2025131710000009.tif169148TIFF2025131710000010.tif225146TIFF2025131710000011.tif207146TIFF2025131710000012.tif30128. [The present invention 1023] R 1a or R 1b independently, C 1~6 Alkyl, C 1~6 The compound of the present invention 1022, which is a deuterated alkyl, amino, or halo. [The present invention 1024] R 1a or R 1b The compound of the present invention 1023, wherein is methyl or CD3. [The present invention 1025] R 1a or R 1bThe compound of claim 1023, wherein is F, Cl, or Br. [The present invention 1026] R attached to nitrogen 1a or R 1b are respectively, C 1~6 The compound of the present invention 1023, which is alkyl. [The present invention 1027] R 1a or R 1b is methyl or ethyl. [The present invention 1028] R 1 But the following structure: Compounds of the present invention 1001 or 1017 to 1019 having one of TIFF2025131710000013.tif141146. [The present invention 1029] R 1 But the following structure: Compound 1001 or any of compounds 1017 to 1019 of the present invention, having one of TIFF2025131710000014.tif113146TIFF2025131710000015.tif218148TIFF2025131710000016.tif112145. [The present invention 1030] R 1 But the following structure: Compound 1001 or any of compounds 1017 to 1019 of the present invention having one of TIFF2025131710000017.tif95146. [The present invention 1031] R 1 1001. A compound of the present invention wherein is substituted or unsubstituted cycloalkyl. [The present invention 1032] R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. [The present invention 1033] R 1 The compound of any one of 1001 or 1031 to 1032 of the present invention, wherein is substituted C3-C6 cycloalkyl. [The present invention 1034] R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e C3-C6 cycloalkyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10, S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1033 of the present invention. [This invention 1035] R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, Halo, CN, OR 13 , S.R.13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1034 of the present invention. [The present invention 1036] R 1 is an unsubstituted C3-C6 cycloalkyl. [This invention 1037] R 1 1001. A compound of the present invention, wherein is substituted or unsubstituted heterocyclyl. [The present invention 1038] R 1 The compound of the present invention 1001 or 1037, wherein is substituted or unsubstituted 4- to 10-membered heterocyclyl. [This invention 1039] R 1 The compound of any one of claims 1001 and 1037 to 1038, wherein is substituted 4- to 10-membered heterocyclyl. [The present invention 1040] R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e and R is a 4- to 10-membered heterocyclyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11, C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1039 of the present invention. [The present invention 1041] R 1a , R 1b , R 1c , R 1d, or R 1e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1040 of the present invention. [The present invention 1042] R 1 The compound of the present invention 1037, wherein is unsubstituted 4-10 membered heterocyclyl. [This invention 1043] R 2 is hydrogen, C1-C6 alkyl, or R 2 and R 3 are taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4- to 7-membered heterocyclyl. [This invention 1044] R 2 is a C1-C6 alkyl. [This invention 1045] R 2 The compound of any one of claims 1001 to 1044 of the present invention, wherein is -CH3. [The present invention 1046] R 2 The compound of any one of claims 1001 to 1044 of the present invention, wherein is -CH2OH. [This invention 1047] R 2 and R 3 are taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4- to 7-membered heterocyclyl. [This invention 1048] R 2 and R 3 are taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4-, 5-, or 6-membered heterocyclyl. [This invention 1049] R 2 and R 3 are taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4-membered heterocyclyl. [The present invention 1050] The following structure (IA1a), (IB1a), (IC1a), (ID1a), (IE1a), (IF1a), (IG1a), or (IH1a): Any of compounds 1001 to 1045 of the present invention having one of TIFF2025131710000018.tif168128. [This invention 1051] The following structure (IA1b), (IB1b), (IC1b), (ID1b), (IE1b), (IF1b), (IG1b), or (IH1b): Any of compounds 1001 to 1045 of the present invention having one of TIFF2025131710000019.tif167130. [This invention 1052] The following structure (IA2a), (IB2a), (IC2a), (ID2a), (IE2a), (IF2a), (IG2a), or (IH2a): Any of compounds 1001 to 1043 or 1047 to 1049 of the present invention having one of TIFF2025131710000020.tif180133. [This invention 1053] The following structure (IA2b), (IB2b), (IC2b), (ID2b), (IE2b), (IF2b), (IG2b), or (IH2b): Any of compounds 1001 to 1043 or 1047 to 1049 of the present invention having one of TIFF2025131710000021.tif190130. [This invention 1054] The following structure (IA3a), (IB3a), (IC3a), (ID3a), (IE3a), (IF3a), (IG3a), or (IH3a): Any of compounds 1001 to 1043 or 1047 to 1048 of the present invention having one of TIFF2025131710000022.tif180133. [This invention 1055] The following structure (IA3b), (IB3b), (IC3b), (ID3b), (IE3b), (IF3b), (IG3b), or (IH3b): Any of compounds 1001 to 1043 or 1047 to 1048 of the present invention having one of TIFF2025131710000023.tif191130. [This invention 1056] The following structure (IA4a), (IB4a), (IC4a), (ID4a), (IE4a), (IF4a), (IG4a), or (IH4a): Any of compounds 1001 to 1043 or 1047 to 1048 of the present invention having one of TIFF2025131710000024.tif178133. [This invention 1057] The following structure (IA4b), (IB4b), (IC4b), (ID4b), (IE4b), (IF4b), (IG4b), or (IH4b): Any of compounds 1001 to 1043 or 1047 to 1048 of the present invention having one of TIFF2025131710000025.tif178130. [This invention 1058] The following structure (IA5a), (IB5a), (IC5a), (ID5a), (IE5a), (IF5a), (IG5a), or (IH5a): TIFF2025131710000026.tif176133, In the formula, R 2a and R 2b are each independently hydrogen or halo; The compound of any one of 1001 to 1043 or 1047 to 1048 of the present invention. [This invention 1059] The following structure (IA5b), (IB5b), (IC5b), (ID5b), (IE5b), (IF5b), (IG5b), or (IH5b): TIFF2025131710000027.tif176130, In the formula, R 2a and R 2b are each independently hydrogen or halo; The compound of any one of 1001 to 1043 or 1047 to 1048 of the present invention. [The present invention 1060] R 2a and R 2b The compound of the present invention 1058 or 1059, wherein each of [This invention 1061] R 2a and R 2b The compound of the present invention 1060, wherein all of are fluoro. [This invention 1062] R 4 is a substituted or unsubstituted aryl. [This invention 1063] R 4 Substituted or unsubstituted C6-C 10 The compound of any one of 1001 to 1062 of the present invention, which is aryl. [This invention 1064] R 4 is a substituted or unsubstituted phenyl. [This invention 1065] R 4 The compound of any one of claims 1001 to 1064, wherein is unsubstituted phenyl. [The present invention 1066] R 4 But R 4a , R 4b , R 4c , R 4d , or R 4e and wherein R is a phenyl substituted with one or more of 4a , R 4b , R 4c , R 4d , and R 4e are each independently, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , S.R. 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 ,OC(O)R 17 ,OC(O)OR 17 , OC(O)NR 17 R 18 , N.R. 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(=NR 17 )NR 18 R 19 , C(=NOR 17 )NR 18 R 19 , C(=NOC(O)R 17 )NR 18 R 19 , C(=NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(=NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O)2R 17 , N(R 17 )S(O)2R 18 , S(O)NR 17 R 18 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 17 , R 18 , R 19 , and R 20 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Any of the compounds 1001 to 1064 of the present invention. [This invention 1067] R 4a , R 4b , R 4c , R 4d , or R 4e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 4a , R 4b , R 4c , R 4d , or R 4e But, OR 21 , S.R. 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 ,OC(O)R 21 , OC(O)NR 21 R 22 , N.R. 21 R 22 , N.R. 21 C(O)R 22 , N.R. 21 C(O)NR 22 R 23 , N.R.21 C(O)OR 22 , C(=NR 21 )NR 22 R 23 , N.R. 21 C(=NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O)2R 21 , N.R. 21 S(O)2R 22 , S(O)NR 21 R 22 and oxo, where R 21 , R 22 , R 23 , and R 24 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1066 of the present invention. [The present invention 1068] R 4 But the following structure: Any of compounds 1001 to 1063 of the present invention having one of TIFF2025131710000028.tif177148. [This invention 1069] R 4 is a substituted or unsubstituted heteroaryl. [The present invention 1070] R 4 is a 4- to 10-membered heteroaryl. [This invention 1071] R 4 is an unsubstituted 4- to 10-membered heteroaryl. [This invention 1072] R 4 But R 4a , R 4b , R 4c , R 4d , or R 4e and R is a 4- to 10-membered heteroaryl substituted with one or more of 4a , R 4b , R 4c , R 4d , and R 4e are each independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , S.R. 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 ,OC(O)R 17 ,OC(O)OR 17 , OC(O)NR 17 R 18 , N.R. 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(=NR 17 )NR 18 R 19 , C(=NOR 17 )NR 18 R 19 , C(=NOC(O)R 17 )NR 18 R 19 , C(=NR 17 )N(R 18 )C(O)OR 19 , N(R 17)C(=NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O)2R 17 , N(R 17 )S(O)2R 18 , S(O)NR 17 R 18 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 17 , R 18 , R 19 , and R 20 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Any of compounds 1001 to 1061 of the present invention. [This invention 1073] R 4a , R 4b , R 4c , R 4d , or R 4e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 4a , R 4b , R 4c , R 4d , or R 4e But, Halo, CN, OR 21 , S.R. 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 ,OC(O)R 21 , OC(O)NR 21 R 22 , N.R. 21 R 22 , N.R. 21 C(O)R 22 , N.R. 21 C(O)NR 22 R 23 , N.R. 21 C(O)OR 22 , C(=NR 21 )NR 22 R 23 , N.R. 21 C(=NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O)2R 21 , N.R. 21 S(O)2R 22 , S(O)NR 21 R 22 and oxo, where R 21 , R 22 , R 23 , and R 24 Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1072 of the present invention. [This invention 1074] R 4 But the following structure: Any of compounds 1001 to 1061 of the present invention having one of TIFF2025131710000029.tif55131. [This invention 1075] R 5 The compound of any one of claims 1001 to 1074 of the present invention, wherein is hydrogen. [This invention 1076] R 5 is alkyl, phosphonoalkyl, (CH2) m NR 6 S(O)2R 7 , or (CH2) m C(=O)OR 6 The compound of any one of claims 1001 to 1074 of the present invention, [This invention 1077] R 5 The compound of the present invention 1076, wherein is alkyl. [This invention 1078] R 5 The compound of the present invention 1076 or 1077, wherein is methyl. [This invention 1079] R 5 The compound of claim 1076 or 1077, wherein is ethyl. [The present invention 1080] R 5 (CH2) m C(=O)OR 6 The compound of the present invention 1076, [This invention 1081] R 5 But the following structure: Compounds of the present invention 1076 or 1080 having one of TIFF2025131710000030.tif15128. [This invention 1082] R 5 The compound of the present invention 1076, wherein is phosphonoalkyl. [This invention 1083] R 5 But the following structure: The compound of the present invention 1082 having one of TIFF2025131710000031.tif17128. [This invention 1084] R 5 (CH2) m NR 6 S(O)2R 7 The compound of the present invention 1076, [This invention 1085] R 5 But the following structure: Compound of the present invention 1084 having TIFF2025131710000032.tif16128. [The present invention 1086] A compound of any one of claims 1001 to 1085, wherein each occurrence of TIFF2025131710000033.tif2128 represents a single bond. [This invention 1087] The compound of any one of claims 1001 to 1086, wherein TIFF2025131710000034.tif2128 represents a double bond in at least one occurrence. [This invention 1088] L 1 The compound of any one of claims 1001 to 1087, wherein is a direct bond. [This invention 1089] L 1 The compound of any one of claims 1001 to 1087, wherein is -O-. [The present invention 1090] L 1 The compound of any one of claims 1001 to 1087, wherein is -CH2-. [This invention 1091] L 1 Ga-CR 8a R 8b - and R 8a and R 8b are taken together with the carbon to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl. [This invention 1092] R 8a and R 8b are taken together with the carbon to which they are attached to form an optionally substituted 3-, 4-, or 5-membered cycloalkyl. [This invention 1093] R 8a and R 8b are taken together with the carbon to which they are attached to form an optionally substituted 3-membered cycloalkyl. [This invention 1094] 1093. The compound of the present invention, wherein the 3-membered cycloalkyl is unsubstituted. [This invention 1095] A compound having one of the structures in Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. [This invention 1096] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1095 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. [This invention 1097] A method for treating a MASP-2-related disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of any of the compounds of the present invention 1001 to 1095 or the pharmaceutical composition of the present invention 1096. [This invention 1098] The method of the present invention 1097, wherein the compound is administered in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. [This invention 1099] The method of claim 1097, wherein said subject has been diagnosed with a lectin complement-associated disease or disorder in need of treatment. [The present invention 1100] 1097. The method of claim 1097, wherein the disease or disorder is thrombotic microangiopathy (TMA), a renal condition, an inflammatory response due to tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ocular disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, venous occlusive disease, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome, fluid overload, or a combination thereof. [The present invention 1101] 1097. The method of claim 1097, wherein the disease or disorder is thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), factor H-independent atypical hemolytic uremic syndrome, aHUS secondary to infection, plasma therapy-refractory aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplant, TMA associated with hematopoietic stem cell transplantation, or a combination thereof. [The present invention 1102] The method of claim 1097, wherein the disease or disorder is graft-versus-host disease. [The present invention 1103] The method of claim 1097, wherein the disease or disorder is diffuse alveolar hemorrhage (DAH). [The present invention 1104] The method of claim 1097, wherein the disease or disorder is veno-occlusive disease (VOD). [This invention 1105] The method of claim 1097, wherein the disease or disorder is a renal condition. [The present invention 1106] The method of the present invention 1097, wherein the renal condition is mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangial capillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, microimmune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, or a combination thereof. [This invention 1107] The method of claim 1097, wherein the disease or disorder is renal fibrosis, proteinuria, or a combination thereof. [This invention 1108] The method of claim 1097, wherein the disease or disorder is an inflammatory response due to tissue transplantation or solid organ transplantation. [This invention 1109] The method of claim 1097, wherein the disease or disorder is ischemia-reperfusion injury (I / R). [The present invention 1110] The method of claim 1097, wherein the disease or disorder is complications associated with non-obese diabetes, complications associated with type 1 diabetes, complications associated with type 2 (adult-onset) diabetes, or a combination thereof. [The present invention 1111] The method of claim 1097, wherein the disease or disorder is a cardiovascular disease or disorder. [The present invention 1112] The method of claim 1097, wherein the disease or disorder is an inflammatory gastrointestinal disorder. [The present invention 1113] The method of claim 1097, wherein the disease or disorder is a pulmonary disorder. [This invention 1114] The method of claim 1097, wherein the disease or disorder is an in vitro exposure-induced inflammatory response. [This invention 1115] The method of claim 1114, further comprising treating a subject undergoing extracorporeal circulation treatment. [The present invention 1116] The method of claim 1097, wherein the disease or disorder is inflammatory arthritis, non-inflammatory arthritis, a musculoskeletal disorder, or a combination thereof. [This invention 1117] The method of claim 1097, wherein the disease or disorder is a skin disorder. [This invention 1118] The method of claim 1097, wherein the disease or disorder is a peripheral nervous system (PNS) disorder or injury, a central nervous system (CNS) disorder or injury, or a combination thereof. [This invention 1119] The method of claim 1097, wherein the disease or disorder is sepsis or a septic state. [The present invention 1120] The method of claim 1097, wherein the disease or disorder is a genitourinary disorder. [This invention 1121] The method of claim 1097, wherein the disease or disorder is an inflammatory response in a subject being treated with a chemotherapeutic agent, radiation therapy, or a combination thereof. [This invention 1122] The method of claim 1097, wherein the disease or disorder is an angiogenesis-dependent cancer. [This invention 1123] The method of claim 1097, wherein the disease or disorder is an angiogenesis-dependent benign tumor. [This invention 1124] The method of claim 1097, wherein the disease or disorder is an endocrine disorder. [Invention 1125] The method of claim 1097, wherein the disease or disorder is an ocular disease or disorder. [The present invention 1126] The method of claim 1097, wherein the disease or disorder is an intraocular neovascular disease or condition. [This invention 1127] The method of claim 1097, wherein the disease or disorder is disseminated intravascular coagulation (DIC), a complement-mediated coagulopathy, or a combination thereof. [This invention 1128] The method of the present invention 1097, wherein the disease or disorder is acute radiation syndrome, dense deposit disease, Degos disease, fulminant antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia, paroxysmal nocturnal hemoglobinuria ("PNH"), cold agglutinin disease, or a combination thereof. [This invention 1129] The method of claim 1097, wherein the disease or disorder is atypical hemolytic uremic syndrome (aHUS). [The present invention 1130] The method of claim 1097, wherein the disease or disorder is hematopoietic stem cell transplantation-associated TMA. [This invention 1131] The method of claim 1097, wherein the disease or disorder is immunoglobulin A nephropathy (IgAN). [This invention 1132] The method of claim 1097, wherein the disease or disorder is lupus nephritis (LN). [This invention 1133] R 1 But the following structure: The compound of the present invention 1001 has one of the following: TIFF2025131710000035.tif66149. These and other aspects, objects and embodiments will become more apparent from the following detailed description and drawings. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials similar or equivalent to those described herein can be used to implement or test the subject matter of this disclosure, and suitable methods and materials are described below.Furthermore, the materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0013] Certain embodiments herein refer to disclosed features and aspects, including method steps. All possible combinations of such features and aspects within the disclosed embodiments are included, at least to the extent that such combinations are not inconsistent. For example, if an embodiment describes aspects A, B, and C, it is understood that this also discloses embodiments including both aspects A and B, both aspects B and C, and both aspects A and C, as well as embodiments having aspects A, B, and C.

[0014] The terms "a," "an," or "the" not only include aspects having one element, but also aspects having multiple elements. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, and a reference to "the agent" includes a reference to one or more agents known to those of skill in the art.

[0015] The terms "about" and "approximately" refer to an acceptable degree of error for a measured quantity, given the nature or precision of the measurement. Typical and illustrative degrees of error are within ±20 percent (%) of a given value or range of values; preferably within ±10%; and more preferably within ±5%. Any reference to "about X" specifically refers to at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide support for a claim limitation, such as "0.98X." Alternatively, in biological systems, the terms "about" and "approximately" can refer to values ​​within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical values ​​given herein are approximate unless otherwise specified, meaning that the term "about" or "approximately" can be inferred unless explicitly stated. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5-20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 7, 9, or 11 mg / kg" is equivalent to "about 7, about 9, or about 11 mg / kg."

[0016] The term "MASP-2" refers to mannan-binding lectin-associated serine protease-2. The human MASP-2 protein has UniProt accession code O00187 (SEQ ID NO:1). The serine protease domain ('B chain' = mannan-binding lectin serine protease 2 B chain, based on UniProtKB - O00187 (MASP-2_HUMAN)) comprises (or consists of) residues 445-686.

[0017] The term "MASP-2-dependent complement activation" refers to MASP-2-dependent activation of the lectin pathway, which under physiological conditions (i.e., Ca) leads to the formation of the lectin pathway C3 convertase C4b2a and, upon accumulation of the C3 cleavage product C3b, the subsequent C5 convertase C4b2a(C3b)n. ++ occurs in the presence of

[0018] The term "MASP-2-dependent complement-associated disease or disorder" refers to a disease or disorder associated with MASP-2-dependent complement activation.

[0019] The term "MASP-2-associated disease or disorder" refers to a disease or disorder associated with the activation or activity of MASP-2, including a MASP-2-dependent complement-associated disease or disorder, in which inhibition of MASP-2 is or is expected to be therapeutically beneficial.

[0020] The term "lectin pathway" refers to complement activation that occurs through the specific binding of serum and non-serum carbohydrate-binding proteins, including mannan-binding lectin (MBL), CL-11, and ficolins (H-ficolin, M-ficolin, or L-ficolin).

[0021] The term "classical pathway" refers to complement activation, which is triggered by antibodies bound to foreign substances and requires the binding of the recognition molecule Clq.

[0022] Amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine ​​(Cys; C), glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G), histidine (His; H), isoleucine (Ile), leucine (Leu), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0023] In the broadest sense, naturally occurring amino acids can be divided into groups based on the chemical properties of the side chains of the individual amino acids. By "hydrophobic" amino acid, it is meant either His, Leu, Met, Phe, Trp, Tyr, Val, Ala, Cys, or Pro. By "hydrophilic" amino acid, it is meant either Gly, Asn, Gln, Ser, Thr, Asp, Glu, Lys, Arg, or His. This grouping of amino acids can be further subdivided as follows: by "uncharged hydrophilic" amino acid, it is meant either Ser, Thr, Asn, or Gln. by "acidic" amino acid, it is meant either Glu or Asp. by "basic" amino acid, it is meant either Lys, Arg, or His.

[0024] The term "conservative amino acid substitution" describes substitutions between amino acids within each of the following groups: (1) glycine, alanine, valine, leucine, and isoleucine; (2) phenylalanine, tyrosine, and tryptophan; (3) serine and threonine; (4) aspartate and glutamate; (5) glutamine and asparagine; and (6) Lysine, arginine and histidine.

[0025] The term "subject" includes all mammals, including, but not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cattle, rabbits, pigs, and rodents.

[0026] "Mammal" includes both humans and domestic animals, such as laboratory animals and pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0027] The terms "small molecule" and "small organic molecule" refer to small carbon-containing molecules having a molecular weight of about 2500 daltons or less. In some embodiments, small molecules have a molecular weight of about 2000 daltons or less. In some embodiments, small molecules have a molecular weight of about 1500 daltons or less. In some embodiments, small molecules have a molecular weight of about 1000 daltons or less. In some embodiments, small molecules have a molecular weight of about 750 daltons or less. In some embodiments, small molecules have a molecular weight of about 500 daltons or less. In some embodiments, small molecules have a molecular weight of about 50 daltons or more. In some embodiments, small molecules have a molecular weight of about 75 daltons or more. In some embodiments, small molecules have a molecular weight of about 100 daltons or more. In some embodiments, small molecules have a molecular weight of about 150 daltons or more. In some embodiments, small molecules have a molecular weight of about 250 daltons or more. In some embodiments, small molecules may have a molecular weight ranging from about 50 daltons to about 500 daltons, about 50 daltons to about 750 daltons, about 50 daltons to about 1000 daltons, about 50 daltons to about 1500 daltons, about 50 daltons to about 2000 daltons, or about 50 daltons to about 2500 daltons. When the term "compound" is used herein, it is expressly intended to include small molecule compounds as defined herein, including any of their embodiments.

[0028] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular ailment or condition may not have a known causative agent (and thus its etiology is not yet understood) and is therefore not yet recognized as a disease, but only as an undesirable state or syndrome (where a more or less specific set of symptoms has been identified by clinicians). In some embodiments, a disease is a pathological condition of an organ, body part, or system resulting from a variety of causes, such as infection, genetic defect, or environmental stress, characterized by a distinguishable group of symptoms.

[0029] A "therapeutically effective amount," "effective amount," or "effective dose" refers to the amount of a disclosed compound that, when administered to a mammal (e.g., a human), is sufficient to effect the below-defined treatment of a disease or condition in the mammal, preferably a human. The amount of a disclosed compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0030] The term "subcutaneous administration" refers to administration of a formulation below all layers of a subject's skin.

[0031] The term "histidine" specifically includes L-histidine unless otherwise specified.

[0032] The term "isotonic" refers to a formulation that has essentially the same osmotic pressure as human blood. Isotonic formulations generally have an osmotic pressure of about 250 to about 350 mOsmol / L. Isotonicity can be measured, for example, using a vapor pressure or freezing point depression osmometer.

[0033] The term "hypertonic" refers to a formulation whose osmolality is higher than that of humans (ie, greater than 350 mOsm / L).

[0034] The term "hydrogen bond" refers to the partial electrostatic attraction between a hydrogen (H) bonded to a more electronegative atom, such as nitrogen (N) or oxygen (O), and another adjacent atom with a lone pair of electrons. For example, when nitrogen is described as acting as a "hydrogen bond donor," this means that the hydrogen (H) bonded to the nitrogen (N) is donated by the neighboring atom with a lone pair of electrons, such as oxygen, as it is electrostatically attracted to or accepted by the neighboring atom. Similarly, when oxygen is described as acting as a "hydrogen bond acceptor," this means that the hydrogen (H) bonded to a more electronegative atom, such as nitrogen (N), is electrostatically attracted to or "accepted" by a neighboring atom with a lone pair of electrons, such as oxygen. Hydrogen-bonded atoms may be described without explicitly describing the origin and presence of the intermediate hydrogen atom. The term "hydrogen bond" is used when LigPlot+ software predicts hydrogen-bonding interactions using its algorithm and a parameter of 3.35 Å applied to the maximum distance between the hydrogen bond donor and acceptor. Not all hydrogen bonds actually exist simultaneously; this is evident from the fact that some atoms are chemically capable of only three hydrogen bonds in a given case, even though they are shown to putatively form four hydrogen bonds. Generally, crystal structures such as the co-crystal structure information herein do not directly show or detect hydrogen bonds, but the software used to describe the co-crystal predicts that such H-bonds exist. Thus, throughout the disclosure, when an H-bond exists and is described, it can be said that it is "predicted" to exist by the software.

[0035] The term ionic bond includes a type of chemical bond that is the primary interaction occurring in ionic compounds, involving electrostatic attraction between ions of opposite charge.

[0036] The term "van der Waals" interactions includes weak, short-range electrostatic attractions between uncharged molecules resulting from the interaction of permanent or transient electric dipole moments. Such interactions include all contacts calculated using non-bonded contact parameters ranging from hydrophobic contacts to any contact between them, as determined by LigPlot+ software employing a model derived from the corresponding crystallographic MASP-2 compound co-structure, for interactions with a maximum contact distance of 3.90 Å.

[0037] The terms "π-π interactions" or "π-π stacking" interactions include attractive non-covalent interactions (e.g., "edge-face" interactions) between aromatic rings oriented nearly parallel or nearly perpendicular to each other because the aromatic rings contain π bonds.

[0038] Typically, the active site of serine proteases, such as MASP-2, is shaped like a cleft where a polypeptide substrate or inhibitor binds. Schechter and Berger labeled the amino acid residues of a polypeptide substrate from the N- to C-terminus as follows: Pi, ..., P3, P2, P1, P1', P2', P3', ..., Pj) and their respective binding subsites Si, ..., S3, S2, S1, S1', S2', S3', ..., Sj. Cleavage is catalyzed between P1 and P1' (Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27 (1967)).

[0039] The term "binding site" refers to an area on a protein with which a small molecule can interact, such as a region on the surface of MASP-2. A binding site or region may not overlap or only partially overlap with the active site, but may still render the MASP-2 molecule less active or inactive.

[0040] The term "or" refers to alternatives and should generally be construed as non-exclusive. For example, a reference to "a composition comprising A or B" would typically indicate an aspect having a composition that includes both A and B. However, "or" should be construed to exclude stated aspects that cannot be consistently combined (e.g., a composition pH of 9-10 or 7-8).

[0041] The group "A or B" is equivalent to the group "selected from the group consisting of A and B."

[0042] The transition words "comprising" or "comprise" are not exclusive. For example, a "composition comprising A" must include at least component A, but may also include one or more other components (e.g., B; B and C; B, C, and D; etc.). Thus, the term "comprising" should generally be interpreted as not excluding additional components. For example, a claim "a composition comprising A" would encompass compositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; etc.

[0043] The term "hypertonic" refers to a formulation having an osmolality greater than that of humans (ie, greater than 350 mOsm / KglHhO).

[0044] The term "agent" refers to a compound or mixture of compounds that, when added to a composition, tends to affect the properties of the composition. For example, a composition that includes a thickening agent tends to be more viscous than an otherwise identical comparative composition without the thickening agent.

[0045] A "synthetic" compound means a compound that does not occur in nature and is synthesized by humans. Reference to a compound herein may be understood to include reference to a synthetic compound unless the context indicates otherwise.

[0046] As used herein, the expressions "ambient temperature" and "room temperature" are art-recognized and generally refer to reaction temperatures that are about the same as, for example, the temperature of the room in which the reaction is carried out, e.g., from about 20°C to about 30°C.

[0047] At various places in this specification, certain features of compounds are disclosed in groups or ranges. It is specifically intended that such disclosure include every individual subcombination of the members of such groups and ranges. For example, "C 1~6 The terms "alkyl" and "C1-C6 alkyl" are specifically intended to independently disclose (and not be limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0048] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. Unless otherwise indicated, the term "substituted" refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, penta-, or higher, where such substitution is permissible (e.g., results in a stable compound). Substituents are independently selected, and substitution may occur at any chemically accessible position. It is understood that substitution at a given atom is limited by valency. The phrase "optionally substituted" means substituted or unsubstituted. The term "substituted" means that at least a hydrogen atom is replaced with a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0049] "C" where n and m are integers n~m " and "C n ~C m The term "" refers to a group containing n to m carbon atoms. Examples are C 1~4 , C 1~6 etc. The term includes all members within the scope, i.e., C n , C n+1 , C n+2 ...C m-2 , Cm-1 , C m For example, C 1~6 is intended to disclose C1, C2, C3, C4, C5, and C6. As used herein, "C n~m " is "C n ~C m " has the same meaning as ".

[0050] The term "n-membered" (e.g., 6-membered), where n is an integer, typically describes the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. The term "n- to m-membered" (e.g., 6- to 10-membered), where n and m are integers, describes a range of n to m ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocyclyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0051] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. In certain specific embodiments, an alkyl group may be substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, etc. 100 , -OC(O)R 100 , -N(R 100 )2, -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 )2, -N(R 20 )C(O)OR 102 , -N(R 100 )C(O)R 102, -N(R 102 )S(O) p R 102 (where p is 1 to 2), -S(O) p OR 102 (where p is 1 to 2), -S(O) t R 102 (where t is 0 to 2), and -S(O) p N(R 100 )2 (where p is 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0052] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 12 carbon atoms, preferably from 2 to 8 carbon atoms, attached to the remainder of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. In certain embodiments, the alkyl group may be substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 100 , -OC(O)R 100 , -N(R 100 )2, -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 )2, -N(R 20 )C(O)OR 102 , -N(R 100 )C(O)R 102 , -N(R 102 )S(O) p R 102(where p is 1 to 2), -S(O) p OR 102 (where p is 1 to 2), -S(O) t R 102 (where t is 0 to 2), and -S(O) p N(R 100 )2 (where p is 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0053] "Alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group as defined above, having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced at the point of attachment of the alkyl group to the remainder of the compound. n~m alkynyl" and "C n ~C m The term "alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Unless otherwise indicated, an alkynyl group may be substituted.

[0054] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, that connects the remainder of the molecule to a radical group or connects two portions of the molecule, such as, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may optionally contain one or more heteroatoms, where a carbon of the alkylene chain is replaced by a heteroatom selected from oxygen, nitrogen, or sulfur. The alkylene chain is attached to the remainder of the molecule through a single bond and to a radical group through a single bond, or to two portions of the molecule through single bonds at each point of attachment. In some embodiments, the alkyl group may be substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 100 , -OC(O)R 100 , -N(R 100 )2, -C(O)R 100 , -C(O)OR 100 , -C(O)N(R 100 )2, -N(R 20 )C(O)OR 102 , -N(R 100 )C(O)R 102 , -N(R 102 )S(O) p R 102 (where p is 1 to 2), -S(O) p OR 102 (where p is 1 to 2), -S(O) t R 102 (where t is 0 to 2), and -S(O) p N(R 100 )2 (where p is 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 102is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0055] The term "hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a hydroxy group (i.e., -OH). n~m The term "hydroxyalkyl" refers to a group having n to m carbon atoms and at least one hydroxy group. n~m It refers to an alkyl group. In some embodiments, a hydroxyalkyl group contains one hydroxy group. In certain aspects, a hydroxyalkyl group contains two or more hydroxy groups, each on the same or different carbon atoms (e.g., a "dihydroxyalkyl"). In certain aspects, a hydroxyalkyl group has one, two, three, four, five, six, or more hydroxy groups. Examples can include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0056] "Aminylalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an aminyl group (i.e., -NR 100 R 101 , where R 100 and R 101 refers to an alkyl group, as defined above, replaced with hydrogen, alkyl, alkenyl, or alkynyl, as defined herein. In some embodiments, an aminylalkyl comprises one aminyl group. In some embodiments, the aminyl group is -NH.

[0057] "Carboxyalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a carboxy group (i.e., -C(O)OH). In some embodiments, the carboxyalkyl contains one carboxy group.

[0058] "Phosphonoalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a phosphonate group (e.g., -P(=O)(OR)2, where R is hydrogen, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl). In some embodiments, a phosphonoalkyl group is -(CH2) n P(=O)(OR)2, where each R at each occurrence is independently hydrogen, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In some more specific embodiments, each R at each occurrence is independently hydrogen or alkyl. In some embodiments, the phosphonoalkyl comprises one phosphonate group.

[0059] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this disclosure, aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, aryl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 101 -OR 100 , -R 101 OC(O)R 100 , -R 101 -N(R 100 )2, -R 101 -N(R 100 )-R 103 -OR 100 , -R 101 -C(O)R 100 , -R 101 -C(O)OR 100 , -R101 -C(O)N(R 100 )2, -R 101 -N(R 100 )C(O)OR 102 , -R 101 -N(R 100 )C(O)R 102 , -R 101 -N(R 100 )S(O) p R 102 (where p is 1 to 2), -R 101 -N=C(OR 100 )R 100 , -R 101 -S(O) p OR 102 (where p is 1 to 2), -R 101 -S(O) t R 102 (where t is between 0 and 2), and -R 101 -S(O) p N(R 100 )2 (wherein p is 1 to 2); wherein each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 103 is a direct bond or a straight or branched alkylene chain. In some embodiments, the aryl group has the structure: TIFF2025131710000036.tif23128

[0060] "Arylalkyl" or "aralkyl" refers to a group of the formula -alkylene-aryl, where the alkylene and aryl groups are each as defined herein. In some embodiments, arylalkyl is C 6~10 Aryl-C 1~3 In some embodiments, arylalkyl is C 6~10 Aryl-C 1~4 In some embodiments, arylalkyl is C 6~10 Aryl-C 1~3 In some embodiments, arylalkyl is phenyl-C 1~3 In some embodiments, the arylalkyl is an optionally substituted benzyl.

[0061] "Aryloxy" refers to a group having the formula -O-aryl, where aryl is as defined above. In some embodiments, the aryloxy group is -OC 6~10 In some embodiments, the aryloxy is substituted or unsubstituted phenyloxy (i.e., —O—C aryl).

[0062] "Arylalkoxy" refers to a group having the formula -alkoxy-aryl, where alkoxy and aryl are each defined above. In some embodiments, arylalkoxy is C 6~10 Aryl-C 1~3 In some embodiments, the arylalkoxy is C 6~10 Aryl-C 1~4 In some embodiments, the arylalkoxy is C 6~10 Aryl-C 1~3 In some embodiments, the arylalkoxy is phenyl-C 1~3 Alkoxy (eg, methoxy).

[0063] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. In some embodiments, cycloalkyl groups include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R 101 -OR 100 , -R 101 -OC(O)-R 100 , -R 101 -N(R 100 )-R 103 -OR 100 , -R 101 -N(R 100 )2, -R 101 -C(O)R 100 , -R 101 -C(O)OR 100 , -R 101 -C(O)N(R 100 )2, -R 101 -N(R 100 )C(O)OR 102 , -R 101 -N(R 100 )C(O)R 102 , -R 101 -N(R 100 )S(O) p R 102 (where p is 1 to 2), -R 101 -N=C(OR 100 )R 100 , -R 101 -S(O) p OR 102 (where p is 1 to 2), -R 101 -S(O) t R 102(where t is between 0 and 2), and -R 101 -S(O) p N(R 100 )2 (wherein p is 1 to 2), wherein each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 103 is a direct bond or a straight or branched alkylene chain.

[0064] "Cycloalkylalkyl" refers to a group of the formula -R 100 R 101 where R 100 is an alkylene chain as defined above, and R 101 is a cycloalkyl radical as defined above. Where specifically stated in the specification, the alkylene chain and / or the cycloalkyl radical may be optionally substituted as defined above for optionally substituted alkylene chains and optionally substituted cycloalkyl.

[0065] "Alkoxy" refers to a radical group having the formula "-O-alkyl," where the alkyl group is as defined herein above. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Unless otherwise indicated, an alkoxy group may be substituted.

[0066] "Alkoxyalkyl" refers to a radical having the following formula: "-alkylene-O-alkyl," where the alkylene and alkyl groups are each as defined herein above. In some embodiments, the alkoxyalkyl group contains one -O-alkyl group. In some embodiments, the alkoxyalkyl group contains two or more alkoxy groups. Examples can include, but are not limited to, methoxymethyl, ethoxymethyl, 3-ethoxyethyl, and 1-methoxyethyl. Unless otherwise indicated, the alkoxyalkyl group may be substituted.

[0067] "Oxo" refers to the =O group. For example, oxo attached to a carbon atom forms a carbonyl group (i.e., C=O). Alternatively, when the oxo group is attached to a heteroatom, for example, a sulfoxide, sulfone, or N-oxide group is formed.

[0068] "Sulfide" refers to the group =S.

[0069] "Amino" refers to the group -NH2.

[0070] "Carbamyl" refers to the group -C(O)NH2.

[0071] "Carboxy" refers to the group --C(O)OH.

[0072] "Carbonyl" refers to the group C(=O), which may also be written as C(O).

[0073] "Cyano" or "nitrile" refers to the group -C≡N, which may also be written as -CN.

[0074] "Nitro" refers to the -NO2 group.

[0075] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0076] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0077] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of the haloalkyl radical is optionally substituted on the alkyl group as defined above.

[0078] The term "haloalkoxy," employed alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, where haloalkyl is as defined above. Exemplary haloalkoxy radicals include trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and the like.

[0079] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical, which consists of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, bridged, and spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be oxidized and the nitrogen atom can be quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals are azetidinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1-azaspiro[3.3]heptan-1-yl, 5-azaspiro[2.3]hexan-5-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1-oxa-6-azaspiro[3.4]octan ... sa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, Including, but not limited to, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.In certain aspects, the heterocyclyl group is alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 101 -OR 100 , -R 101 -OC(O)-R 100 , -R 101 -N(R 100 )-R 103 -OR 100 , -R 101 -N(R 100 )2, -R 101 -C(O)R 100 , -R 101 -C(O)OR 100 , -R 101 -C(O)N(R 100 )2, -R 101 -N(R 100 )C(O)OR 102 , -R 101 -N(R 100 )C(O)R 102 , -R 101 -N(R 100 )S(O) p R 102 (where p is 1 to 2), -R 101 -N=C(OR 100 )R 102 , -R 101 -S(O) p OR 102 (where p is 1 to 2), -R 101 -S(O) t R 102 (where t is between 0 and 2), and -R 101 -S(O) p N(R 100 )2 (wherein p is 1 to 2), wherein each R 100is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R 103 is a direct bond or a straight or branched alkylene chain.

[0080] "Heterocyclylalkyl" refers to a group of the formula -R 100 R 101 where R 100 is an alkylene chain as defined above, and R 101 is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at a nitrogen atom. In some embodiments, the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted alkylene chain. In some embodiments, the heterocyclyl portion of the heterocyclylalkyl radical may be optionally substituted as defined above for an optionally substituted heterocyclyl group.

[0081] "Heteroaryl" refers to a 4- to 14-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized.Examples are azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benz Zothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolethionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxa Zolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, purinyl

[0023] In certain embodiments, heteroaryl groups include, but are not limited to, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, thioxo, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -R. 101 -OR 100 , -R 101-OC(O)-R 100 , -R 101 -N(R 100 )-R 103 -OR 100 , -R 101 -N(R 100 )2, -R 101 -C(O)R 100 , -R 101 -C(O)OR 100 , -R 101 -C(O)N(R 100 )2, -R 101 -N(R 100 )C(O)OR 102 , -R 101 -N(R 100 )C(O)R 100 )C(O)R 102 , -R 101 -N(R 100 )S(O) p R 102 (where p is 1 to 2), -R 101 -N=C(OR 100 )R 100 , -R 101 -S(O) p OR 102 (where p is 1 to 2), -R 101 -S(O) t R 102 (where t is between 0 and 2), and -R 101 -S(O) p N(R 100 )2 (wherein p is 1 to 2), wherein each R 100 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 101 is independently a direct bond or a straight or branched alkylene chain; each R 102 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R103 is a direct bond or a linear or branched alkylene chain. 1 An optional substituent on the optionally substituted bicyclic heteroaryl group for is halo. Preferably, R 1 The optional substituents on the optionally substituted monocyclic heteroaryl group for are alkyl. The term "heteroaryl" includes, for example, the following structures: TIFF2025131710000037.tif23128

[0082] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen. The point of attachment of the N-heteroaryl to the rest of the molecule may be through a nitrogen atom or a carbon atom in the N-heteroaryl. Where specifically described herein, the N-heteroaryl radical may be optionally substituted as described above for optionally substituted heteroaryl radicals.

[0083] "Heteroarylalkyl" refers to a group of the formula -R 100 R 101 where R 100 is an alkylene chain as defined above, and R 101 is a heteroaryl radical as defined above. Where specifically described herein, the heteroaryl portion of a heteroarylalkyl radical is optionally substituted as defined above for an optionally substituted heteroaryl group. In some specific aspects, the alkylene chain portion of a heteroarylalkyl radical is optionally substituted as defined above for an optionally substituted alkylene chain.

[0084] The compounds and methods of the disclosure are also meant to encompass all pharmaceutically acceptable compounds of structure (I) that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number.

[0085] Examples of isotopes that can be incorporated into the disclosed compounds are 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, 125 The radioactive isotopes of structure (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. These radiolabeled compounds may be useful in determining or measuring the effectiveness of compounds, for example, by characterizing the site or mechanism of action or binding affinity. Certain isotopically labeled compounds of structure (I), for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and convenient means of detection.

[0086] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. In one embodiment, the compound of structure (I) is enriched with deuterium. Such deuterated compounds can be achieved by methods known to those skilled in the art, such as exchanging protons for deuterium, or by synthesizing the molecule with enriched starting materials.

[0087] 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the examples and preparations set forth below, substituting appropriate isotopically labeled reagents for previously employed non-labeled reagents.

[0088] The present disclosure is also meant to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like, primarily by enzymatic processes, of the administered compound. Accordingly, the present disclosure includes compounds produced by a process comprising contacting a compound of the present disclosure with a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0089] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0090] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and the description includes both substituted aryl radicals and aryl radicals that have no substitution ("unsubstituted"). If a functional group is described as "optionally substituted," and in turn, a substituent on the functional group is also described as "optionally substituted," etc., for purposes of this disclosure, such repetitions are limited to five, and preferably such repetitions are limited to two.

[0091] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0092] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0093] "Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and also includes, but is not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptan-1,2-one, and the like. It refers to salts formed with organic acids such as carboxylic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0094] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0095] Crystallization often produces solvates of the disclosed compounds (e.g., compounds of structure (I)). As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of a solvent together with one or more molecules of a disclosed compound. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the disclosed compounds can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. While the disclosed compounds may be true solvates, in other cases, the disclosed compounds may merely retain incidental water or may be a mixture of water and some incidental solvent.

[0096] A "pharmaceutical composition" refers to a formulation of a disclosed compound with a vehicle generally accepted in the art for delivery of biologically active compounds to mammals, e.g., humans. Such a vehicle includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0097] As used herein, "treating" or "treatment" includes treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes: (a) preventing the occurrence of a disease or condition in a mammal, particularly where such mammal is predisposed to the condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition, i.e., arresting the progression of the disease or condition; (c) alleviating (or ameliorating) the disease or condition, i.e., causing regression of the disease or condition; or (d) For example, alleviating (or ameliorating) symptoms caused by a disease or condition without addressing the underlying disease or condition. Includes.

[0098] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular ailment or condition may not have a known causative agent (and thus the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable state or syndrome (where a more or less specific set of symptoms has been identified by clinicians).

[0099] The disclosed compounds or their pharmaceutically acceptable salts may contain one or more stereocenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be specified in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or separated using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers that give rise to geometric asymmetry, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers, as well as all tautomeric forms.

[0100] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including enantiomers, which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. For a detailed description of the structure and properties of enantiomers and stereoisomers, see, for example, Smith, MB and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007).

[0101] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the aforementioned compounds.

[0102] The use of parentheses and square brackets in substituents is used herein to conserve space. Thus, the use of parentheses in a substituent indicates that the group enclosed in the parentheses is directly bonded to the atom preceding the parentheses. The use of square brackets in a substituent indicates that the group enclosed in the parentheses is also directly bonded to the atom preceding the parentheses.

[0103] The chemical naming protocols and structural diagrams used herein are modifications of the IUPAC nomenclature using the ChemBioDraw Ultra Version 14.0 software program. In complex chemical names used herein, substituents are listed before the group to which they are attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. In chemical structural diagrams, all bonds are identified except for some carbon atoms, which are assumed to be connected to sufficient hydrogen atoms to satisfy the valence.

[0104] At certain positions, the definitions or embodiments may refer to specific rings (e.g., azetidine rings, pyridine rings, etc.) Unless otherwise indicated, these rings can be attached to any ring member as long as the valence of the atom is not exceeded.

[0105] When any two groups or two instances of the same substituent are "independently selected" from a list of alternatives, the groups may be the same or different. For example, R a and R b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, two R a group and two R b A molecule having groups may have all groups being alkyl groups (e.g., four different alkyl groups). Alternatively, the first R a may be alkyl, and the second R a may be fluoro, and the first R b may be hydroxyalkyl, and the second R b Alternatively, R may be amino (or any other substituent selected from the group). a and the first R b while both R and R may be fluoro. b may be alkyl (i.e., some pairs of substituents may be the same, and other pairs may be different). Unless otherwise indicated, two or more groups having the same definition are present, but where the definition provides alternatives, each occurrence of the same group should be understood to be independently selected from the possible alternatives. For example, if a compound has two or more R a groups are present, and R a The definition of R a Each R present in the compound may be A, B, or C. a The R groups present in the compound are independently selected from A, B, and C. a It is to be understood that the groups may be the same or different.

[0106] Compounds and their salts, including pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (for example, hydrates and solvates), or can be isolated.When in solid state, the compounds described herein and their salts can exist in various forms, for example, they can be in the form of solvates, including hydrates.Since the compounds can be in any solid form, such as polymorphs or solvates, unless otherwise specified, reference to compounds and their salts should be understood to include any solid form of the compounds.

[0107] In some embodiments, the compounds described herein or salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the disclosed compounds. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the disclosed compounds or salts thereof.

[0108] II. Compound In certain aspects, the present disclosure provides a compound having the following structure (I): TIFF2025131710000038.tif39128In formula, TIFF2025131710000039.tif2128 represents a double bond or a single bond independently at each occurrence; R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or cycloalkyl; R 3is hydrogen, alkyl, haloalkyl, or cycloalkyl, or R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl; R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH2) m C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , (CH2) m NR 6 S(O)2R 7 , or C(=O)NR 6 R 7 and; R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; L 1 is a direct bond, -CR 8a R 8b -, -S(O) t -, NR 8c , or -O-; R 8a and R 8b are each independently hydrogen, alkyl, or R 8a and R 8b together with the carbons to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl; R 8cis hydrogen, alkyl, haloalkyl, (C=O)alkyl, (C=O)Oalkyl, (C=O)cycloalkyl, (C=O)Ocycloalkyl, (C=O)aryl, (C=O)Oaryl, (C=O)heteroaryl, (C=O)Oheteroaryl, (C=O)heterocyclyl, (C=O)Oheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heterocyclylalkyl; n is 1 or 2; m is 1, 2, 3, 4, 5, or 6; t is 0, 1, or 2; However, the compound of structure (I) does not have the structure in Table A below.

[0109] (Table A) Compounds not included in structure (I) TIFF2025131710000040.tif69150TIFF2025131710000041.tif211150TIFF202513171000004 2.tif213150TIFF2025131710000043.tif203150TIFF2025131710000044.tif214150TIFF2025 131710000045.tif220150TIFF2025131710000046.tif208150TIFF2025131710000047.tif21 8150TIFF2025131710000048.tif202150TIFF2025131710000049.tif232150TIFF20251317100 00050.tif198150TIFF2025131710000051.tif218150TIFF2025131710000052.tif210150TIF F2025131710000053.tif199150TIFF2025131710000054.tif215150TIFF2025131710000055.t if214150TIFF2025131710000056.tif215150TIFF2025131710000057.tif211150TIFF2025131 710000058.tif203150TIFF2025131710000059.tif209150TIFF2025131710000060.tif154150

[0110] In some embodiments, the compound of structure (I) does not have the following structure: TIFF2025131710000061.tif27128

[0111] In some embodiments, the compound of structure (I) does not have the structure of any of the compounds of International Application No. PCT / US19 / 34225, International Application No. PCT / US19 / 34220, or U.S. Patent Application No. 16 / 425,791 (e.g., the compounds listed in Table 1 or in the Examples of each of the above applications).

[0112] In some embodiments, R 1 is substituted or unsubstituted aryl. In certain embodiments, R1 is substituted or unsubstituted C6-C 10 In some particular embodiments, R 1 is substituted or unsubstituted phenyl. In certain specific embodiments, R 1 is a substituted phenyl.

[0113] In some more specific embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , or R 1e and wherein R is a phenyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 )NH2, C(=NOH)NH2, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 9 , R 10 , R 11 , and R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl.

[0114] In certain more specific aspects, R 1a , R 1b , R 1c , R 1d , or R 1e is substituted C 6~10Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, wherein R 13 , R 14 , R 15 , and R 16 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0115] In some embodiments, R 1 is halo, haloalkyl, C(=NR 9 )NR 10 R 11 , C(=NR 9 )NR 10 C(O)OR 11 and 5- to 10-membered heteroaryl. 1 are -C(=NH)NH2, chloro, fluoro, -CHF2, and TIFF2025131710000062.tif14128.

[0116] In some embodiments, R 1 has one of the following structures: TIFF2025131710000063.tif182146

[0117] In some more specific embodiments, R 1 has one of the following structures: TIFF2025131710000064.tif106142

[0118] In some embodiments, R 1 has one of the following structures: TIFF2025131710000065.tif58128

[0119] In some embodiments, R 9 is C 1~6 Alkyl or C 1~6 In certain embodiments, R 9is methyl. In some particular embodiments, R 9 is trifluoromethyl. In certain specific embodiments, R 1 is unsubstituted phenyl.

[0120] In some more specific embodiments, R 1 is substituted or unsubstituted heteroaryl. In some embodiments, R 1 is a substituted or unsubstituted 5-10 membered heteroaryl. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted thienopyridinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoindolinyl, or substituted or unsubstituted benzothiazolyl.

[0121] In some more specific embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , or R 1e and heteroaryl substituted with one or more of the following: 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9)C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 9 , R 10 , R 11 , and R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0122] In certain more specific aspects, R 1a , R 1b , R 1c , R 1d , or R 1e is substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14and oxo, wherein R 13 , R 14 , R 15 , and R 16 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0123] In some embodiments, R 1 has one of the following structures: TIFF2025131710000066.tif85148TIFF2025131710000067.tif204148TIFF2025131710000068.tif213146TIFF2025131710000069.tif131146

[0124] In some embodiments, R 1a or R 1b is independently C 1~6 Alkyl, C 1~6 deuterated alkyl, amino, or halo. 1a or R 1b is methyl or CD3. In some particular embodiments, R 1a or R 1b is F, Cl, or Br. In certain specific embodiments, R attached to a nitrogen 1a or R 1b are C 1~6 In some more specific embodiments, R 1a or R 1b is methyl or ethyl.

[0125] In some embodiments, R 1has one of the following structures: TIFF2025131710000070.tif143147

[0126] In certain embodiments, R 1 has one of the following structures: TIFF2025131710000071.tif118146TIFF2025131710000072.tif216147TIFF2025131710000073.tif99152

[0127] In some embodiments, R 1 has one of the following structures: TIFF2025131710000074.tif95146

[0128] In some embodiments, R 1 has one of the following structures: TIFF2025131710000075.tif99149

[0129] In some embodiments, R 1 has one of the following structures: TIFF2025131710000076.tif66149

[0130] In some embodiments, R 1 is substituted or unsubstituted cycloalkyl. In certain embodiments, R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some specific embodiments, R 1 is a substituted C3-C6 cycloalkyl.

[0131] In some more specific embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , or R 1e wherein R is a C3-C6 cycloalkyl substituted with one or more of 1a , R 1b , R1c , R 1d , and R 1e are each independently 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 9 , R 10 , R 11 , and R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0132] In certain more specific aspects, R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e , Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, wherein R 13 , R 14 , R 15 , and R 16 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0133] In some embodiments, R 1 is unsubstituted C3-C6 cycloalkyl. In certain embodiments, R 1 is substituted or unsubstituted heterocyclyl. In some specific embodiments, R 1 is a substituted or unsubstituted 4-10 membered heterocyclyl. In certain specific embodiments, R 1 is a substituted 4-10 membered heterocyclyl.

[0134] In some more specific embodiments, R 1 is R 1a , R1b , R 1c , R 1d , or R 1e and R is a 4- to 10-membered heterocyclyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 9 , R 10 , R 11 , and R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0135] In certain more specific aspects, R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e is OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14, C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, wherein R 13 , R 14 , R 15 , and R 16 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0136] In some embodiments, R 1 is unsubstituted 4-10 membered heterocyclyl. In certain embodiments, R 2 is hydrogen, C1-C6 alkyl, or R 2 and R 3taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl.

[0137] In some particular embodiments, R 2 is C1-C6 alkyl. In certain specific embodiments, R 2 is —CH3. In some more specific embodiments, R 2 is -CH2OH.

[0138] In some embodiments, R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl. 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4-, 5-, or 6-membered heterocyclyl. 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4-membered heterocyclyl.

[0139] In some embodiments, the compound has one of the following structures: (IA1a), (IB1a), (IC1a), (ID1a), (IE1a), (IF1a), (IG1a), or (IH1a). TIFF2025131710000077.tif164128

[0140] In certain embodiments, the compound has one of the following structures: (IA1b), (IB1b), (IC1b), (ID1b), (IE1b), (IF1b), (IG1b), or (IH1b). TIFF2025131710000078.tif164130

[0141] In some embodiments, the compound has one of the following structures: (IA2a), (IB2a), (IC2a), (ID2a), (IE2a), (IF2a), (IG2a), or (IH2a). TIFF2025131710000079.tif174133

[0142] In certain specific embodiments, the compound has one of the following structures: (IA2b), (IB2b), (IC2b), (ID2b), (IE2b), (IF2b), (IG2b), or (IH2b). TIFF2025131710000080.tif189130

[0143] In some embodiments, the compound has one of the following structures: (IA3a), (IB3a), (IC3a), (ID3a), (IE3a), (IF3a), (IG3a), or (IH3a). TIFF2025131710000081.tif178133

[0144] In certain embodiments, the compound has one of the following structures: (IA3b), (IB3b), (IC3b), (ID3b), (IE3b), (IF3b), (IG3b), or (IH3b). TIFF2025131710000082.tif189130

[0145] In certain embodiments, the compound has one of the following structures: (IA4a), (IB4a), (IC4a), (ID4a), (IE4a), (IF4a), (IG4a), or (IH4a). TIFF2025131710000083.tif180133

[0146] In some particular embodiments, the compound has one of the following structures: (IA4b), (IB4b), (IC4b), (ID4b), (IE4b), (IF4b), (IG4b), or (IH4b). TIFF2025131710000084.tif177130

[0147] In some more specific embodiments, the compound has one of the following structures (IA5a), (IB5a), (IC5a), (ID5a), (IE5a), (IF5a), (IG5a), or (IH5a): TIFF2025131710000085.tif176133In formula, R 2a and R 2b are each independently hydrogen or halo.

[0148] In certain more specific embodiments, the compound has one of the following structures (IA5b), (IB5b), (IC5b), (ID5b), (IE5b), (IF5b), (IG5b), or (IH5b): TIFF2025131710000086.tif176130In the formula, R 2a and R 2b are each independently hydrogen or halo.

[0149] In some embodiments, R 2a and R 2b are both halo (e.g., F, Br, Cl, or I). In certain embodiments, R 2a and R 2b are all fluoro.

[0150] In some particular embodiments, R 4 is substituted or unsubstituted aryl. In certain embodiments, R 4 is substituted or unsubstituted C6-C 10 In some more specific embodiments, R 4 is substituted or unsubstituted phenyl. In certain embodiments, R 4 is unsubstituted phenyl.

[0151] In some particular embodiments, R 4 is R 4a , R 4b , R 4c , R 4d , or R 4eand wherein R is a phenyl substituted with one or more of 4a , R 4b , R 4c , R 4d , and R 4e are each independently C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , S.R. 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 ,OC(O)R 17 ,OC(O)OR 17 , OC(O)NR 17 R 18 , N.R. 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(=NR 17 )NR 18 R 19 , C(=NOR 17 )NR 18 R 19 , C(=NOC(O)R 17 )NR 18 R 19 , C(=NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(=NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O)2R 17 , N(R 17 )S(O)2R 18 , S(O)NR 17 R 18 , oxo, substituted or unsubstituted C6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 17 , R 18 , R 19 , and R 20 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0152] In some embodiments, R 4a , R 4b , R 4c , R 4d , or R 4e is substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 4a , R 4b , R 4c , R 4d , or R 4e is OR 21 , S.R. 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 ,OC(O)R 21 , OC(O)NR 21 R 22, N.R. 21 R 22 , N.R. 21 C(O)R 22 , N.R. 21 C(O)NR 22 R 23 , N.R. 21 C(O)OR 22 , C(=NR 21 )NR 22 R 23 , N.R. 21 C(=NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O)2R 21 , N.R. 21 S(O)2R 22 , S(O)NR 21 R 22 and oxo, wherein R 21 , R 22 , R 23 , and R 24 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0153] In some embodiments, R 4 has one of the following structures: TIFF2025131710000087.tif181148

[0154] In some embodiments, R 4 is substituted or unsubstituted heteroaryl. In certain embodiments, R 4 is a 4-10 membered heteroaryl. In some particular embodiments, R 4is an unsubstituted 4-10 membered heteroaryl.

[0155] In some more specific embodiments, R 4 is R 4a , R 4b , R 4c , R 4d , or R 4e and R is a 4- to 10-membered heteroaryl substituted with one or more of 4a , R 4b , R 4c , R 4d , and R 4e are each independently C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , S.R. 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 ,OC(O)R 17 ,OC(O)OR 17 , OC(O)NR 17 R 18 , N.R. 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(=NR 17 )NR 18 R 19 , C(=NOR 17 )NR 18 R 19 , C(=NOC(O)R 17 )NR 18 R 19 , C(=NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(=NR 18 )NR 19 R20 , S(O)R 17 , S(O)NR 17 R 18 , S(O)2R 17 , N(R 17 )S(O)2R 18 , S(O)NR 17 R 18 , oxo, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 17 , R 18 , R 19 , and R 20 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0156] In certain more specific aspects, R 4a , R 4b , R 4c , R 4d , or R 4e is substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 4a , R 4b , R 4c , R 4d, or R 4e Halo, CN, OR 21 , S.R. 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 ,OC(O)R 21 , OC(O)NR 21 R 22 , N.R. 21 R 22 , N.R. 21 C(O)R 22 , N.R. 21 C(O)NR 22 R 23 , N.R. 21 C(O)OR 22 , C(=NR 21 )NR 22 R 23 , N.R. 21 C(=NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O)2R 21 , N.R. 21 S(O)2R 22 , S(O)NR 21 R 22 and oxo, wherein R 21 , R 22 , R 23 , and R 24 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0157] In some embodiments, R 4 has one of the following structures: TIFF2025131710000088.tif56131

[0158] In some embodiments, R 5 is hydrogen. In certain embodiments, R 5 is alkyl, phosphonoalkyl, (CH2) m NR 6 S(O)2R 7 , or (CH2) m C(=O)OR 6 is.

[0159] In some particular embodiments, R 5 is alkyl. In certain specific embodiments, R 5 is methyl. In more specific embodiments, R 5 is ethyl. In certain specific embodiments, R 5 (CH2) m C(=O)OR 6 In some embodiments, R 5 has one of the following structures: TIFF2025131710000089.tif15128

[0160] In some embodiments, R 5 is phosphonoalkyl. In more specific embodiments, R 5 has one of the following structures: TIFF2025131710000090.tif17128

[0161] In some embodiments, R 5 (CH2) m NR 6 S(O)2R 7 In a more specific embodiment, R 5 has the following structure: TIFF2025131710000091.tif16128

[0162] In certain embodiments, TIFF2025131710000092.tif2128 represents a single bond at each occurrence. In other embodiments, at least one occurrence of TIFF2025131710000093.tif2128 represents a double bond. In some more specific embodiments, in one occurrence, TIFF2025131710000094.tif2128 represents a double bond. In certain more specific embodiments, in two occurrences, TIFF2025131710000095.tif2128 represents a double bond.

[0163] In some embodiments, L 1 is a direct bond. Thus, in certain embodiments, the compound of structure (I) has the structure: TIFF2025131710000096.tif26128

[0164] In some embodiments, L 1 is —O—. Thus, in certain embodiments, the compound of structure (I) has the following structure: TIFF2025131710000097.tif34128

[0165] In some embodiments, L 1 is —CH—. That is, in certain embodiments, the compound of structure (I) has the following structure: TIFF2025131710000098.tif34128

[0166] In some embodiments, L 1 Ha-CR 8a R 8b - and R 8a and R 8b taken together with the carbons to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl. In certain embodiments, R 8a and R 8b taken together with the carbon to which they are attached form an optionally substituted 3-, 4-, or 5-membered cycloalkyl. In some particular embodiments, R 8a and R8b taken together with the carbons to which they are attached form an optionally substituted 3-membered cycloalkyl. In certain specific embodiments, the 3-membered cycloalkyl is unsubstituted.

[0167] In some more specific embodiments, the compound of structure (I) has one of the following structures: TIFF2025131710000099.tif70128

[0168] In some embodiments, R 8c is hydrogen, alkyl, haloalkyl, or substituted or unsubstituted cycloalkyl.

[0169] In some embodiments, the compounds of structure (I) and embodiments thereof may be in the form of a salt, such as a pharmaceutically acceptable salt.

[0170] Compounds of structure (I) and embodiments thereof are useful as inhibitors of MASP-2 and for therapeutic use. Compounds of structure (I) and embodiments thereof are useful in the treatment of MASP-2-associated diseases and disorders and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods for treating MASP-2-associated diseases and disorders, comprising administering to a patient a therapeutically effective amount of a compound of structure (I) or an embodiment thereof, optionally in the form of a salt.

[0171] In some embodiments, the structure of structure (I) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, e.g., a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0172] In certain aspects, the compound is one or more selected from the compounds of structure (I) described in the Examples, including the compounds listed in Table 1 (e.g., compounds having selectivity for MASP-2 over thrombin). In certain aspects, one or more of the variables defining a compound of structure (I) are selected from the corresponding substituents in the compounds of structure (I) in the Examples, including the compounds listed in Table 1, preferably those of compounds having selectivity for MASP-2 over thrombin.

[0173] In certain aspects, the disclosure describes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more stereocenters). Unless specifically indicated, any compound having one or more stereocenters is intended to include and describe both the (+) and (-) pure enantiomers, any other diastereomers, enantiomerically or diastereomerically enriched mixtures (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0174] Certain embodiments provide pharmaceutically acceptable salts (e.g., hydrogen halides such as hydrochloride or dihydrochloride salts) of the indicated chemical structures. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, fatty acid salts, and the like. Salts can be prepared by a variety of methods known to those skilled in the art, including precipitation with a conjugate acid or base (e.g., treatment with HCl gas or HCl solution).

[0175] In certain embodiments, prodrugs are provided. Prodrugs are compounds that are converted into biologically active forms under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., esters to acid forms, carbamates to amino or hydroxy groups, hydroxyamidines to amidines). Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for amidine groups include amidoximes, O-alkylamidoximes, acylamidines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0176] In certain aspects, the compounds are useful for selectively inhibiting MASP-2 relative to thrombin, and the methods include administering a compound described herein. In certain aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0177] III. synthesis The compounds described herein, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized by any of a number of possible synthetic routes, such as those shown in the Examples below.

[0178] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0179] The preparation of the disclosed compounds may involve the protection and deprotection of various chemical groups.The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art.The chemical properties of protecting groups are described, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0180] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0181] The specific synthetic methods used in the examples provide general guidance regarding the preparation of the disclosed compounds, and those skilled in the art will recognize that, using their general knowledge of organic chemistry, the preparation methods can be modified or optimized to prepare a variety of compounds within the scope of the present disclosure.

[0182] Starting materials, reagents, and intermediates whose synthesis is not described herein are either commercially available, known in the literature, or can be prepared by methods known to those skilled in the art.

[0183] Those skilled in the art will recognize that the described processes are not the only means by which the disclosed compounds may be synthesized, and that a wide repertoire of synthetic organic reactions is available that may be employed in synthesizing the disclosed compounds. Those skilled in the art will know how to select and carry out appropriate synthetic routes.Suitable synthetic methods for the starting materials, intermediates, and products are described in Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry, Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991), and other references.

[0184] IV. Disposal method In another aspect, the present disclosure provides a method for treating a patient suffering from or at risk of developing a MASP-2-associated disease or disorder, such as a MASP-2-dependent complement-associated disease or disorder, comprising administering a small molecule inhibitor of MASP-2.

[0185] The compound may be any small molecule inhibitor of MASP-2. In some embodiments, the compound may be a small molecule inhibitor of MASP-2 that binds to the serine protease domain of MASP-2. In some embodiments, the compound may be a small molecule inhibitor, such as a synthetic small molecule inhibitor of MASP-2. In some embodiments, the compound may be a small molecule inhibitor of MASP-2 that binds to the catalytic substrate binding region of MASP-2. In some embodiments, the compound selectively inhibits MASP-2 compared to thrombin. For example, in some embodiments, the compound is a compound of structure (I) according to any of the preceding embodiments.

[0186] U.S. Patent No. 7,919,094; U.S. Patent No. 8,840,893; U.S. Patent No. 8,652,477; U.S. Patent No. 8,951,522; U.S. Patent No. 9,011,860; U.S. Patent No. 9,475,885; U.S. Patent No. 9,644,035; U.S. Patent Application Publication Nos. 2013 / 0344073, 2013 / 0266560, 2015 / 0166675, and 2017 / 013753 As described in International Publication Nos. 2017 / 0166660, 2017 / 0189525, 2017 / 0267781, 2017 / 0283508, 2017 / 0253667, 2018 / 0105604, and International Publication Nos. 2018 / 045054, 2019 / 036460, and co-pending U.S. patent application Ser. No. 62 / 688,611 (each of which is assigned to Omeros Corporation, the assignee of the present application, and each of which is incorporated herein by reference), MASP-2-dependent complement activation has been implicated in contributing to the pathogenesis of numerous acute and chronic conditions. For example, as described in U.S. Patent No. 8,951,522, the primary function of the complement system, part of the innate immune system, is to protect the host from infectious agents. However, inappropriate or excessive activation of the complement system can lead to serious diseases, such as thrombotic microangiopathy (aHUS, TTP, and TMA, including HUS), in which endothelial damage and fibrin- and platelet-rich clots in microvessels lead to organ damage. The lectin pathway plays a major role in activating complement and preventing the activation of MASP-2 under conditions of endothelial stress or injury. The lectin pathway halts the series of enzymatic reactions that lead to the formation of the membrane attack complex, platelet activation, and leukocyte recruitment. As described in U.S. Patent No. 8,652,477, in addition to initiating the lectin pathway, MASP-2 can also activate the coagulation system, cleaving prothrombin to thrombin.

[0187] Thus, in some embodiments, the method includes administering to a patient suffering from or at risk of developing a MASP-2-dependent complement-related disease or disorder an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the method may further include determining that the patient is suffering from a lectin complement-related disease or disorder before administering the disclosed compound to the patient.

[0188] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of thrombotic microangiopathy (TMA), renal disease, inflammatory responses resulting from tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, cardiovascular diseases or disorders, inflammatory gastrointestinal disorders, pulmonary disorders, eye diseases or disorders, disseminated intravascular coagulation, graft-versus-host disease, venous occlusive disease, diffuse alveolar hemorrhage, and the like, or combinations thereof.

[0189] In some embodiments, the MASP-2-dependent complement-related disease or disorder is thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic syndrome (aHUS), factor H-independent atypical hemolytic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplantation, or TMA associated with hematopoietic stem cell transplantation.

[0190] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing graft-versus-host disease (GVHD), including acute GVHD, chronic GVHD, or steroid-resistant GVHD, an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing GVHD has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0191] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing diffuse alveolar hemorrhage (DAH) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing DAH has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0192] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing veno-occlusive disease (VOD) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing VOD has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0193] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing idiopathic pneumonia syndrome (IPS) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing IPS has previously undergone, is undergoing, or will undergo hematopoietic stem cell transplantation.

[0194] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing capillary leak syndrome (CLS) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing CLS has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0195] In some embodiments, the method comprises administering to a patient suffering from or at risk of developing engraftment syndrome (ES) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing ES has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0196] In some embodiments, the method includes administering to a patient suffering from or at risk of developing fluid overload (FO) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject suffering from or at risk of developing FO has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0197] In some embodiments, the method includes administering to a patient suffering from any of the above-referenced diseases or conditions an amount of a compound disclosed in International Application No. PCT / US19 / 34225, which is incorporated herein in its entirety.

[0198] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a renal disease, including mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangial capillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, microimmune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, and the like, or combinations thereof.

[0199] In some embodiments, the MASP-2-dependent complement-related disease or disorder is chronic kidney disease, chronic renal failure, glomerular disease (e.g., focal segmental glomerulosclerosis), immune complex disorders (e.g., IgA nephropathy, membranous nephropathy), lupus nephritis, nephrotic syndrome, diabetic nephropathy, tubulointerstitial injury and glomerulonephritis (e.g., C3 glomerulopathy), or nephrotic syndrome, pre-eclampsia, eclampsia, toxic nephropathy, amyloidosis, collagen vascular disease (e.g., systemic lupus erythematosus), dehydration, or , glomerular diseases (e.g., membranous glomerulonephritis, focal segmental glomerulonephritis, C3 glomerulopathy, minimal change disease, lipid nephropathy), strenuous exercise, stress, benign orthostatic (postural) proteinuria, focal segmental glomerulosclerosis, IgA nephropathy (i.e., Berger's disease), IgM nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, minimal change disease, sarcoidosis, Alport syndrome, diabetes (diabetic nephropathy), drug-induced toxicity (e.g., NSAIDs, nicotine, penicillamine, lithium carbonate, gold and other heavy metals, ACE inhibitors, antibiotics (e.g., adriamycin), opiates (e.g., heroin), or other nephrotoxins); Fabry disease, infectious diseases (e.g., HIV, syphilis, hepatitis A, B, or C, post-streptococcal infections, urinary schistosomiasis); aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, sickle cell disease, hemoglobinuria, multiple myeloma, myoglobinuria, organ rejection (e.g., renal transplant rejection), Ebola hemorrhagic fever, Renal fibrosis (e.g., tubulointerstitial fibrosis) and / or proteinuria in a subject suffering from or at risk of developing a disease or condition associated with proteinuria, including, but not limited to, nail-patella syndrome, familial Mediterranean fever, HELLP syndrome, systemic lupus erythematosus, Wegener's granulomatosis, rheumatoid arthritis, glycogen storage disease type 1, Goodpasture's syndrome, Henoch-Schönlein purpura, urinary tract infection that has spread to the kidney, Sjogren's syndrome, and post-infectious glomerulonephritis.

[0200] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory response resulting from tissue or solid organ transplantation, including allografts or xenografts of whole organs (e.g., kidney, heart, liver, pancreas, lung, cornea, etc.) or tissue transplants (e.g., valve, tendon, bone marrow, etc.).

[0201] In some embodiments, the MASP-2-dependent complement-associated disorder is ischemia-reperfusion injury (I / R), including myocardial I / R, gastrointestinal I / R, renal I / R, and I / R after aortic aneurysm repair, I / R associated with cardiopulmonary bypass, cerebral I / R, stroke, organ transplant, or reattachment of amputated or traumatized limbs or digits; revascularization of grafts and / or regrafts, and shock, hemodynamic resuscitation after surgical procedures, and the like, or combinations thereof.

[0202] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a complication associated with non-obese diabetes (type 1 diabetes or insulin-dependent diabetes) and / or a complication associated with type 1 or type 2 (adult-onset) diabetes, including diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, diabetic macular edema, etc., or combinations thereof.

[0203] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a cardiovascular disease or disorder, including Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis (also known as malignant rheumatoid arthritis), immune complex vasculitis, and Takayasu's disease; dilated cardiomyopathy; diabetic angiopathy; Kawasaki disease (arteritis); venous gas embolism (VGE); and inhibition of restenosis after stent placement, rotational atherectomy, percutaneous transluminal coronary angioplasty (PTCA), and the like, or combinations thereof.

[0204] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory gastrointestinal disorder, including Crohn's disease, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease (IBD), including pancreatitis, diverticulitis, and intestinal disorders, and combinations thereof.

[0205] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a pulmonary disorder, including acute respiratory distress syndrome, transfusion-related acute lung injury, ischemia / reperfusion acute lung injury, chronic obstructive pulmonary disease, asthma, Wegener's granulomatosis, anti-glomerular basement membrane disease (Goodpasture's disease), meconium aspiration syndrome, aspiration pneumonia, bronchiolitis obliterans syndrome, idiopathic pulmonary fibrosis, acute lung injury secondary to burns, non-cardiogenic pulmonary edema, transfusion-related respiratory depression, emphysema, and the like, or combinations thereof.

[0206] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an inflammatory response caused by extracorporeal exposure, and the method includes treating a subject undergoing an extracorporeal circulation procedure. In some embodiments, the extracorporeal circulation procedure includes hemodialysis, plasma exchange, leukopheresis, extracorporeal membrane oxygenation (ECMO), heparin-induced extracorporeal membrane oxygenation LDL precipitation (HELP), cardiopulmonary bypass (CPB), etc.

[0207] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from inflammatory or non-inflammatory arthritis and other musculoskeletal disorders, such as osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, neuropathic arthropathy, psoriatic arthritis, ankylosing spondylitis or other spondyloarthropathy and crystalline arthropathies, muscular dystrophies, systemic lupus erythematosus (SLE), etc., or combinations thereof.

[0208] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a skin disorder, such as psoriasis, autoimmune bullous dermatosis, eosinophilic spongiosis, bullous pemphigoid, epidermolysis bullosa acquisita, atopic dermatitis, herpes gestationis, and other skin disorders. In some embodiments, the MASP-2-dependent complement-related disease or disorder is a thermal injury, a chemical burn, or a combination thereof, including capillary leakage caused by them.

[0209] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a peripheral nervous system (PNS) and / or central nervous system (CNS) disorder or injury, including multiple sclerosis (MS), myasthenia gravis (MG), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Guillain-Barré syndrome, reperfusion after stroke, intervertebral disc degeneration, brain trauma, Parkinson's disease (PD), Alzheimer's disease (AD), Miller-Fisher syndrome, brain trauma and / or hemorrhage, traumatic brain injury, demyelination, meningitis, and the like, or combinations thereof.

[0210] In some embodiments, the MASP-2-dependent complement-related disease or disorder is sepsis or a condition resulting from sepsis, including severe sepsis, septic shock, sepsis-induced acute respiratory distress syndrome, hemolytic anemia, systemic inflammatory response syndrome, hemorrhagic shock, and the like, or combinations thereof.

[0211] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a urogenital disorder, including painful bladder disease, sensory bladder disease, chronic sterile cystitis and interstitial cystitis, male and female infertility, placental insufficiency and miscarriage, preeclampsia, and the like, or combinations thereof.

[0212] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory response in a subject being treated with chemotherapy and / or radiation therapy, including treatment of a cancerous disease.

[0213] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an angiogenesis-dependent cancer, including solid tumors, blood-borne tumors, high-risk carcinoid tumors, tumor metastasis, and the like, or combinations thereof.

[0214] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an angiogenesis-dependent benign tumor, including hemangioma, acoustic neuroma, neurofibroma, trachoma, carcinoid tumor, pyogenic granuloma, and the like, or combinations thereof.

[0215] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an endocrine disorder, including Hashimoto's thyroiditis, which involves the regulated release of prolactin, growth or insulin-like growth factors, adrenocorticotropic hormones from the pituitary gland, stress, anxiety, other underlying hormonal disorders, and the like, or combinations thereof.

[0216] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an ocular disease or disorder, including age-related macular degeneration, glaucoma, endophthalmitis, and the like, or combinations thereof.

[0217] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an ocular neovascular disease or condition, including age-related macular degeneration, uveitis, ocular melanoma, corneal neovascularization, primary pterygium, HSV stromal keratitis, HSV-1-induced corneal lymphangiogenesis, proliferative diabetic retinopathy, diabetic macular edema, retinopathy of prematurity, retinal vein occlusion, corneal graft rejection, neovascular glaucoma, vitreous hemorrhage secondary to proliferative diabetic retinopathy, neuromyelitis optica, rubeosis, and the like, or combinations thereof.

[0218] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is disseminated intravascular coagulation (DIC) or other complement-mediated coagulation disorder, including DIC secondary to sepsis, severe trauma including neurological trauma (e.g., acute head injury; see Kumura et al, Acta Neurochirurgica 55:23-28(1987)), infection (e.g., bacterial, viral, fungal, parasitic), cancer, obstetric complications, liver disease, severe toxic reactions (e.g., snake bite, insect bite, transfusion reaction), shock, heat stroke, transplant rejection, vascular aneurysm, liver failure, cancer treatment with chemotherapy or radiation therapy, burns, or accidental radiation exposure.

[0219] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of acute radiation syndrome, dense deposit disease, Degos disease, fulminant antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia, paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease, and combinations thereof.

[0220] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is selected from the group consisting of aHUS, HSCT-TMA, IgAN, lupus nephritis (LN), and combinations thereof.

[0221] In some embodiments, the method includes administering to a patient suffering from or at risk of developing a disease, disorder, or condition associated with fibrin-induced activation of the complement system and associated activation of the coagulation and / or contact systems an amount of a compound according to any one of the above-described embodiments (e.g., a compound of structure (I)) in an amount sufficient to inhibit MASP-2-dependent complement activation in the mammalian subject, thereby treating the disease or disorder. In some embodiments, the subject is suffering from or at risk of developing a disease, disorder, or condition associated with complement-associated inflammation, excessive coagulation, or activation of the contact system initiated by fibrin or activated platelets. In some embodiments, the subject suffers from a disease or disorder selected from the group consisting of arterial thrombosis, venous thrombosis, deep vein thrombosis, postoperative thrombosis, restenosis after coronary artery bypass surgery and / or interventional cardiovascular procedures (e.g., angioplasty or stent placement), atherosclerosis, plaque rupture, plaque instability, restenosis, hypotension, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation (DIC), venous occlusive disease (VOD), thrombotic microangiopathy, lupus nephritis, superficial thrombophlebitis, factor V Leiden mutation, ischemic / reperfusion injury, human immunodeficiency virus (HIV) infection, receiving hormone replacement therapy (HRT), Alzheimer's disease, and / or suffers from a hypercoagulable state.

[0222] In some embodiments, the subject suffers from or is at risk of developing an acquired hypercoagulable state due to at least one or more of the following: receiving treatment with an agent selected from the group consisting of 5-FU, GM-CSF, cisplatin, heparin, COX-2 inhibitors, contrast agents, corticosteroids, and antipsychotics; venous congestion (restriction, surgery, etc.), antiphospholipid syndrome, cancer (promyelocytic leukemia, tumors of the lung, breast, prostate, pancreas, stomach, and colon), tissue damage from trauma or surgery, the presence of a catheter in a central vein, an acquired deficiency of a protein involved in blood clot formation (e.g., protein C), paroxysmal nocturnal hemoglobinuria (PNH), elevated homocysteine ​​levels, Heart failure, presence of a mechanical valve, pulmonary hypertension with in situ thrombosis, atrial fibrillation, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), Kawasaki disease with in situ thrombosis, Takayasu's arteritis with in situ thrombosis, thrombophilia in metastatic cancer, elevated factor VIII levels, pregnancy, inflammatory bowel disease (IBD), or a genetic abnormality that causes or increases the risk of developing a hypercoagulable state, such as a genetic abnormality selected from the group consisting of prothrombin 20210 gene mutation, MTHFR mutation, protein C deficiency, protein S deficiency, protein A deficiency, protein Z deficiency, antithrombin deficiency, and a genetic disorder that results in a thrombophilia.

[0223] In some embodiments, the subject suffers from or is at risk of developing a disease or disorder suitable for treatment with a kallikrein inhibitor. In some embodiments, the subject suffers from or is at risk of developing a disease or disorder suitable for treatment with a kallikrein inhibitor selected from the group consisting of hereditary angioedema, diabetic macular edema, and bleeding during cardiopulmonary bypass. In some embodiments, the subject suffers from or is at risk of developing a disease or disorder suitable for treatment with a thrombin inhibitor, such as arterial thrombosis, venous thrombosis, pulmonary embolism, atrial fibrillation, heparin-induced thrombocytopenia, conversion from one anticoagulant to another, or off-label use of continuous renal replacement therapy (CRRT) for extracorporeal circuit patency (maintenance) in severely ill patients with HIT.

[0224] In some embodiments, the subject has previously experienced, is currently suffering from, or is at risk of developing atrial fibrillation, and the MASP-2 inhibitor compound (e.g., a compound of structure (I)) is administered in an amount sufficient to reduce the risk of stroke in the subject. In some embodiments, the subject is suffering from or is at risk of developing a disease or disorder suitable for treatment with a factor XII inhibitor, such as deep vein thrombosis (both primary prevention and long-term treatment), pulmonary embolism, non-valvular atrial fibrillation, prevention of recurrent ischemia after acute coronary syndrome in subjects with or without atrial fibrillation, end-stage renal disease, cerebral ischemia, angina pectoris, or reducing or preventing clotting associated with medical devices (e.g., valves, small-caliber grafts, etc.) and / or extracorporeal circuits.

[0225] In some embodiments, the subject has previously experienced, is currently suffering from, or is at risk of developing non-valvular atrial fibrillation, and the MASP-2 inhibitory compound (e.g., a compound of structure (I)) is administered in an amount sufficient to reduce the risk of stroke and / or embolism in the subject. In some embodiments, the subject has an acquired disease or disorder that increases the propensity for thromboembolism, such as atherosclerosis, antiphospholipid antibodies, cancer (e.g., promyelocytic leukemia, lung, breast, prostate, pancreas, stomach, and colon), hyperhomocysteinemia, infection, tissue injury, venous congestion (such as due to surgery, orthopedic or paralytic restraints, heart failure, pregnancy, or obesity), and the subject taking estrogen-containing oral contraceptives.

[0226] In some embodiments, the subject requires anticoagulant therapy, and the MASP-2 inhibitory compound (e.g., a compound of structure (I)) is used as a substitute for standard anticoagulant therapy (e.g., warfarin). In some embodiments, the subject has a condition for which standard anticoagulant therapy is normally contraindicated, such as CNS amyloid angiopathy. In some embodiments of the method, the MASP-2 inhibitory compound is administered as a bridging agent perioperatively to subjects receiving standard anticoagulant therapy. In some embodiments, the subject has sickle cell disease, a vaso-occlusive disorder involving platelet activation.

[0227] Atypical hemolytic uremic syndrome (aHUS) is part of a spectrum of conditions referred to as "thrombotic microangiopathy." In atypical forms of HUS (aHUS), the disease is associated with dysregulation of complement and can be either sporadic or familial. Familial cases of aHUS are associated with mutations in genes encoding complement activation or complement regulatory proteins, including complement factors H, I, and B, the CD46 membrane cofactor, and complement factor H-related protein 1 (CFHR1) and 3 (CFHR3) (Zipfel, PF, et al., PloS Genetics 3(3):e41 (2007)). A unifying feature of this diverse set of genetic mutations associated with aHUS is a predisposition to enhanced complement activation on cell or tissue surfaces. A subject is at risk for developing aHUS upon the occurrence of at least one or more symptoms indicative of aHUS (e.g., the presence of anemia, thrombocytopenia, and / or renal failure) and / or the presence of thrombotic microangiopathy in a biopsy obtained from the subject. Determining whether a subject is at risk for developing aHUS includes: Determining whether a subject has a genetic predisposition to developing aHUS, which may be performed by evaluating genetic information (e.g., from a database containing the subject's genotype) or by performing at least one genetic screening test on the subject to determine the presence or absence of a genetic marker associated with aHUS (i.e., determining the presence or absence of a genetic mutation associated with aHUS in a gene encoding complement factor H (CFH), factor I (CFI), factor B (CFB), membrane complement factors CD46, C3, complement factor H-related protein 1 (CFHR1), or THBD (which encodes the anticoagulant protein thrombomodulin) or complement factor H-related protein 3 (CFHR3), or complement factor H-related protein 4 (CFHR4)), either via genomic sequencing or gene-specific analysis (e.g., PCR analysis); and / or To determine whether a subject has a family history of aHUS Methods for genetic screening for mutations in genes associated with aHUS are well established, see, e.g., Norris M et al. "Atypical Hemolytic-Uremic Syndrome," 2007 Nov 16 [Updated 2011 Mar 10]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™, Seattle (WA): University of Washington, Seattle.

[0228] Hematopoietic stem cell transplant-associated TMA (HSCT-TMA) is a life-threatening complication caused by endothelial injury. While the kidney is the most commonly affected organ, HSCT-TMA can be a multisystem disease involving the lungs, intestine, heart, and brain. Even mild cases of TMA are associated with long-term renal dysfunction. The incidence of allogeneic HSCT-associated TMA varies based on various diagnostic criteria and conditions, as well as on graft-versus-host disease prophylaxis regimens, with calcineurin inhibitors being the most frequently implicated medications (Ho VT et al., Biol Blood Marrow Transplant, 11(8):571-5, 2005).

[0229] Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease that results in intrarenal inflammation and kidney damage. IgAN is the most common primary glomerular disease worldwide. In the United States, the annual incidence is approximately 2.5 per 100,000, with an estimated 1 in 1,400 people developing IgAN. As many as 40% of IgAN patients will develop end-stage renal disease (ESRD). Patients typically present with microscopic hematuria with mild to moderate proteinuria and varying degrees of renal failure (Wyatt RJ, et al., NEnglJ Med 36S(25):2402-4, 2013). Clinical markers such as renal dysfunction, persistent hypertension, and severe proteinuria (>1 g / day) are associated with poor prognosis (Goto M et al., Nephrol Dial Transplant 24(10):3068-74, 2009; Berthoux F. et al., J Am Soc Nephrol 22(4):752-61, 2011). Proteinuria is the strongest prognostic factor independent of other risk factors in several large observational and prospective studies (Coppo R. et al., J Nephrol 18(5):503-12, 2005; Reich HN, et al., J Am Soc Nephrol 18(12):3177-83, 2007). If left untreated, it is estimated that 15-20% of patients will develop ESRD within 10 years of disease onset (D'Amico G., Am J Kidney Dis 36(2):227-37, 2000). The diagnostic hallmark of IgAN is the predominance of IgA deposits in the mesangial glomeruli, either alone or in combination with IgG, IgM, or both.

[0230] A major complication of systemic lupus erythematosus (SLE) is nephritis, also known as lupus nephritis, which is classified as a secondary form of glomerulonephritis. Up to 60% of adults with SLE have some form of kidney involvement late in the disease course (Koda-Kimble et al., Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs, 10th Ed., Lippincott Williams & Wilkins: pages 792-9, 2012), with a prevalence of 20-70 per 100,000 people in the United States. Lupus nephritis often occurs in patients with other symptoms of active SLE, including fatigue, fever, rash, arthritis, serositis, or central nervous system disease (Pisetsky DS et al., Med Clin North Am 81(1):113-28, 1997). Some patients have asymptomatic lupus nephritis; however, laboratory abnormalities such as elevated serum creatinine levels, decreased albumin levels, or urinary protein or sediment at regular follow-up appointments suggest active lupus nephritis.

[0231] V. Composition, dosage, dosage The compounds described herein (e.g., compounds of structure (I)) can be administered in a manner compatible with the dosage formulation, and in an amount effective or suitable for treatment. The amount administered will vary depending on various factors, including, for example, the individual's age, weight, physical activity, and diet, as well as the desired effect. In certain embodiments, the size of the dose will also be determined by the existence, nature, and extent of any adverse side effects associated with the administration of the compound in a particular individual.

[0232] However, it will be understood that the specific dose level and frequency of administration for any particular patient may vary from physician to physician and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, age, body weight, genetic characteristics, general health, sex, diet, mode and timing of administration, excretion rate, drug combination, severity of the particular condition, and the host being treated.

[0233] In certain embodiments, the dose may be in solid, semi-solid, or liquid form, preferably in unit dosage form suitable for easy administration of precise doses.

[0234] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a single dosage for humans and other mammals, each unit containing a predetermined quantity of active agent calculated to provide a desired onset, tolerability, and / or effective effect, in association with a suitable pharmaceutical excipient (e.g., an ampoule). Additionally, more concentrated dosage forms may be prepared, which may result in more dilute unit dosage forms.

[0235] The compounds described herein (e.g., compounds of structure (I)) can be administered to a subject in need of treatment by methods known in the art, such as oral administration or injection. Injection can be, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular. As described herein, parenteral preparations can be prepared in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a single dosage form for each subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect.

[0236] The pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of structure (I)) formulated with one or more pharmaceutically acceptable carriers or excipients. As used herein, the term "pharmaceutically acceptable carrier" means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Pharmaceutical compositions for this use can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), bucally, or as an oral or nasal spray.

[0237] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfumes.

[0238] Injectable preparations include sterile injectable aqueous or oleaginous suspensions formulated according to known techniques, for example, using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, USP Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild, fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0239] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the drug will depend on its dissolution rate, which in turn will depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0240] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar or high molecular weight polyethylene glycols and the like.

[0241] The active compound can also be in microencapsulated form, containing one or more of the above-mentioned excipients.Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation field.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms can also contain, as is customary, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents.

[0242] Dosage forms for topical or transdermal administration of the compounds disclosed in the foregoing embodiments (e.g., compounds of structure (I)) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. For example, the active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and any needed preservatives or buffers, as may be required.

[0243] Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0244] According to the disclosed methods of treatment, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound according to any one of the foregoing embodiments, in an amount and for a time necessary to achieve the desired result. As is well understood in the medical field, a therapeutically effective amount of a compound will be present at a reasonable benefit / risk ratio applicable to any medical treatment.

[0245] In general, the compound (e.g., a compound of structure (I)) is administered in a therapeutically effective amount, either alone or in combination with one or more other therapeutic agents, through any of the usual and acceptable methods known in the art. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.

[0246] Generally, satisfactory results are around 0.03 to 2.5 mg It has been shown that a daily dose per kg of body weight can be obtained systemically. Suggested daily doses for larger mammals, such as humans, range from about 0.5 mg to about 250 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 10 mg to about 75 mg, or about 10 mg to about 50 mg, e.g., 10, 20, 30, 40, or about 50 mg, conveniently administered, for example, in divided doses or delayed form up to four times daily. Suitable unit dosage forms for oral administration contain about 1 to 60 mg of active ingredient.

[0247] In certain embodiments, a therapeutic amount or dose of a compound (e.g., a compound of structure (I)) is about 0.1 mg / kg ~about 500 mg / kg , or about 1 mg / kg ~about 50 mg / kg In general, treatment regimens according to the present application involve administration of about 10 mg to about 1000 mg of compound per day in single or multiple doses to a patient in need of such treatment. The therapeutic amount or dose will also vary depending on the route of administration and possible co-administration with other drugs.

[0248] Once the subject's condition has improved, a maintenance dose of the compound, composition, or combination of the present application may be administered as needed. Thereafter, depending on the symptoms, the dosage or frequency of administration, or both, may be reduced to a level at which the improved condition is maintained, and treatment should be terminated when the symptoms have been alleviated to a desired level. However, upon recurrence of disease symptoms, the subject may require intermittent treatment on a long-term basis.

[0249] However, it will be understood that the total daily usage of the compound (e.g., compound of structure (I)) and compositions thereof will be determined by the attending physician within the scope of sound medical judgment. The specific inhibitory amount for any particular patient will vary depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination or simultaneously with the specific compound employed; and similar factors well known in the medical field.

[0250] This application is a) a first agent that is a compound of the present application disclosed herein in free form or in pharmaceutically acceptable salt form; and b) at least one auxiliary agent; Also provided is a pharmaceutical combination, e.g., a kit, comprising: The kit may include instructions for its administration.

[0251] Methods for preparing such dosage forms are known to those skilled in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)). Dosage forms typically contain a conventional pharmaceutical carrier or excipient and may further contain other medicinal agents, carriers, adjuvants, diluents, tissue penetration enhancers, solubilizers, etc. Appropriate excipients can be tailored for particular dosage forms and administration routes by methods well known in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)).

[0252] The following abbreviations may be used herein and have the meanings indicated unless otherwise specified: ACN (acetonitrile); chrom. (chromatography); CHCl (dichloromethane); DIAD (diisopropyl azodicarboxylate); m- (meta); Ms (methanesulfonyl); NCS (N-chlorosuccinimide); NIS (N-iodosuccinimide); NMR (nuclear magnetic resonance); obsd (observed values); Phth (phthalimide); TPP (triphenylphosphine); and Tr (trityl). Other abbreviations may be used and have meanings that will be understood by those skilled in the art. [Example]

[0253] The following examples are offered by way of illustration only, and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially similar results.

[0254] General method Unless otherwise stated, chromatography refers to flash chromatography performed on silica gel.

[0255] HPLC purification was performed by one of two methods: Method 1: UV / ELS detector (254 nm and 280 nm) and ThermoFisher Hypersil GOLD Agilent (21.2 x 250 mm) 5 μm C 18 The eluent was a mixture of water and acetonitrile (containing 0.05% trifluoroacetic acid). The flow rate was typically a linear gradient of 2-90% water in acetonitrile, 20 min. mL / 分 The injection volume was 1–3 mL with a maximum of 20 mg per injection. Method 2: UV / MS detector (254 nm and 280 nm) and XBridge Prep (19 x 50 mm) C 18 The eluent was a mixture of water and acetonitrile (containing 0.05% trifluoroacetic acid). The flow rate was typically a linear gradient of 5-95% water in acetonitrile, 50% in 8 min. mL / 分 The injection volume was 0.2 to 1 mL with a maximum of 20 mg per injection.

[0256] abbreviation μ Micro ℃ Celsius Ac Acetyl anhyd aq water-based ATM atmosphere Bn Benzyl Boc tert-butoxycarbonyl Bu butyl calcd calculated value Cbz benzyloxycarbonyl CPME Cyclopentyl methyl ether concd concentration conc concentration DCC N,N'-dicyclohexylcarbodiimide DIEA N,N-Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF Dimethylformamide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride equiv equivalent ES Electrospray Et Ethyl Et2O diethyl ether g grams h time HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HPLC High Performance Liquid Chromatography / High Performance Liquid Chromatography HOBt 1-Hydroxybenzotriazole Hydrate iPrOH isopropanol L liters LiOH Lithium hydroxide m millimeter M molar concentration MeCN acetonitrile min mL milliliter mol mole; molecule (as in mol wt) MS mass spectrometry MW molecular weight NBS N-Bromosuccinimide NHS N-hydroxysuccinimide NMM 4-methylmorpholine NMR nuclear magnetic resonance o Ortho obsd measurements p Para Ph Phenyl ppt precipitate Pr Propyl psi pounds per square inch temp temperature TFA trifluoroacetic acid THF tetrahydrofuran

[0257] Example 1 Preparation of (2R,4R)-N-((S)-1-(((4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-1) TIFF2025131710000100.tif30128 Project 1 To a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (1.0 g, 3.43 mmol) in acetonitrile (70 mL, 0.05 M) was added HOBt (577 mg, 3.77 mmol), DIEA (2.39 mL, 13.7 mmol), and EDC (585 mg, 3.77 mmol). After stirring at room temperature for 30 minutes, benzyl L-alanine hydrochloride (814 mg, 3.77 mmol) was added and stirred for 16 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and 10% KHSO solution. The organic layer was separated and washed with H2O and saturated aqueous NaHCO3. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product tert-butyl (2R,4R)-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (1.33 g, 86% yield), which was used in the next step without further purification.

[0258] TIFF2025131710000101.tif30131 Project 2 A solution of the crude product, tert-butyl (2R,4R)-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (1.55 g, 3.42 mmol) in MeOH (50 mL, 0.07 M) was degassed with a stream of argon for 2 minutes. 10% Pd / C (70 mg) was added and vacuum was pulled for 1 minute. A H2 balloon was added and the reaction was monitored for consumption of starting material for 1.5 hours. The catalyst was filtered off and the solution was evaporated to give ((2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (1.24 g, 100% yield).

[0259] TIFF2025131710000102.tif19128 Project 3 To a solution of methyl 4-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1 g, 3.9 mmol) in THF (20 mL, 0.2 M) at 0 °C was added lithium aluminum hydride (1.0 M in THF, 6.3 mL, 6.3 mmol). After stirring at the same temperature for 1 h, the reaction was quenched by the addition of HO and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0–100% ethyl acetate–hexane) to give (4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (412 mg, 46% yield).

[0260] TIFF2025131710000103.tif19128 Project 4 To a solution of (4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (206 mg, 0.91 mmol) in CHCl (1.5 mL, 0.6 M) was added HCl (4.0 M in dioxane, 2.2 mL). After stirring at room temperature for 15 minutes, the reaction mixture was evaporated to dryness. To this residue at 0 °C was added thionyl chloride (1 mL). The mixture was heated to 80 °C and stirred for 2 minutes, at which point the residue became a white solid, indicating completion. The residue was concentrated under reduced pressure to give the crude product, 4-bromo-2-(chloromethyl)-1H-pyrrolo[2,3-c]pyridine (256 mg, 100% yield), which was used in the next step without further purification.

[0261] TIFF2025131710000104.tif21128 Project 5 Di-tert-butyl iminodicarboxylate (295 mg, 1.36 mmol) was dissolved in DMF (5 mL, 0.27 M) and sodium hydride (50 mg, 2.0 mmol) was added portionwise. The reaction mixture was stirred for 30 minutes, at which point a DMF solution of 4-bromo-2-(chloromethyl)-1H-pyrrolo[2,3-c]pyridine (256 mg, 0.91 mol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, at which point another 0.5 equivalents of sodium hydride was added. After stirring at the same temperature for 16 hours, the reaction was quenched by the addition of HO and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was dissolved in CHCl (5 mL) and HCl (4.0 M in dioxane, 10 mL) was added. After stirring at room temperature for 22 hours, the reaction mixture was concentrated to give the crude product (4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methanamine hydrochloride (233 mg, 100% yield), which was used in the next step without further purification.

[0262] TIFF2025131710000105.tif34129 Project 6 To a solution of (4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methanamine hydrochloride (233 mg, 0.78 mmol) in DMF (10 mL, 0.08 mmol) was added ((2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (217 mg, 0.6 mmol). The resulting mixture was cooled to 0 °C. To the above mixture were added HBTU (296 mg, 0.78 mmol) and DIEA (0.42 mL, 2.4 mmol). After stirring at the same temperature for 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for 90 minutes and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate-CHCl and washed with 10% KHSO, H2O, saturated aqueous NaHCO, and brine. The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by chromatography (0–100% [5% 7N NH in MeOH / CH2Cl2]—CH2Cl2) to give tert-butyl (2R,4R)-2-(((S)-1-(((4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (22 mg, 5% yield).

[0263] TIFF2025131710000106.tif33147 Project 7 To a solution of tert-butyl (2R,4R)-2-(((S)-1-((4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (22 mg, 0.04 mmol) in CHCl (0.5 mL, 0.08 M) at 0 °C was added 20% TFA in CHCl (0.5 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated. The crude material was purified using reverse-phase HPLC to give (2R,4R)—N-((S)-1-(((4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (1.5 mg, 25% yield).

[0264] Example 2 Preparation of (2R,4R)-N-((S)-1-(((1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-3) TIFF2025131710000107.tif34148 Project 1 A solution of (2R,4R)—N-((S)-1-(((4-bromo-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide trifluoroacetate (2 mg, 0.004 mmol, prepared according to steps 1-7 of the procedure for compound I-1) was degassed with a stream of argon for 2 minutes. 10% Pd / C (1.2 mg) was added and vacuum was pulled for 1 minute. A H2 balloon was added and the reaction was monitored for consumption of starting material for 4 hours. The catalyst was filtered off and the solution was evaporated to give (2R,4R)—N-((S)-1-(((1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (2.0 mg, 100% yield).

[0265] Example 3 Preparation of (2R,4S)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-2) TIFF2025131710000108.tif29128 Project 1 To a solution of 2-benzyl 1-(tert-butyl)(R)-5-oxopyrrolidine-1,2-dicarboxylate (600 mg, 1.88 mmol) in THF (12.5 mL) at −78 °C under Ar, lithium bis(trimethylsilyl)amide (1.0 M THF solution, 2.06 mL, 2.06 mmol) was slowly added. After stirring at the same temperature for 1 h, a solution of 4-(bromomethyl)-2-chloro-1-fluorobenzene (505 mg, 2.26 mmol) in 1 mL of THF was added, and stirring was continued for an additional 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH₄Cl and extracted with diethyl ether. The combined extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (ethyl acetate-hexane) to give 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-chloro-4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (450 mg, yield 62%).

[0266] TIFF2025131710000109.tif29128 Project 2 To a solution of 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-chloro-4-fluorobenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (450 mg, 0.97 mmol) in THF (5 mL, 0.2 M) at −78 °C under Ar, lithium triethylborohydride solution (1.0 M in THF, 1.07 mL, 1.07 mmol) was added. After stirring at the same temperature for 30 min, the reaction mixture was quenched with saturated aqueous NaHCO (3 mL) and warmed to 0 °C. 30% H O (approximately 10 drops) was added, and the reaction mixture was stirred at the same temperature for 30 min. The organic volatiles were removed under reduced pressure, and the aqueous layer was extracted with CHCl. The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated to give 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-chloro-4-fluorobenzyl)-5-hydroxypyrrolidine-1,2-dicarboxylate (350 mg), which was used in the next step without further purification.

[0267] TIFF2025131710000110.tif29128 Project 3 To a solution of 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-chloro-4-fluorobenzyl)-5-hydroxypyrrolidine-1,2-dicarboxylate (350 mg, 0.75 mmol) in CHCl (5 mL, 0.15 M) at −78 °C under Ar, triethylsilane (0.25 mL, 1.56 mmol) and boron trifluoride diethyl etherate (0.19 mL, 1.56 mmol) were added. After stirring at the same temperature for 30 min, additional triethylsilane (0.25 mL, 1.56 mmol) and boron trifluoride diethyl etherate (0.19 mL, 1.56 mmol) were added. After stirring at the same temperature for 2 h, the reaction mixture was quenched by the addition of saturated aqueous NaHCO (5 mL) and extracted with CHCl. ​​The combined extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (ethyl acetate-hexane) to give 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-1,2-dicarboxylate (220 mg, 51% yield over two steps).

[0268] TIFF2025131710000111.tif29128 Project 4 To a solution of 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-1,2-dicarboxylate (220 mg, 0.49 mmol) in THF (12 mL), MeOH (6 mL), and water (6 mL) was added lithium hydroxide (176 mg, 7.4 mmol). After stirring at room temperature for 4 hours, 6 mL of 1N HCl was added to the reaction mixture, and the organic volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxylic acid (158 mg, 90% yield), which was used in the next step without further purification.

[0269] TIFF2025131710000112.tif21128 Project 5 tert-Butyl (S)-(1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (683 mg, 63% yield) was synthesized from (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (500 mg, 3.4 mmol) and (tert-butoxycarbonyl)-L-alanine (495 mg, 2.6 mmol) according to step 6 of the procedure for compound I-1.

[0270] TIFF2025131710000113.tif28128 Project 6 Deprotection of tert-butyl (S)-(1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (683 mg, 2.15 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0271] TIFF2025131710000114.tif31148 Project 7 tert-Butyl (2R,4S)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-1-carboxylate (27 mg, 69% yield) was synthesized from tert-butyl (S)-(1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate ditrifluoroacetate (37 mg, 0.08 mmol) and (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxylic acid (25 mg, 0.07 mmol) according to step 6 of the procedure for compound I-1.

[0272] TIFF2025131710000115.tif29151 Project 8 Deprotection of tert-butyl (2R,4S)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-1-carboxylate (27 mg, 0.05 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0273] Example 4 Preparation of (2R,4R)-N-((S)-1-(((4-chlorobenzo[d]thiazol-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide trifluoroacetate (compound I-4) TIFF2025131710000116.tif17128 Project 1 A solution of 4-chlorobenzo[d]thiazole-2-carbonitrile (70 mg, 0.36 mmol) in MeOH (1.5 mL) and 7 mL of 7N NH3MeOH solution was degassed twice with a stream of argon. Raney nickel (100 mg) was added and vacuum was pulled for 1 minute. A H2 balloon was added and the reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was degassed twice with a stream of argon. The catalyst was removed by filtration through diatomaceous earth and the solution was concentrated. The residue was taken up in 5% HO in MeOH, filtered (0.2 μm syringe filter), and the filtrate was concentrated under reduced pressure to give 3-(aminomethyl)-5-chloropyridin-2-amine (55 mg, 77% yield).

[0274] TIFF2025131710000117.tif39128 Project 2 tert-Butyl (2R,4R)-2-(((S)-1-(((4-chlorobenzo[d]thiazol-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (34 mg, 29%) was synthesized from 3-(aminomethyl)-5-chloropyridin-2-amine (55 mg, 0.28 mmol) and ((2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (77 mg, 0.21 mmol, prepared according to step 2 of the procedure for compound I-1) according to step 6 of the procedure for compound I-1.

[0275] TIFF2025131710000118.tif40149 Project 3 Deprotection of tert-butyl (2R,4R)-2-(((S)-1-(((4-chlorobenzo[d]thiazol-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (34 mg, 0.06 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0276] Example 5 Preparation of (2R,4S)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chlorobenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-5) (2R,4S)—N—((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chlorobenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-2.

[0277] Example 6 Preparation of (2R,4R)-N-((S)-1-(((1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-6) (2R,4R)—N-((S)-1-(((1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-1, starting from commercially available (1H-pyrrolo[3,2-b]pyridin-2-yl)methanamine.

[0278] Example 7 Preparation of (2R,4R)-N-((S)-1-(((3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-7) TIFF2025131710000119.tif19128 Project 1 To a solution of (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (200 mg, 1.36 mmol) in acetonitrile (15 mL, 0.09 M) was added EtN (0.57 mL, 4.08 mmol), BocO (593 mg, 2.72 mmol), and DMAP (166 mg, 1.36 mmol). After stirring at room temperature for 16 h, the reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and HO. The organic layer was separated, washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0–100% ethyl acetate–hexane) to give tert-butyl ((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (69 mg, 21% yield).

[0279] TIFF2025131710000120.tif19128 Project 2 To a solution of tert-butyl ((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (69 mg, 0.28 mmol) in acetonitrile (4 mL) and acetic acid (0.4 mL) was added Selectfluor™ (148 mg, 0.42 mmol). After stirring at 50 °C under N for 1 h, the reaction was quenched by the addition of HO and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0–100% ethyl acetate–hexane) to give tert-butyl ((3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (14 mg, 19% yield).

[0280] TIFF2025131710000121.tif23128 Project 3 Deprotection of tert-butyl ((3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (14 mg, 0.05 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0281] TIFF2025131710000122.tif34128 Project 4 tert-Butyl (2R,4R)-2-(((S)-1-(((3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate was synthesized from (3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine ditrifluoroacetate (26 mg, 0.07 mmol) and ((2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (19 mg, 0.05 mmol, prepared according to steps 1-2 of the procedure for compound I-1) according to step 6 of the procedure for compound I-1.

[0282] TIFF2025131710000123.tif34144 Project 5 Deprotection of tert-butyl ((3-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamate (14 mg, 0.05 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0283] Example 8 Preparation of (2R,4S)-4-benzyl-N-((S)-1-((isoindolin-5-ylmethyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-9) TIFF2025131710000124.tif27130 Project 1 To a solution of (2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (500 mg, 1.64 mmol, prepared according to steps 1–4 of the procedure for compound I-2) in acetonitrile (10 mL, 0.16 M) was added HOBt (326 mg, 2.13 mmol), DIEA (1.14 mL, 6.55 mmol), and EDC (391 mg, 2.05 mmol). After stirring at room temperature for 30 minutes, benzyl L-alanine hydrochloride (423 mg, 1.97 mmol) was added and stirred for 16 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and 10% KHSO solution. The organic layer was separated and washed with HO and saturated aqueous NaHCO solution. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0–100% ethyl acetate–hexane) to give tert-butyl (2R,4S)-4-benzyl-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (272 mg, 36% yield).

[0284] TIFF2025131710000125.tif27139 Project 2 A solution of the crude product, tert-butyl (2R,4S)-4-benzyl-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (272 mg, 0.58 mmol), was degassed with a stream of argon for 2 minutes. 10% Pd / C (13 mg) was added and vacuum was pulled for 1 minute. A H2 balloon was added and the reaction was monitored for consumption of starting material for 1.5 hours. The catalyst was filtered off and the solution was evaporated to give ((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)-L-alanine (227 mg, 100% yield).

[0285] TIFF2025131710000126.tif27146 Project 3 tert-Butyl 5-(((S)-2-((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)propanamido)methyl)isoindoline-2-carboxylate (42 mg, 58% yield) was synthesized from tert-butyl 5-(aminomethyl)isoindoline-2-carboxylate (39 mg, 0.16 mmol) according to step 6 of the procedure for compound I-1.

[0286] TIFF2025131710000127.tif26147 Project 4 Deprotection of tert-butyl 5-(((S)-2-((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)propanamido)methyl)isoindoline-2-carboxylate ditrifluoroacetate (45 mg, 0.12 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0287] Example 9 Preparation of (2R,4S)-4-benzyl-N-((S)-1-(((4-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-10) (2R,4S)-4-benzyl-N-((S)-1-(((4-fluoro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide bistrifluoroacetate was synthesized by following the procedure for compound I-7 and steps 1-2 of the procedure for compound I-9.

[0288] Example 10 Preparation of (2R,4S)-4-benzyl-N-((S)-1-(((3-chlorothieno[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate (compound I-11) TIFF2025131710000128.tif17128 Project 1 To a solution of thieno[2,3-b]pyridine-5-carbonitrile (500 mg, 3.12 mmol) in acetic acid (10 mL, 0.006 M) was added N-chlorosuccinimide (417 mg, 3.12 mmol). After stirring at reflux for 20 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with HO, saturated aqueous NaHCO, and brine. The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by chromatography (50–100% ethyl acetate–hexane) to give 3-chlorothieno[2,3-b]pyridine-5-carbonitrile (152 mg, 25% yield).

[0289] TIFF2025131710000129.tif17128 Project 2 To a solution of 3-chlorothieno[2,3-b]pyridine-5-carbonitrile (40 mg, 0.21 mmol) in MeOH (5 mL, 0.04 M) at 0 °C was added NiCl (50 mg, 0.21 mmol) and di-tert-butyl dicarbonate (90 mg, 0.41 mmol). To the above mixture was added NaBH (100 mg, 2.87 mmol) in several portions, and the reaction mixture was stirred at room temperature for 5 days. Upon completion, the reaction mixture was concentrated, and the residue was dissolved in CHCl. ​​The mixture was washed with H2O, saturated aqueous NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (50–100% ethyl acetate–hexane) to give tert-butyl ((3-chlorothieno[2,3-b]pyridin-5-yl)methyl)carbamate (11 mg, 17% yield).

[0290] TIFF2025131710000130.tif21128 Project 3 Deprotection of tert-butyl ((3-chlorothieno[2,3-b]pyridin-5-yl)methyl)carbamate (11 mg, 0.04 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0291] TIFF2025131710000131.tif29131 Project 4 tert-Butyl (2R,4S)-4-benzyl-2-(((S)-1-(((3-chlorothieno[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (17 mg, 80%) was synthesized from (3-chlorothieno[2,3-b]pyridin-5-yl)methanamine trifluoroacetate (12 mg, 0.04 mmol) and ((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)-L-alanine (11 mg, 0.03 mmol) according to step 6 of the procedure for compound I-1.

[0292] TIFF2025131710000132.tif27149 Project 5 Deprotection of tert-butyl (2R,4S)-4-benzyl-2-(((S)-1-(((3-chlorothieno[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (17 mg, 0.03 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0293] Example 11 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-4-((2R,4S)-4-benzylpyrrolidine-2-carbonyl)morpholine-3-carboxamide bistrifluoroacetate (Compound I-12) TIFF2025131710000133.tif29128 Project 1 Methyl (S)-4-((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)morpholine-3-carboxylate (68 mg, 58% yield) was synthesized from methyl (S)-morpholine-3-carboxylate according to step 1 of the procedure for compound I-9.

[0294] TIFF2025131710000134.tif29128 Project 2 To a solution of methyl (S)-4-((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)morpholine-3-carboxylate (68 mg, 0.16 mmol) in THF (1.5 mL) and HO (1.5 mL) was added lithium hydroxide (8 mg, 0.32 mmol). After stirring at room temperature for 4 hours, the reaction mixture was concentrated to remove THF. 10% KHSO solution was added to the above mixture, extracted with ethyl acetate, dried over anhydrous NaSO, and concentrated under reduced pressure to give crude (S)-4-((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)morpholine-3-carboxylic acid (66 mg, 100% yield), which was used in the next step without further purification.

[0295] TIFF2025131710000135.tif44128 Project 3 tert-Butyl (2R,4S)-2-((S)-3-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)morpholine-4-carbonyl)-4-benzylpyrrolidine-1-carboxylate (47 mg, 56% yield over two steps) was synthesized from 5-(aminomethyl)-6-methylpyridin-2-amine (28 mg, 0.2 mmol) and ((2R,4S)-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)-L-alanine (66 mg, 0.16 mmol) according to step 6 of the procedure for compound I-1.

[0296] TIFF2025131710000136.tif46128 Project 4 Deprotection of tert-butyl (2R,4S)-2-((S)-3-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)morpholine-4-carbonyl)-4-benzylpyrrolidine-1-carboxylate (47 mg, 0.09 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0297] Example 12 Preparation of (2R,4R)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(m-tolyl)pyrrolidine-2-carboxamide (compound I-13) TIFF2025131710000137.tif22128 Project 1 To a solution of 1-(tert-butyl) 2-methyl(R)-4-oxopyrrolidine-1,2-dicarboxylate (1.50 g, 6.16 mmol) in THF (15 mL, 0.4 mmol) at −78°C under Ar, lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.40 mL, 7.40 mmol) was slowly added. After stirring at the same temperature for 1 h, a solution of Comins' reagent (2.99 g, 7.40 mmol) in THF (5 mL) was added, and stirring was continued for an additional 1 h. After stirring at −20°C for 18 h, the reaction was quenched by the addition of 20 mL of water and extracted with diethyl ether. The combined extracts were washed with 2 N NaOH solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0–100% ethyl acetate–hexane) to give 1-(tert-butyl) 2-methyl(R)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.85 g, 80% yield).

[0298] TIFF2025131710000138.tif29128 Project 2 To a solution of 1-(tert-butyl) 2-methyl(R)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (400 mg, 1.06 mmol) in dioxane (7 mL, 0.15 mmol) were added Pd(PPh3)4 (123 mg, 0.11 mmol) and m-tolylboronic acid (215 mg, 1.17 mmol), followed by K2CO3 (442 mg, 3.20 mmol) as an aqueous solution in 1.5 mL of water. The mixture was heated to 80 °C and stirred for 30 minutes, at which point the solution turned from orange to deep black, indicating completion. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with HO, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0 to 100% ethyl acetate-hexane) to give 1-(tert-butyl) 2-methyl(R)-4-(m-tolyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (330 mg, 86% yield) as a colorless solid.

[0299] TIFF2025131710000139.tif29128 Project 3 To a solution of 1-(tert-butyl) 2-methyl (R)-4-(m-tolyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (317 mg, 1 mmol) in THF (24 mL), MeOH (12 mL), and water (12 mL) was added lithium hydroxide (360 mg, 15 mmol). After stirring at room temperature for 4 hours, 12 mL of 1N HCl was added to the reaction mixture, and the organic volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (R)-1-(tert-butoxycarbonyl)-4-(m-tolyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (288 mg crude product, 95% yield), which was used in the next step without further purification.

[0300] TIFF2025131710000140.tif29128 Project 4 To a solution of (R)-1-(tert-butoxycarbonyl)-4-(m-tolyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (134 mg, 0.44 mmol) in THF (6 mL) and MeOH (6 mL) was added EtN (0.06 mL, 0.44 mmol) and a solution of chlorotris(triphenylphosphine)rhodium (40 mg, 0.04 mmol) in anhydrous THF (15 mL), MeOH (15 mL), and EtN (0.13 mL, 0.95 mmol). The mixture was sparged with argon for 5 min, a H2 balloon was added, and the reaction was monitored for consumption of the starting material for 3 days. The volatiles were evaporated, and the residue was diluted with saturated aqueous NaHCO3, and the pH was adjusted to approximately 10 with 1 N NaOH. The mixture was washed with ethyl acetate, the organic layer was washed with saturated aqueous NaHCO3, and the combined aqueous layers were brought to pH 3-4 using 1 M HCl. The aqueous layer was then back-extracted with ethyl acetate, and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (2R,4R)-1-(tert-butoxycarbonyl)-4-(m-tolyl)pyrrolidine-2-carboxylic acid (80 mg, 60% yield).

[0301] TIFF2025131710000141.tif16128 Project 5 A mixture of 4-(aminomethyl)benzonitrile hydrochloride (20.1 g, 119.2 mmol) in acetonitrile (100 mL, 1.19 M) was placed under N2 and treated with DIEA (23 mL) and (Boc)2O (27.5 g, 126 mmol) at room temperature. The reaction was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed twice with 10% KHSO4. It was washed with brine, dried over Na2SO4, filtered under reduced pressure, and evaporated under reduced pressure to give tert-butyl (4-cyanophenyl)carbamate (27.2 g, 98% yield).

[0302] TIFF2025131710000142.tif17128 Project 6 A mixture of tert-butyl (4-cyanophenyl)carbamate (27.2 g, 117.0 mmol) and hydroxylamine hydrochloride (32.5 g, 468.0 mmol) in MeOH (300 mL, 0.39 M) was placed under N2 and treated with DIEA (82.0 mL, 471.0 mmol). The reaction was heated at 90 °C for 4 h. Volatiles were removed under reduced pressure. The crude product was mixed with water (200 mL). A white solid formed, which was collected by filtration, washed twice with water, and dried to give tert-butyl (Z)-(4-(N'-hydroxycarbamimidoyl)benzyl)carbamate (26 g, 84% yield).

[0303] TIFF2025131710000143.tif24128 Project 7 A solution of tert-butyl (Z)-(4-(N'-hydroxycarbamimidoyl)benzyl)carbamate (25.9 g, 97.6 mmol) and acetic anhydride (14.0 mL, 148.0 mmol) in acetic acid (220.0 mL, 0.44 M) was degassed with argon for 3 minutes. 10% Pd / C (1.45 g) was added. The mixture was evacuated and refilled with N2 five times, after which H2 was introduced from a balloon. The reaction was stirred overnight, filtered through a pad of Celite, and washed twice with MeOH (50.0 mL). The volatiles were evaporated under reduced pressure. The residue was mixed with ether (200 mL) and filtered. The white solid was collected, washed twice with ether (50 mL), and dried to give tert-butyl (4-carbamimidoylbenzyl)carbamate acetate (24.5 g, 81% yield).

[0304] TIFF2025131710000144.tif24131 Project 8 A mixture of tert-butyl (4-carbamimidoylbenzyl)carbamate acetate (24.5 g, 79.2 mmol) and saturated NaHCO3 / THF solution (220 mL) was treated with CbzCl (12.3 mL, 87.2 mmol) at room temperature. The reaction was stirred overnight and diluted with ethyl acetate. The organic layer was collected, washed with brine, dried over Na2SO4, filtered under reduced pressure, and evaporated under reduced pressure. The crude product was dissolved in CHCl2 and adsorbed onto silica gel. Purification by chromatography (0–100% ethyl acetate-DCM) gave tert-butyl (4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamate (18.1 g, 60% yield).

[0305] TIFF2025131710000145.tif14129 Project 9 A solution of tert-butyl (4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamate (4.6 g, 12.0 mmol) in MeOH (20 mL, 0.6 M) was placed under N2 and treated with HCl in MeOH (30 mL, approximately 10 M) at 0 °C. The reaction was stirred at room temperature overnight. Evaporation of volatiles under reduced pressure gave the crude product, benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride. The crude product was dissolved in CHCl2 and adsorbed onto silica gel. Purification by chromatography (0–10% 7N NH3 in MeOH-DCM) gave benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate (2.71 g, 80% yield).

[0306] TIFF2025131710000146.tif32143 Project 10 Benzyl (S)-((4-((2-((tert-butoxycarbonyl)amino)propanamido)methyl)phenyl)(imino)methyl)carbamate was synthesized by following step 3 of the procedure for compound I-17.

[0307] TIFF2025131710000147.tif20147 Project 11 Benzyl (S)-((4-((2-aminopropanamido)methyl)phenyl)(imino)methyl)carbamate was synthesized by following step 4 of the procedure for compound I-17.

[0308] TIFF2025131710000148.tif35148 Project 12 tert-Butyl (2R,4R)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(m-tolyl)pyrrolidine-1-carboxylate (69 mg, 41% yield) and its unknown diastereomer (35 mg, 21% yield) were synthesized from benzyl (S)-((4-((2-aminopropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride (133 mg, 0.34 mmol) and (2R,4R)-1-(tert-butoxycarbonyl)-4-(m-tolyl)pyrrolidine-2-carboxylic acid (80 mg, 0.26 mmol) according to step 6 of the procedure for compound I-1.

[0309] TIFF2025131710000149.tif36148 Project 13 Deprotection of tert-butyl (2R,4R)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(m-tolyl)pyrrolidine-1-carboxylate (69 mg, 0.11 mmol) was carried out according to step 7 of the procedure for compound I-1, except the crude material was purified by chromatography (0–100% [5% 7N NH in MeOH / CHCl]—CHCl) to give benzyl (imino(4-(((S)-2-((2R,4R)-4-(m-tolyl)pyrrolidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate.

[0310] TIFF2025131710000150.tif37148 Project 14 Deprotection of benzyl (imino(4-(((S)-2-((2R,4R)-4-(m-tolyl)pyrrolidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate (63 mg, 0.12 mmol) was carried out according to step 2 of the procedure for compound I-1.

[0311] Example 13 Preparation of N-(1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(m-tolyl)pyrrolidine-2-carboxamide (compound I-14) N-(1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(m-tolyl)pyrrolidine-2-carboxamide was synthesized according to the procedure for compound I-13 from the diastereomer of tert-butyl (2R,4R)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(m-tolyl)pyrrolidine-1-carboxylate (prepared in step 12 of the procedure for compound I-13).

[0312] Example 14 Preparation of (2R,4R)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-(1-phenylcyclopropyl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-8) TIFF2025131710000151.tif32128 Project 1 To a solution of 1-(tert-butyl) 2-methyl(R)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (400 mg, 1.06 mmol, prepared according to step 1 of the procedure for compound I-13) in toluene (20 mL) and water (2 mL) was added potassium trifluoro(1-phenylcyclopropyl)boranide (216 mg, 1 mmol), cataCXium® A Pd G (30 mg, 0.05 mmol), and CsCO (652 mg, 2 mmol). The resulting mixture was degassed by bubbling N through the solution for 10 minutes. After stirring at 95 °C for 2 hours, the reaction mixture was cooled to room temperature, the catalyst was removed by filtration through diatomaceous earth, and the solution was concentrated. The residue was purified by chromatography (0-100% ethyl acetate-hexane) to give 1-(tert-butyl) 2-methyl(R)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (250 mg, 73% yield) as a colorless solid.

[0313] TIFF2025131710000152.tif32128 Project 2 (R)-1-(tert-Butoxycarbonyl)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (240 mg, 99% yield) was synthesized from 1-(tert-butyl) 2-methyl (R)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (250 mg, 0.73 mmol) according to step 3 of the procedure for compound I-13.

[0314] TIFF2025131710000153.tif32128 Project 3 (2R,4R)-1-(tert-butoxycarbonyl)-4-(1-phenylcyclopropyl)pyrrolidine-2-carboxylic acid (150 mg, 62% yield) was synthesized from (R)-1-(tert-butoxycarbonyl)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (240 mg, 0.73 mmol) according to step 4 of the procedure for compound I-13.

[0315] TIFF2025131710000154.tif31144 Project 4 The crude material was purified by chromatography (0–100% [5% 7N in MeOH / CH2Cl2]). tert-Butyl (2R,4R)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(1-phenylcyclopropyl)pyrrolidine-1-carboxylate (39 mg, 61% yield) was synthesized from tert-butyl (S)-(1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate ditrifluoroacetate (67 mg, 0.14 mmol) and (2R,4R)-1-(tert-butoxycarbonyl)-4-(1-phenylcyclopropyl)pyrrolidine-2-carboxylic acid (40 mg, 0.12 mmol) according to step 1 of the procedure for compound I-1, except that the eluate was purified using [NH]—CHCl].

[0316] TIFF2025131710000155.tif31149 Project 5 Deprotection of tert-butyl (2R,4R)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(1-phenylcyclopropyl)pyrrolidine-1-carboxylate (39 mg, 0.07 mmol) was carried out according to step 7 of the procedure for compound I-1.

[0317] Example 15 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(3-carbamoylphenyl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-15) TIFF2025131710000156.tif29128 Project 1 A solution of crude (R)-1-(tert-butoxycarbonyl)-4-(3-cyanophenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (148 mg, 0.47 mmol, prepared according to steps 1–3 of the procedure for compound I-13) in MeOH (10 mL, 0.05 M) was degassed with a stream of Ar for 2 min. 10% Pd / C (10 mg) was added and vacuum was pulled for 1 min. A H2 balloon was added and the reaction was monitored for consumption of starting material for 16 h. The catalyst was filtered off, and the solution was evaporated to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-cyanophenyl)pyrrolidine-2-carboxylic acid (1.24 g, 100% yield).

[0318] TIFF2025131710000157.tif32128 Project 2 To a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-cyanophenyl)pyrrolidine-2-carboxylic acid (75 mg, 0.24 mmol) in methanol at 0 °C was added 30% HO (0.08 mL, 0.7 mmol) and 1 N NaOH (0.23 mL). After stirring at room temperature for 4 h, the reaction was quenched by the addition of saturated aqueous NaCO at 0 °C. The mixture was washed with ethyl acetate, the organic layer was washed with saturated aqueous NaHCO, and the combined aqueous layers were brought to pH 3–4 using 10% KHSO. The aqueous layers were then back-extracted with ethyl acetate and CHCl. ​​The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0–100% [5% 7N NH in MeOH / CH Cl]—CH Cl) to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-carbamoylphenyl)pyrrolidine-2-carboxylic acid (25 mg, 0.08 mmol).

[0319] TIFF2025131710000158.tif38148 Project 3 tert-Butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-carbamoylphenyl)pyrrolidine-1-carboxylate (38 mg, 78% yield) was synthesized from benzyl (S)-((4-((2-aminopropanamido)methyl)phenyl)(imino)methyl)carbamate (35 mg, 0.1 mmol, prepared according to steps 5 to 11 of the procedure for compound I-13) and (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-carbamoylphenyl)pyrrolidine-2-carboxylic acid (25 mg, 0.08 mmol) according to step 12 of the procedure for compound I-13.

[0320] TIFF2025131710000159.tif41148 Project 4 Deprotection of tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-carbamoylphenyl)pyrrolidine-1-carboxylate (38 mg, 0.06 mmol) was carried out according to step 13 of the procedure for compound I-13.

[0321] TIFF2025131710000160.tif36149 Project 5 Deprotection of tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-carbamoylphenyl)pyrrolidine-1-carboxylate (8 mg, 0.01 mmol) was carried out according to step 14 of the procedure for compound I-13, except the crude material was purified using reverse-phase HPLC.

[0322] Example 16 Preparation of (2R,4R)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(3-methoxyphenyl)pyrrolidine-2-carboxamide dihydrochloride (compound I-16) (2R,4R)—N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(3-methoxyphenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedure for compound I-13, except the final compound was converted to the hydrochloride salt.

[0323] Example 17 Preparation of (2R,4R)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4,5-dibromothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-17) TIFF2025131710000161.tif37128 Project 1 2-Benzyl 1-(tert-butyl)(2R,4R)-4-((4,5-dibromothiophen-2-yl)methyl)pyrrolidine-1,2-dicarboxylate ditrifluoroacetate was synthesized by following steps 1 to 3 of the procedure for compound I-2.

[0324] TIFF2025131710000162.tif29128 Project 2 To a solution of 2-benzyl 1-(tert-butyl)(2R,4R)-4-((4,5-dibromothiophen-2-yl)methyl)pyrrolidine-1,2-dicarboxylate (87.6 mg, 0.157 mmol) in THF (3.6 mL), MeOH (1.8 mL), and water (1.8 mL) was added lithium hydroxide (56.7 mg, 2.37 mmol). The reaction was stirred at room temperature for 16 hours, diluted with water, and washed with ethyl acetate. The aqueous layer was collected, acidified to pH ∼3 with 1 M KHSO solution, and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over NaSO, filtered under reduced pressure, and evaporated under reduced pressure to give the crude product (2R,4R)-1-(tert-butoxycarbonyl)-4-((4,5-dibromothiophen-2-yl)methyl)pyrrolidine-2-carboxylic acid.

[0325] TIFF2025131710000163.tif30130 Project 3 To a solution of (tert-butoxycarbonyl)-L-alanine (3.4 g, 18.0 mmol) in DCM (300 mL) was added NHS (2.3 g, 20.0 mmol) and DCC (4.0 g, 19.4 mmol). After purging with N2, the reaction was stirred at room temperature for 45 minutes, and tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (4.7 g, 19.8 mmol) was added. The reaction was stirred at room temperature for 16 hours and evaporated to dryness under reduced pressure. The crude product was dissolved in CHCl and adsorbed onto silica gel. Purification by chromatography (0–10% MeOH—CH 2 Cl 2 ) gave tert-butyl (S)-(1-(((6-((tert-butoxycarbonyl)amino)-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (6.4 g, 87%).

[0326] TIFF2025131710000164.tif19139 Project 4 To a solution of tert-butyl (S)-(1-(((6-((tert-butoxycarbonyl)amino)-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (6.4 g, 15.7 mmol) in MeOH (30 mL) was added a solution of HCl in MeOH (approximately 10 M) at 0 °C. The reaction was stirred at room temperature for 16 h and evaporated to dryness under reduced pressure. The crude product was dissolved in CHCl and adsorbed onto silica gel. Purification by chromatography (0–10% 7N NH in MeOH-CHCl) gave (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)propenamide (3.0 g, 92% yield).

[0327] TIFF2025131710000165.tif36147 Project 5 tert-Butyl (2R,4R)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-((4,5-dibromothiophen-2-yl)methyl)pyrrolidine-1-carboxylate was synthesized by following step 3 of the procedure for compound I-17.

[0328] TIFF2025131710000166.tif24147 Project 6 Deprotection of (2R,4R)—N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4,5-dibromothiophen-2-yl)methyl)pyrrolidine-2-carboxamide was carried out according to step 7 of the procedure for compound I-1.

[0329] Example 18 Preparation of (2R,4R)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4,5-dichlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-18) (2R,4R)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4,5-dichlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate was synthesized by following steps 1-6 of the procedure for compound I-17.

[0330] Example 19 Preparation of (2R,4R)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-21) TIFF2025131710000167.tif37128 Project 1 (2R,4R)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid was synthesized by following steps 1-2 of the procedure for compound I-17.

[0331] TIFF2025131710000168.tif34128 Project 2 (S)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-aminopropanamide ditrifluoroacetate was synthesized by following steps 5–6 of the procedure for compound I-2.

[0332] TIFF2025131710000169.tif34147 Project 3 (2R,4R)—N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate was synthesized by following steps 6-7 of the procedure for compound I-1, except that the final product was purified using reverse-phase HPLC.

[0333] Example 20 Preparation of (2R,4R)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4,5-dichlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate (Compound I-22) (2R,4R)—N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-((4,5-dichlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide bistrifluoroacetate was synthesized by following steps 1-3 of the procedure for compound I-21.

[0334] Example 21 Preparation of (2R,4R)-N-((S)-1-((4-carbamimidoyl-2-chlorobenzyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (compound I-24) TIFF2025131710000170.tif32128 Project 1 ((2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was synthesized according to steps 1 to 2 of the procedure for compound I-1.

[0335] TIFF2025131710000171.tif19128 Project 2 To a solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.08 g, 17.7 mmol) in DMF (28 mL) was added NaN (2.3 g, 35.4 mmol). The reaction was placed under N and stirred at room temperature overnight, then quenched with water. The mixture was extracted three times with ethyl acetate. The organic layers were combined, washed three times with water, washed with brine, dried over NaSO, filtered under reduced pressure, and evaporated under reduced pressure. The crude product was dissolved in CHCl and adsorbed onto silica gel. Purification by chromatography (0–40% ethyl acetate–hexane) gave 4-(azidomethyl)-3-chlorobenzonitrile (3.61 g, 93% yield).

[0336] TIFF2025131710000172.tif28128 Project 3 A solution of 4-(azidomethyl)-3-chlorobenzonitrile (3.88 g, 20.2 mmol) in EtOH (100 mL) was placed under Ar and HCl gas was bubbled through at 0° C. for 45 min. The reaction was allowed to warm to room temperature and stirred for 5.5 h. Volatiles were removed under reduced pressure to give the crude product, ethyl 4-(azidomethyl)-3-chlorobenzimidate hydrochloride, which was used in the next step.

[0337] TIFF2025131710000173.tif28128 Project 4 A mixture of crude ethyl 4-(azidomethyl)-3-chlorobenzimidate hydrochloride in EtOH (75 mL) was placed under argon and NH gas was bubbled through at 0° C. for 10 minutes. The solution was allowed to warm to room temperature and stirred overnight. Volatiles were removed under reduced pressure to give crude 4-(azidomethyl)-3-chlorobenzimidamide, which was used in the next step.

[0338] TIFF2025131710000174.tif24128 Project 5 To a solution of the crude product, 4-(azidomethyl)-3-chlorobenzimidamide, in THF (50 mL) and acetonitrile (25 mL) was added DIEA (7.5 mL, 43.1 mmol) and BocO (4.7 g, 21.5 mmol). The reaction was placed under N2, stirred at room temperature overnight, and concentrated. The residue was dissolved in ethyl acetate. The organic layer was washed twice with 10% KHSO4, washed with brine, dried over Na2SO4, filtered under reduced pressure, and evaporated under reduced pressure. The crude product was dissolved in CHCl2 and adsorbed onto silica gel. Purification by chromatography (0–100% ethyl acetate–hexane) gave tert-butyl ((4-(azidomethyl)-3-chlorophenyl)methyl)carbamate (5.5 g, 88% yield over three steps).

[0339] TIFF2025131710000175.tif24128 Project 6 To a solution of tert-butyl ((4-(azidomethyl)-3-chlorophenyl)(imino)methyl)carbamate (534 mg, 1.72 mmol) in THF (6 mL) and water (0.69 mL) was added PPh3 (676 mg, 2.58 mmol). The reaction was stirred overnight at room temperature, quenched with 1 M KHSO4 (40 mL), and washed three times with water. The ether layer was discarded. The pH of the aqueous layer was adjusted to 12 by adding 5 M NaOH solution. The basic aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered under reduced pressure, and evaporated under reduced pressure. The crude product was dissolved in CHCl2 and adsorbed onto silica gel. Purification by chromatography (0-10% 7N NH3 in MeOH-CH2Cl2) gave tert-butyl ((4-(aminomethyl)-3-chlorophenylmino)methyl)carbamate (309 mg, 63% yield).

[0340] TIFF2025131710000176.tif43145 Project 7 tert-Butyl (2R,4R)-2-(((S)-1-((4-(N-(tert-butoxycarbonyl)carbamimidoyl)-2-chlorobenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate was synthesized by following step 3 of the procedure for compound I-17.

[0341] TIFF2025131710000177.tif34142 Project 8 To a solution of tert-butyl (2R,4R)-2-(((S)-1-((4-(N-(tert-butoxycarbonyl)carbamimidoyl)-2-chlorobenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (29.2 mg, 0.0442 mmol) in DCM (1 mL) was added TES (50 mL) at room temperature. The reaction was placed under N2 and cooled to 0 °C. TFA (0.5 mL) was added and the reaction was allowed to warm to room temperature and stirred overnight. Volatiles were evaporated under reduced pressure. The residue was purified by reverse-phase HPLC to give (2R,4R)-N-((S)-1-((4-carbamimidoyl-2-chlorobenzyl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide bistrifluoroacetate (11 mg, 37% yield).

[0342] Example 22 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-23) TIFF2025131710000178.tif32128 Project 1 (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxylic acid was synthesized by following steps 1-2 of the procedure for compound I-17.

[0343] TIFF2025131710000179.tif17128 Project 2 tert-Butyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate was synthesized by following steps 2 to 6 of the procedure for compound I-24.

[0344] TIFF2025131710000180.tif46148 Project 3 (2R,4S)—N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide was synthesized by following steps 7–8 of the procedure for compound I-24.

[0345] Example 23 Preparation of (2R,4S)-4-benzyl-N-((S)-1-(((3-chloro-1-(methyl-d3)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide hydrochloride (compound I-45) TIFF2025131710000181.tif19128 Project 1 To a solution of 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.04 g, 7.24 mmol) in anhydrous DMF (14 mL) under argon was added NCS (1.06 g, 6.9 mmol). The mixture was heated at 55 °C for 2.5 h, cooled to room temperature, and then diluted with HO to a final volume of approximately 90 mL. The mixture was cooled, and the solid was isolated by filtration, rinsed with HO, and dried in a vacuum oven (at room temperature) to give 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.2 g, 93% yield).

[0346] TIFF2025131710000182.tif22128 Project 2 To an ice-cooled suspension of NaH (60% in oil; 538 mg, 13.4 mmol) in dry DMF (2 mL) under Ar was added a solution of 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (215 mg, 1.21 mmol) in dry DMF (7 mL). After stirring at room temperature for 30 min, the mixture was slowly cooled on an ice bath, and iodomethane-d3 (0.22 mL, 3.5 mmol) was added over 5 min. The mixture was allowed to warm slowly to room temperature, stirred for 3 h, and then cooled on an ice bath. The reaction was quenched with H2O, followed by the addition of ethyl acetate. The layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography (10-35% ethyl acetate-hexane) gave 3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (226 mg, 97% yield).

[0347] TIFF2025131710000183.tif21128 Project 3 To a suspension of 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.50 g, 2.8 mmol) in MeOH (75 mL) was added di-tert-butyl dicarbonate (1.29 g, 5.9 mmol) and CoCl₂·6H₂O (0.36 g, 1.5 mmol). NaBH₄ (0.37 g, 9.8 mmol) was added in four aliquots over 20 minutes. After stirring the mixture for 2 hours, additional NaBH₄ (0.21 g, 5.6 mmol) was added and stirred overnight. The reaction was acidified with 0.5 M KHSO₄ until the pH was neutral. After removing the volatiles in vacuo, the aqueous mixture was extracted twice with 10% MeOH-CHCl₂. The aqueous layer was readjusted to neutral pH and extracted with 10% MeOH-CHCl₂. The combined organic layers were concentrated in vacuo to remove all volatiles and H₂O. Purification by chromatography (two runs: 0-5% MeOH-CH2Cl2, then 0-25% acetone-CH2Cl2) gave tert-butyl ((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate (307 mg, 39% yield).

[0348] TIFF2025131710000184.tif21128 Project 4 To a suspension of tert-butyl ((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate (305 mg, 1.08 mmol) in MeOH (6 mL) was added 3M HCl-cyclopentyl methyl ether (CPME; 9 mL). The resulting solution was stirred for 2.5 hours, and then additional 3M HCl-CPME (5 mL) was added. After stirring for 45 minutes, the solution was concentrated under reduced pressure. The residue was dissolved in methanol and concentrated under reduced pressure. The solid was suspended in MeOH-EtO, collected by filtration, and air-dried to give (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine hydrochloride (285 mg, quantitative).

[0349] TIFF2025131710000185.tif26128 Project 5 (S)-2-amino-N-((3-chloro-1-(methyl-d3)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)propenamide hydrochloride was synthesized by following steps 4-5 of the procedure for compound I-44.

[0350] TIFF2025131710000186.tif38148 Project 6 (2R,4S)-4-benzyl-N-((S)-1-(((3-chloro-1-(methyl-d3)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide hydrochloride was synthesized by following steps 6-7 of the procedure for compound I-44.

[0351] Example 24 Preparation of (2R,4R)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)-N-((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate (Compound I-19) TIFF2025131710000187.tif37128 Project 1 (2R,4R)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid was synthesized by following steps 1-2 of the procedure for compound I-17.

[0352] TIFF2025131710000188.tif26128 Project 2 (S)-2-amino-N-((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)propenamide was synthesized by following steps 1 to 4 of the procedure for compound I-45.

[0353] TIFF2025131710000189.tif43154 Project 3 (2R,4R)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)-N-((S)-1-(((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate was synthesized by following steps 6-7 of the procedure for compound I-1, except that the final product was purified using reverse-phase HPLC.

[0354] Example 25 Preparation of (2R,4R)-4-((4,5-dichlorothiophen-2-yl)methyl)-N-((S)-1-(((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate (compound I-20) (2R,4R)-4-((4,5-dichlorothiophen-2-yl)methyl)-N-((S)-1-(((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate was synthesized by following steps 1-3 of the procedure for compound I-19.

[0355] Example 26 Preparation of (2R,4S)-N-((S)-1-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide trifluoroacetate (compound I-25) TIFF2025131710000190.tif19128 Project 1 To a solution of 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.04 g, 7.24 mmol) in anhydrous DMF (14 mL) under argon was added N-chlorosuccinimide (1.06 g, 6.9 mmol). The mixture was heated at 55° C. for 2.5 h, cooled to room temperature, and then diluted with HO to a final volume of approximately 90 mL. The mixture was cooled, and the solid was isolated by filtration, rinsed with HO, and dried in a vacuum oven (at room temperature) to give 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1.2 g, 93% yield).

[0356] TIFF2025131710000191.tif19128 Project 2 To a suspension of 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.50 g, 2.8 mmol) in MeOH (75 mL) was added di-tert-butyl dicarbonate (1.29 g, 5.9 mmol) and CoCl₂·6H₂O (0.36 g, 1.5 mmol). NaBH₄ (0.37 g, 9.8 mmol) was added in four aliquots over 20 minutes. After stirring the mixture for 2 hours, additional NaBH₄ (0.21 g, 5.6 mmol) was added and stirred overnight. The reaction was acidified with 0.5 M KHSO₄ until the pH was neutral. The volatiles were then removed under reduced pressure, and the aqueous mixture was extracted twice with 10% MeOH-CHCl₂. The aqueous layer was readjusted to neutral pH and extracted with 10% MeOH-CHCl₂. The combined organic layers were concentrated under reduced pressure to remove all volatiles and H₂O. Purification by chromatography (two runs: 0-5% MeOH-CH2Cl2, then 0-25% acetone-CH2Cl2) gave tert-butyl ((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate (307 mg, 39% yield).

[0357] TIFF2025131710000192.tif19128 Project 3 To a suspension of tert-butyl ((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate (305 mg, 1.08 mmol) in MeOH (6 mL) was added 3M HCl-CPME (9 mL). The resulting solution was stirred for 2.5 hours, after which additional 3M HCl-CPME (5 mL) was added. After stirring for 45 minutes, the solution was concentrated under reduced pressure. The residue was dissolved in MeOH and concentrated under reduced pressure. The solid was suspended in MeOH-EtO, and the solid was collected by filtration and air-dried to give (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine dihydrochloride (285 mg, quantitative yield).

[0358] TIFF2025131710000193.tif34128 Project 4 (S)-2-amino-N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)propenamide ditrifluoroacetate was synthesized by following steps 5-6 of the procedure for compound I-2.

[0359] TIFF2025131710000194.tif45149 Project 5 (4S)—N-((S)-1-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide trifluoroacetate was synthesized by following steps 6–7 of the procedure for compound I-1.

[0360] Example 27 Preparation of (2R,4S)-N-((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)-1-ethylpyrrolidine-2-carboxamide (compound I-26)

[0361] TIFF2025131710000195.tif19128 Project 1 To an ice-cooled suspension of NaH (60% in oil, 538 mg, 13.4 mmol) in anhydrous DMF (2 mL) under Ar was added a solution of 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (215 mg, 1.21 mmol, prepared according to the procedure for compound I-61) in anhydrous DMF (7 mL). After stirring at room temperature for 30 min, the mixture was slowly cooled on an ice bath, and iodomethane (0.22 μl, 3.5 mmol) was added over 5 min. The mixture was allowed to warm slowly to room temperature, stirred for 3 h, and then cooled on an ice bath. The reaction was quenched with H2O, followed by the addition of ethyl acetate. The layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by chromatography (10-35% ethyl acetate-hexane) gave 3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (226 mg, 97% yield).

[0362] TIFF2025131710000196.tif23128 Project 2~3 3-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile was reduced using steps 2-3 of the two-step procedure described for compound I-25 to give (3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine dihydrochloride (75 mg, 54% over two steps).

[0363] TIFF2025131710000197.tif34128 Project 4 (S)-2-amino-N-((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)propenamide ditrifluoroacetate was synthesized by following steps 5-6 of the procedure for compound I-2.

[0364] TIFF2025131710000198.tif45149 Project 5 (4S)—N-((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide trifluoroacetate was synthesized by following steps 6–7 of the procedure for compound I-1.

[0365] TIFF2025131710000199.tif34146 Project 6 To a stirred solution of (2R,4S)—N—((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide trifluoroacetate (35 mg, 0.048 mmol) in DCM (1 mL) and EtN (0.1 mL) was added ethyl bromide (0.017 mL, 0.24 mmol) under an argon atmosphere. After stirring at room temperature for 18 hours, the reaction mixture was concentrated and purified on an amine column using 100% ethyl acetate as the mobile phase to give (2R,4S)—N-((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)-1-ethylpyrrolidine-2-carboxamide (12 mg, 47%).

[0366] Example 28 Preparation of (2R,4S)-N-((S)-1-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)-1-ethylpyrrolidine-2-carboxamide (compound I-27) (2R,4S)—N-((S)-1-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)-1-ethylpyrrolidine-2-carboxamide was synthesized according to the procedure for compound I-26.

[0367] Example 29 Preparation of (2R,4S)-4-benzyl-N-((S)-1-(((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate (compound I-30) (2R,4S)-4-benzyl-N-((S)-1-(((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate was synthesized according to the procedure for compound I-10 using commercially available (1-methyl-1H-benzo[d]imidazol-5-yl)methanamine.

[0368] Example 30 Preparation of (2-((2R,4S)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)ethyl)phosphonic acid ditrifluoroacetate (compound I-39) TIFF2025131710000200.tif35128 Project 1 To a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-2-carboxylic acid (4.5 g, 14.7 mmol) in DMF (35 mL, 0.42 M) was added HOBt (2.2 g, 16.2 mmol), DIEA (3 mL), and EDC (3.1 g, 16.2 mmol). After stirring at room temperature for 30 minutes, benzyl L-alanine hydrochloride (3.5 g, 16.2 mmol) was added and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 10% KHSO solution. The organic layer was separated and washed with H2O and saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (0–20% ethyl acetate–hexane; the third UV-active material eluted from the column) to give tert-butyl (2R,4S)-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (2.59 g, 34% yield).

[0369] TIFF2025131710000201.tif35128 Project 2 To a stirred solution of tert-butyl (2R,4S)-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (200 mg, 0.43 mmol) in DCM (2 mL) was added TFA (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give benzyl ((2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetate (201 mg, 100% yield).

[0370] TIFF2025131710000202.tif47128 Project 3 To a solution of ((2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetate (70 mg, 0.15 mmol) in DMF (2 mL) was added K2CO3 (100 mg, 0.72 mmol) and stirred for 30 minutes. Diethyl (2-bromoethyl)phosphonate (0.2 mL) was added to the above mixture and stirred at 50 °C for 2 hours. The reaction was monitored by LCMS. The crude reaction mixture was quenched with water and extracted with ethyl acetate (2 x 20 mL). The crude product was dissolved in MeOH and 10% Pd / C (7 mg) was added under argon. The reaction was stirred under an H2 atmosphere for 1 hour. The crude reaction mixture was filtered over Celite, washed with methanol, and concentrated under reduced pressure to give ((2R,4S)-1-(2-(diethoxyphosphoryl)ethyl)-4-phenylpiperidine-2-carbonyl)-L-alanine. The crude material was used in the next reaction without further purification.

[0371] TIFF2025131710000203.tif50128 Project 4 To a stirred solution of (2R,4S)-1-(2-(diethoxyphosphoryl)ethyl)-4-phenylpiperidine-2-carbonyl)-L-alanine (50 mg, 0.11 mmol) in DCM (5 mL) was added NHS (13 mg, 0.11 mmol) with stirring at room temperature until dissolved. DCC (23 mg, 0.11 mmol) was added and stirred for 1 h. After stirring, 1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (32 mg, 0.22 mmol) was added with sonication and stirred overnight at room temperature. The solution was filtered and evaporated to dryness. Flash chromatography on an amine column afforded diethyl (2-((2R,4S)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)ethyl)phosphonate (70 mg, 82% yield over two steps) as a white solid.

[0372] TIFF2025131710000204.tif45143 Project 5 To a stirred solution of diethyl (2-((2R,4S)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)ethyl)phosphonate (70 mg, 0.12 mmol) in DCM was added TMSBr (1 mL) and stirred at 40° C. for 3 h. The reaction was monitored by TLC and then slowly quenched with MeOH (2 mL) at 0° C. The solvent was evaporated under reduced pressure, resuspended in MeOH, and purified by HPLC to give (2-((2R,4S)-2-(((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)ethyl)phosphonic acid ditrifluoroacetate (71 mg, 80% yield) as a white solid.

[0373] Example 31 Preparation of ethyl 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (Compound I-31) TIFF2025131710000205.tif35128 Project 1 A solution of tert-butyl (2R,4S)-2-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (2.59 g, 5.54 mmol) (prepared according to step 1 of the procedure for compound I-39) was degassed with a stream of argon for 2 minutes. 10% Pd / C (130 mg) was added and vacuum was pulled for 1 minute. A H2 balloon was added and the reaction was monitored for consumption of starting material for 1.5 hours. The catalyst was filtered off and the solution was evaporated to give ((2R,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-2-carbonyl)-L-alanine (1.8 g, 86%).

[0374] TIFF2025131710000206.tif42144 Project 2 To a stirred solution of tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (200 mg, 0.53 mmol) in DCM was added DCC (109 mg, 0.53 mmol) and NHS (61 mg, 0.53 mmol) and stirred at room temperature for 30 minutes. Benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride (170 mg, 0.53 mmol) suspended in saturated NaHCO3 was added to the reaction mixture and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM (3 x 20 mL). The crude product was purified using flash chromatography (100% ethyl acetate) to afford tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (180 mg, 53% yield) as a white solid.

[0375] TIFF2025131710000207.tif40147 Project 3 To a stirred solution of (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (180 mg, 0.28 mmol) in DCM (5 mL) was added TFA (0.5 mL) and stirred at room temperature for 30 minutes. The solution was concentrated and used in the next reaction without further purification.

[0376] TIFF2025131710000208.tif42148 Project 4 To a stirred solution of benzyl (imino(4-(((S)-2-((2R,4S)-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate trifluoroacetate (100 mg, 0.14 mmol) in DCM (2 mL) and EtN (0.8 mL) under an argon atmosphere was added ethyl 3-bromopropionate (0.2 mL). After stirring at room temperature for 24 h, the reaction mixture was concentrated and purified on an amine column to give ethyl 3-((2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (70 mg, 78% yield) as a white solid.

[0377] TIFF2025131710000209.tif41144 Project 5 To a stirred solution of ethyl 3-((2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (55 mg, 0.085 mmol) in MeOH (15 mL) was added 10% Pd / C (15 mg) and stirred under H for 2 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite and washed with MeOH. The organic residue was concentrated to give ethyl 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (43 mg, 100%) as a white solid.

[0378] Example 32 Preparation of ethyl 3-((2R,4S)-2-(((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (Compound I-28) TIFF2025131710000210.tif42147 Project 1 Following step 2 of the procedure described above for synthesizing compound I-31, (2R,4S)—N—((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide was synthesized using commercially available (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine hydrochloride and tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (synthesized according to step 1 of the procedure for compound I-31).

[0379] Project 2 Ethyl 3-((2R,4S)-2-(((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate was synthesized according to the procedure for compound I-31.

[0380] Example 33 Preparation of 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoic acid ditrifluoroacetate (compound I-32) TIFF2025131710000211.tif41148 To a stirred solution of ethyl 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (20 mg, 0.04 mmol, prepared according to the procedure for compound I-31) in THF (2 mL) was added a solution of LiOH (15 mg) in 2 mL of water at room temperature and stirred for 18 hours at room temperature. The reaction mixture was acidified with TFA and purified by HPLC to give 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoic acid ditrifluoroacetate (15 mg, 53% yield) as a white solid.

[0381] Example 34 Preparation of 3-((2R,4S)-2-(((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoic acid trifluoroacetate (compound I-29) 3-((2R,4S)-2-(((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoic acid trifluoroacetate was synthesized from compound I-56 using the procedure for synthesizing compound I-32.

[0382] Example 35 Preparation of 2-((2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidin-1-yl)acetic acid ditrifluoroacetate (compound I-33) TIFF2025131710000212.tif27128 Project 1 To a stirred solution of (tert-butoxycarbonyl)-L-alanine (1.96 g, 10.38 mmol) in CHCl (55 mL) at room temperature was added NHS (1.25 g, 10.89 mmol). DCC (2.25 g, 10.9 mmol) was added to the above reaction mixture, and the reaction mixture was stirred for 1 hour. 5-(aminomethyl)-6-methylpyridin-2-amine was added to the reaction mixture and sonicated for 5 minutes. 5-(aminomethyl)-6-methylpyridin-2-amine was completely dissolved and stirred at room temperature for 1 hour. The crude reaction mixture was filtered and concentrated under reduced pressure. The crude reaction mixture was purified by chromatography (MeOH / CHCl) to give tert-butyl (S)-(1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (2.35 g, 70% yield) as a white solid.

[0383] TIFF2025131710000213.tif19136 Project 2 To tert-butyl (S)-(1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (2.35 g, 7.62 mmol) was added MeOH-HCl solution (2 M, 19 mL) with stirring at room temperature. After stirring for 1 h, the solution was evaporated to dryness, MeOH (50 mL) was added, and the mixture was evaporated to dryness to remove residual HCl gas, affording (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)propanamide hydrochloride (1.60 g, 90% yield) as an off-white solid (hygroscopic).

[0384] TIFF2025131710000214.tif37149 Project 3 tert-Butyl (2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-1-carboxylate was synthesized from (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxylic acid (steps 1-4 of compound I-2) according to step 3 of the procedure for compound I-17.

[0385] TIFF2025131710000215.tif34149 Project 4 (2R,4S)—N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate was synthesized by following step 7 of the procedure for compound I-1.

[0386] Project 5 The synthesis of 2-((2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidin-1-yl)acetic acid ditrifluoroacetate was carried out according to the procedure for compound I-32.

[0387] Example 36 Preparation of 2-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)acetic acid ditrifluoroacetate (compound I-34) The synthesis of 2-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)acetic acid ditrifluoroacetate was carried out according to the procedure for compound I-32.

[0388] Example 37 Preparation of 2-((2R,4R)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidin-1-yl)acetic acid ditrifluoroacetate (compound I-35) TIFF2025131710000216.tif37150 Project 1 Benzyl (imino(4-(((S)-2-((2R,4R)-4-phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate trifluoroacetate was synthesized from ((2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (100 mg, 0.27 mmol, prepared according to steps 1-2 of the procedure for compound I-1) according to steps 2-3 of the procedure for the synthesis of compound I-31.

[0389] TIFF2025131710000217.tif32149 Project 2 The synthesis of 2-((2R,4R)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidin-1-yl)acetic acid ditrifluoroacetate was carried out according to step 4 of the procedure for compound I-31 and the procedure for compound I-32.

[0390] Example 38 Preparation of 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidin-1-yl)propanoic acid ditrifluoroacetate (compound I-36) The synthesis of 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidin-1-yl)propanoic acid ditrifluoroacetate was carried out according to the procedure for compound I-32, starting from benzyl ((4-(((S)-2-((2R,4S)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamido)propanamido)methyl)phenyl)(imino)methyl)carbamate as described for compound I-23.

[0391] Example 39 Preparation of 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(4-fluorobenzyl)pyrrolidin-1-yl)propanoic acid ditrifluoroacetate (compound I-37) The synthesis of 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(4-fluorobenzyl)pyrrolidin-1-yl)propanoic acid ditrifluoroacetate was carried out according to the procedure for compound I-36 starting from benzyl ((4-(((S)-2-((2R,4S)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamido)propanamido)methyl)phenyl)(imino)methyl)carbamate.

[0392] Example 40 Preparation of (2-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)ethyl)phosphonic acid ditrifluoroacetate (compound I-38) The synthesis of (2-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)ethyl)phosphonic acid ditrifluoroacetate was carried out according to the procedure for compound I-32, except the final deprotection step was performed using step 5 of the procedure for compound I-39.

[0393] Example 41 Preparation of (3-((2R,4S)-2-(((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propyl)phosphonic acid ditrifluoroacetate (compound I-40) The synthesis of (3-((2R,4S)-2-(((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propyl)phosphonic acid trifluoroacetate was carried out according to the procedure for compound I-32, starting from (2R,4S)—N—((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide. The final deprotection step was carried out using step 5 of the procedure for compound I-39.

[0394] Example 42 Preparation of (2R,4S)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (Compound I-41) TIFF2025131710000218.tif50144 Project 1 To a solution of ((2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetate (154 mg, 0.32 mmol, prepared according to steps 1-2 of the procedure for compound I-39) in DMF (2 mL) was added K2CO3 (200 mg, 1.44 mmol). After stirring at room temperature for 30 min, N-(2-bromoethyl)methanesulfonamide (130 mg, 0.64 mmol) was added and stirred at 70 °C for 2 h. The reaction was monitored by LCMS. The crude reaction mixture was quenched with water, extracted with ethyl acetate (2 x 20 mL), and concentrated under reduced pressure. The crude material was used in the next reaction without further purification.

[0395] TIFF2025131710000219.tif52150 Project 2 To a stirred solution of ((2R,4S)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carbonyl)-L-alanine (75 mg, 0.19 mmol) in DCM (15 mL) was added NHS (22 mg, 0.19 mmol) with stirring at room temperature until dissolved. DCC (42 mg, 0.19 mmol) was added and stirred for 1 h, after which 5-(aminomethyl)-6-methylpyridin-2-amine (26 mg, 0.19 mmol) was added with sonication and stirred at room temperature overnight. The solution was filtered and evaporated to dryness. Purification by reverse-phase HPLC chromatography afforded (2R,4S)—N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (30 mg, 18% yield over two steps) as a white solid.

[0396] Example 43 Preparation of (2R,4S)—N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (compound I-42) The synthesis of (2R,4S)—N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamide trifluoroacetate was carried out according to the procedure of compound I-41, except that commercially available (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine was used in step 2.

[0397] Example 44 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (compound I-43) TIFF2025131710000220.tif47148 Project 1 The synthesis of benzyl (imino(4-(((S)-2-((2R,4S)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate was carried out according to step 2 of the procedure for compound I-41, using benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate (synthesized according to steps 5 to 9 of the procedure for compound I-13).

[0398] TIFF2025131710000221.tif41148 Project 2 The synthesis of (2R,4S)—N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-1-(2-(methylsulfonamido)ethyl)-4-phenylpiperidine-2-carboxamide was carried out according to step 5 of the procedure for compound I-31, except the final compound was purified on a reverse-phase HPLC system.

[0399] Example 45 Preparation of (2R,4S)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-cyclopropylbenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-44) TIFF2025131710000222.tif27128 Project 1 2-Benzyl 1-(tert-butyl)(2R,4S)-4-(3-bromobenzyl)pyrrolidine-1,2-dicarboxylate was synthesized by following steps 1 to 3 of the procedure for compound I-2.

[0400] TIFF2025131710000223.tif27128 Project 2 In a 10 mL round-bottom flask equipped with a stir bar and septum, 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-bromobenzyl)pyrrolidine-1,2-dicarboxylate (150 mg, 0.31 mmol), cyclopropylboronic acid (82 mg, 0.95 mmol), Pd(dppf)Cl (12 mg, 0.015 mmol), potassium phosphate tribasic (202 mg, 0.95 mmol), and 1,4-dioxane (1 mL) were added. The resulting mixture was degassed by bubbling N through the solution for 10 minutes. The reaction was then heated to 90 °C for 12 hours. Upon cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, eluted with ethyl acetate, concentrated, and purified by chromatography using ethyl acetate-hexane to give 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-cyclopropylbenzyl)pyrrolidine-1,2-dicarboxylate (60 mg, 43% yield) as a colorless viscous liquid.

[0401] TIFF2025131710000224.tif19128 Project 3 Ar gas was bubbled through a solution of 2-benzyl 1-(tert-butyl)(2R,4S)-4-(3-cyclopropylbenzyl)pyrrolidine-1,2-dicarboxylate (60 mg, 0.14 mmol) in MeOH (2 mL) for 5 min. 10% Pd / C (6 mg) was added to the reaction mixture, and the reaction was stirred under 1 atmosphere of H2 for 2 h. The reaction mixture was filtered (0.2 μm syringe filter), and the filtrate was concentrated under reduced pressure to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-cyclopropylbenzyl)pyrrolidine-2-carboxylic acid (40 mg, 85% yield).

[0402] TIFF2025131710000225.tif27128 Project 4 To a solution of (tert-butoxycarbonyl)-L-alanine (1.96 g, 10.38 mmol) in CHCl (55 mL) was added NHS (1.25 g, 10.89 mmol) at room temperature. DCC (2.25 g, 10.9 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 1 hour. 5-(aminomethyl)-6-methylpyridin-2-amine (1.42 g, 10.38 mmol) was added to the reaction mixture, and the mixture was sonicated for 5 minutes. 5-(aminomethyl)-6-methylpyridin-2-amine was completely dissolved and stirred at room temperature for 1 hour. The crude reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography using MeOH—CH 2 Cl 2 to give tert-butyl (S)-(1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (2.35 g, 70% yield) as a white solid.

[0403] TIFF2025131710000226.tif23128 Project 5 To tert-butyl (S)-(1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (2.35 g, 7.62 mmol) was added MeOH-HCl solution (19 mL, 2 M) with stirring at room temperature while monitoring the consumption of the starting material (approximately 1 h). The solution was evaporated to dryness, and MeOH (50 mL) was added and evaporated to dryness to remove residual HCl gas, affording (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)propanamide dihydrochloride (1.60 g, 76% yield) as an off-white solid (hygroscopic).

[0404] TIFF2025131710000227.tif34147 Project 6 To a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-cyclopropylbenzyl)pyrrolidine-2-carboxylic acid (40 mg, 0.11 mmol) in anhydrous DMF (1 mL) was added HOBt (16 mg, 0.11 mmol), DIEA (0.07 mL, 0.42 mmol), and EDC (22 mg, 0.11 mmol) at room temperature. After stirring at the same temperature for 30 minutes, (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)propanamide dihydrochloride (26 mg, 0.12 mmol) was added to the reaction mixture and stirred overnight. The solution was evaporated to dryness, and the residue was partitioned between ethyl acetate (10 mL) and 10% KHSO (5 mL). The organic layer was separated, washed with saturated NaHCO solution (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by chromatography using MeOH—CH2Cl2 to give tert-butyl (2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-cyclopropylbenzyl)pyrrolidine-1-carboxylate (49 mg, 80% yield) as a white solid.

[0405] TIFF2025131710000228.tif27147 Project 7 To tert-butyl (2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-cyclopropylbenzyl)pyrrolidine-1-carboxylate (49 mg, 0.09 mmol) was added MeOH-HCl solution (2.0 mL, 3 M) with stirring at room temperature while monitoring the consumption of the starting material (approximately 1 h). The solution was evaporated to dryness, and the residue was purified using reverse-phase HPLC to give (2R,4S)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-cyclopropylbenzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (22.2 mg, 67% yield) as a white solid.

[0406] Example 46 Preparation of methyl 3-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate dihydrochloride (compound I-47) TIFF2025131710000229.tif27128 Project 1 2-Benzyl 1-(tert-butyl)(2R,4S)-4-(3-bromobenzyl)pyrrolidine-1,2-dicarboxylate was synthesized by following steps 1 to 3 of the procedure for compound I-2.

[0407] TIFF2025131710000230.tif27135 Project 2 Under atmospheric pressure, a 25 mL vial equipped with a stir bar was charged with (COH HO) (80 mg, 0.63 mmol), Pd(OAc) (1 mg, 0.0042), Xantphos (2.5 mg, 0.0042), benzyl (2R,4S)-4-(3-bromobenzyl)pyrrolidine-2-carboxylate (200 mg, 0.42 mmol), AcO (60 μL, 0.633 mmol), DIEA (0.11 mL, 0.63 mmol), and DMF (2.0 mL). The tube was quickly sealed with a Teflon® high-pressure valve, frozen in liquid nitrogen, evacuated, and refilled with N (5 times). After stirring at 100 °C for 6 h, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL), acidified with 2 M HCl (5 mL, 1×), and washed with brine (5 mL, 2×). The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure to give 3-(((3S,5R)-5-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)benzoic acid (45 mg, 25% yield), which was used directly in the next step without further purification.

[0408] TIFF2025131710000231.tif26145 Project 3 To a solution of 3-(((3S,5R)-5-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)benzoic acid (45 mg, 0.10 mmol) and potassium carbonate (27.6 mg, 0.20 mmol) in DMF (1 mL) was added methyl iodide (12 mL, 0.20 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. The residue was purified by chromatography (ethyl acetate-hexane) to give benzyl (2R,4S)-4-(3-(methoxycarbonyl)benzyl)pyrrolidine-2-carboxylate (50 mg, 99%).

[0409] TIFF2025131710000232.tif27147 Project 4 Methyl 3-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate dihydrochloride was synthesized by following steps 3-7 of the procedure for compound I-44, except the final product was carried forward without further purification.

[0410] Example 47 Preparation of 3-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoic acid ditrifluoroacetate (compound I-48) TIFF2025131710000233.tif25149 Project 1 To a solution of methyl 3-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate (23 mg, 0.057 mmol) in THF (1 mL) and water (0.5 mL) was added LiOH (12 mg, 0.507 mmol) at room temperature. After stirring overnight at the same temperature, the reaction mixture was adjusted to pH 3-4 by adding TFA. The solution was evaporated to dryness and the resulting crude reaction mixture was purified using reverse phase HPLC to provide 3-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoic acid ditrifluoroacetate (13.3 mg, 56% yield) as a white solid.

[0411] Example 48 Preparation of methyl 4-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate dihydrochloride (compound I-50) Methyl 4-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate dihydrochloride was synthesized according to the procedure for compound I-47.

[0412] Example 49 Preparation of 4-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoic acid ditrifluoroacetate (compound I-51) 4-(((3S,5R)-5-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoic acid ditrifluoroacetate was synthesized according to the procedure of compound I-48.

[0413] Example 50 Preparation of (2R,4S)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyrrolidine-2-carboxamide nitrile trifluoroacetate (compound I-53) TIFF2025131710000234.tif24128 Project 1 To a solution of 4-(hydroxymethyl)-1-methylpyridin-2(1H)-one (700 mg, 5.02 mmol) in DMF (20 mL) was added PBr (0.33 mL, 3.51 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were thoroughly dried over NaSO, filtered, and concentrated to give 4-(bromomethyl)-1-methylpyridin-2(1H)-one (crude product 707 mg, 3.51 mmol), which was used directly in the next step without further purification.

[0414] TIFF2025131710000235.tif39128 Project 2 2-Benzyl 1-(tert-butyl)(2R,4S)-4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyrrolidine-1,2-dicarboxylate was synthesized by following steps 1 to 3 of the procedure for compound I-2.

[0415] TIFF2025131710000236.tif29139 Project 3 (2R,4S)—N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyrrolidine-2-carboxamide nitrile trifluoroacetate was synthesized by following steps 3 through 7 of the procedure for compound I-44.

[0416] Example 51 Preparation of (2R,4S)-N-((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenoxypyrrolidine-2-carboxamide trifluoroacetate (compound I-46) TIFF2025131710000237.tif27128 Project 1 To a solution of 2-benzyl 1-(tert-butyl)(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (410 mg, 1.27 mmol), 4-bromophenol (242 mg, 1.39 mmol), and TPP (367 mg, 1.39 mmol) in THF (6.35 mL) was added DIAD (0.27 mL, 1.39 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography using ethyl acetate-hexane to give 2-benzyl 1-(tert-butyl)(2R,4S)-4-(4-bromophenoxy)pyrrolidine-1,2-dicarboxylate (533 mg, 88% yield) as a colorless solid.

[0417] TIFF2025131710000238.tif29128 Project 2 (2R,4S)-1-(tert-butoxycarbonyl)-4-phenoxypyrrolidine-2-carboxylic acid was synthesized from 2-benzyl 1-(tert-butyl)(2R,4S)-4-(4-bromophenoxy)pyrrolidine-1,2-dicarboxylate according to step 3 of the procedure for compound I-44.

[0418] TIFF2025131710000239.tif32149 Project 3 (2R,4S)-N-((S)-1-(((3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenoxypyrrolidine-2-carboxamide trifluoroacetate was synthesized from (2R,4S)-1-(tert-butoxycarbonyl)-4-phenoxypyrrolidine-2-carboxylic acid according to steps 6-7 of the procedure for compound I-44.

[0419] Example 52 Preparation of (2R,4S)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-((3-chloropropyl)carbamoyl)benzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-49) TIFF2025131710000240.tif27128 Project 1 2-Benzyl 1-(tert-butyl)(2R,4S)-4-(3-bromobenzyl)pyrrolidine-1,2-dicarboxylate was synthesized by following steps 1 to 3 of the procedure for compound I-2.

[0420] TIFF2025131710000241.tif27135 Project 2 Under atmospheric pressure, a 25 mL vial equipped with a stir bar was charged with (COH HO) (80 mg, 0.63 mmol), Pd(OAc) (1 mg, 0.0042), Xantphos (2.5 mg, 0.0042), benzyl (2R,4S)-4-(3-bromobenzyl)pyrrolidine-2-carboxylate (200 mg, 0.42 mmol), AcO (60 μL, 0.633 mmol), DIEA (0.11 mL, 0.63 mmol), and DMF (2.0 mL). The tube was quickly sealed with a Teflon® high-pressure valve, frozen in liquid nitrogen, evacuated, and refilled with N (5 times). After stirring at 100 °C for 6 h, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL), acidified with 2 M HCl (5 mL, 1×), and washed with brine (5 mL, 2×). The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure to give 3-(((3S,5R)-5-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)benzoic acid (45 mg, 25% yield), which was used directly in the next step without further purification.

[0421] TIFF2025131710000242.tif27128 Project 3 To a solution of 3-(((3S,5R)-5-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)benzoic acid (45 mg, 0.10 mmol) and triethylamine (0.10 mL, 0.70 mmol) in CHCl (1 mL) was added oxalyl chloride (0.34 mL, 0.40 mmol), azetidine (30 mg, 0.5 mmol), followed by DMF (2 drops) under Ar at 0 °C. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was purified by chromatography (ethyl acetate-hexane) to give benzyl (2R,4S)-4-(3-(azetidine-1-carbonyl)benzyl)pyrrolidine-2-carboxylate (31 mg, 61% yield).

[0422] TIFF2025131710000243.tif29147 Project 4 tert-Butyl (2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-(azetidine-1-carbonyl)benzyl)pyrrolidine-1-carboxylate was synthesized by following steps 3 to 6 of the procedure for compound I-44.

[0423] TIFF2025131710000244.tif93146 Project 5 To tert-butyl (2R,4S)-2-(((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(3-(azetidine-1-carbonyl)benzyl)pyrrolidine-1-carboxylate (70 mg, 0.12 mmol) was added IPA-HCl (3.0 mL, 6 M) with stirring at room temperature while monitoring the consumption of the starting material (2 h). Crude LCMS showed two products. The solution was evaporated to dryness, and the resulting crude reaction mixture was purified using reverse-phase HPLC to separate both compounds. (2R,4S)—N—((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-((3-chloropropyl)carbamoyl)benzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (10 mg, 16% yield) eluted first from HPLC as a white solid. (2R,4S)—N—((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)-4-(3-(azetidine-1-carbonyl)benzyl)pyrrolidine-2-carboxamide bistrifluoroacetate (9.3 mg, 17% yield) eluted second fraction from HPLC as a white solid.

[0424] Example 53 Preparation of methyl 3-(((3S,5R)-5-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate ditrifluoroacetate (compound I-54) TIFF2025131710000245.tif27136 Project 1 (2R,4S)-1-(tert-butoxycarbonyl)-4-(3-(methoxycarbonyl)benzyl)pyrrolidine-2-carboxylic acid was synthesized by following step 3 of the procedure for compound I-44.

[0425] TIFF2025131710000246.tif32141 Project 2 Methyl 3-(((3S,5R)-5-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoate ditrifluoroacetate was synthesized by following steps 5 to 14 of the procedure for compound I-13.

[0426] Example 54 Preparation of 3-(((3S,5R)-5-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoic acid ditrifluoroacetate (compound I-55) TIFF2025131710000247.tif29146 Project 1 3-(((3S,5R)-5-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidin-3-yl)methyl)benzoic acid ditrifluoroacetate was synthesized by following step 2 of the procedure for compound I-48.

[0427] Example 55 Preparation of (R)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-2-carboxamide bistrifluoroacetate (Compound I-52) TIFF2025131710000248.tif32128 Project 1 (R)-1-(tert-butoxycarbonyl)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid was synthesized by following steps 1-2 of the procedure for compound I-76.

[0428] TIFF2025131710000249.tif34146 Project 2 (R)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrrole-2-carboxamide bistrifluoroacetate was synthesized by following steps 5 to 14 of the procedure for compound I-13, except that the reaction was stirred for 30 minutes in step 14.

[0429] Example 56 Preparation of (2R,4S)-4-((2-aminopyridin-4-yl)methyl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide bistrifluoroacetate (compound I-56) TIFF2025131710000250.tif34128 Project 1 2-Benzyl 1-(tert-butyl)(2R,4S)-4-((2-aminopyridin-4-yl)methyl)pyrrolidine-1,2-dicarboxylate was synthesized by following steps 1-3 of the procedure for compound I-44.

[0430] TIFF2025131710000251.tif33147 Project 2 (2R,4S)-4-((2-aminopyridin-4-yl)methyl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide nitrile trifluoroacetate was synthesized by following steps 2-3 of the procedure for compound I-54.

[0431] Example 57 Preparation of (2R,4S)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-3-hydroxy-1-oxopropan-2-yl)-4-benzylpyrrolidine-2-carboxamide dihydrochloride (compound I-57) TIFF2025131710000252.tif33128 Project 1~2 Following steps 4–5 of the procedure for compound I-44, (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-hydroxypropanamide dihydrochloride was prepared as a white crystalline solid (1.09 g, 86% yield over two steps) using the appropriate starting materials.

[0432] TIFF2025131710000253.tif34147 Project 3~4 Following steps 6-7 of the procedure for compound I-44, using the appropriate starting material, except no purification was performed after the final step, the title compound was prepared as a white solid (40.4 mg, 66% yield over two steps).

[0433] Example 58 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((2R,4S)-4-benzylpyrrolidine-2-carbonyl)-2-oxooxazolidine-4-carboxamide bistrifluoroacetate (compound I-58) TIFF2025131710000254.tif23141 Project 1 A 100 mL round-bottom flask was charged with (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-hydroxypropanamide dihydrochloride (480 mg, 1.6 mmol), DIEA (1.27 mL, 73 mmol), and DCM (10 mL) and cooled to 0 °C. To the stirred mixture was added triphosgene (297 mg, 1.0 mmol), and the reaction was allowed to slowly warm to room temperature overnight. The reaction mixture was then quenched with HO, diluted with DCM, and separated. The organic layer was dried over MgSO, concentrated under reduced pressure, and purified by chromatography (0–100% [5% 7N NH in MeOH / CHCl]—CHCl) to give (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-2-oxooxazolidine-4-carboxamide as a white solid (40 mg, 16% yield).

[0434] TIFF2025131710000255.tif35147 Project 2~3 Following step 4 of the procedure for compound I-44 and step 2 of the procedure for compound I-39, using the appropriate starting materials, the title compound was prepared as a white solid (40.4 mg, 66% yield over two steps).

[0435] Example 59 Preparation of (2R,4S)-4-benzyl-N-((S)-1-((imidazo[1,2-a]pyridin-6-ylmethyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate (compound I-59) TIFF2025131710000256.tif17128 Project 1 Imidazo[1,2-a]pyridin-6-ylmethanamine was prepared as a pale green solid (82 mg, quantitative) using the appropriate starting materials according to step 1 of the procedure for compound I-4.

[0436] TIFF2025131710000257.tif45148 Project 2~3 Following steps 4-5 of the procedure for compound I-44, but using the appropriate starting material, the title compound was prepared as a yellow granular solid (3.2 mg, 31% yield).

[0437] Example 60 Preparation of (2R,4S)-4-benzyl-N-((S)-1-(((3-chloroimidazo[1,2-a]pyridin-6-yl)methyl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide trifluoroacetate (compound I-60) TIFF2025131710000258.tif23148 Project 1 tert-Butyl (2R,4S)-4-benzyl-2-(((S)-1-((imidazo[1,2-a]pyridin-6-ylmethyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (28 mg, 0.055 mmol, prepared according to the procedure for compound I-59) was dissolved in CHCl (1 mL) and treated with NCS (8.1 mg, 0.06 mmol) at room temperature. The resulting mixture was stirred for 16 hours, then concentrated and purified by chromatography (ethyl acetate / hexanes) to give tert-butyl (2R,4S)-4-benzyl-2-(((S)-1-(((3-chloroimidazo[1,2-a]pyridin-6-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate as a white solid (16 mg, 74% yield).

[0438] TIFF2025131710000259.tif23150 Project 2 The title compound was prepared as a white granular solid (7 mg, 42% yield) following step 5 of the procedure for compound I-44 using the appropriate starting materials.

[0439] Example 61 Preparation of (R)-N-((6-amino-2-methylpyridin-3-yl)methyl)-1-((2S,4R)-4-(4-bromobenzyl)pyrrolidine-2-carbonyl)-4,4-difluoropyrrolidine-2-carboxamide dihydrochloride (Compound I-61) TIFF2025131710000260.tif37134 Project 1 To a stirred solution of (2S,4R)-4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (83 mg, 0.22 mmol, prepared according to the procedure for compound I-12) in DMF (2 mL) was added HATU (99 mg, 0.26 mmol) and DIEA (115 μL, 0.66 mmol). After stirring at room temperature for 10 minutes, methyl (R)-4,4-difluoropyrrolidine-2-carboxylate (43 mg, 0.26 mmol) was added, and the resulting mixture was stirred for an additional 1.5 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous KHSO, brine, and saturated NaHCO, then dried over NaSO, and concentrated under reduced pressure. The resulting residue was purified by chromatography (30–60% ethyl acetate / hexane) to give tert-butyl (2S,4R)-4-(4-bromobenzyl)-2-((R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate as a colorless oil (91 mg, 78% yield).

[0440] TIFF2025131710000261.tif23148 Project 2 To a solution of tert-butyl (2S,4R)-4-(4-bromobenzyl)-2-((R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate (91 mg, 0.17 mmol) in THF (1.5 mL) and HO (1.5 mL) was added LiOH (11 mg, 0.43 mmol). After stirring at room temperature for 4 h, the reaction mixture was concentrated to remove THF. To this aqueous solution was added 10% KHSO solution, and the resulting precipitate was collected by vacuum filtration and washed with hexane to give (R)-1-((2S,4R)-4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid as a white powder (84 mg, 95% yield).

[0441] TIFF2025131710000262.tif26148 Project 3~4 Following steps 4-5 of the procedure for compound I-44 using the appropriate starting materials, the title compound was prepared as a white fluffy solid (22 mg, 48% yield).

[0442] Example 62 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-fluorophenyl)piperidine-2-carboxamide bistrifluoroacetate (compound I-67) TIFF2025131710000263.tif24128 Project 1 To a solution of N-Boc-D-aspartic acid 1-(tert-butyl) ester (10 g, 35 mmol) and Meldrum's acid (5 g, 35 mmol) in anhydrous dichloromethane (140 mL, 0.25 M) at 0 °C, N,N-dimethylamino-4-pyridine (6.3 g, 52 mmol) was added, followed by EDC (10 g, 52 mmol). The temperature was maintained at 0 °C for 1 h and then allowed to warm to room temperature. Upon completion of the reaction (monitored by TLC), the reaction mixture was washed four times with 1 N KHSO 4 . The reaction mixture was then dried over sodium sulfate, concentrated, and thoroughly dried under vacuum. The crude mixture was then dissolved in anhydrous toluene (350 mL, 0.1 M) and heated to reflux. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled and concentrated under reduced pressure to give di-tert-butyl (R)-4,6-dioxopiperidine-1,2-dicarboxylate as a pale yellow solid (10.34 g, 95%).

[0443] TIFF2025131710000264.tif24128 Project 2 To a solution of di-tert-butyl (R)-4,6-dioxopiperidine-1,2-dicarboxylate (10.34 g, 33 mmol) in anhydrous dichloromethane (110 mL, 0.3 M) was added N-phenyl-bis(trifluoromethanesulfonimide) (14 g, 40 mmol) followed by N,N-diisopropylethylamine (12 mL, 66 mmol) at 0° C. After stirring for 2 h at 0° C., the reaction mixture was concentrated and purified on a silica column using ethyl acetate / heptane to give di-tert-butyl (R)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,2(2H)-dicarboxylate as a white solid (11.5 g, 78%).

[0444] TIFF2025131710000265.tif39128 Project 3 To a solution of di-tert-butyl (R)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,2(2H)-dicarboxylate (500 mg, 1.1 mmol), 4-fluoroboronic acid (230 mg, 1.65 mmol), and bis(triphenylphosphine)palladium(II) chloride (40 mg, 0.055 mmol) in THF (28 mL, 0.04 M) was added potassium carbonate solution (2 N aqueous solution, 16 mL, 0.07 M). The solution was then sparged with argon for 10 minutes and heated to 40 °C until the reaction was complete. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and partitioned. The organic solvent was then dried over sodium sulfate, concentrated, and purified on a silica column using ethyl acetate / heptane to give di-tert-butyl (R)-4-(4-fluorophenyl)-6-oxo-3,6-dihydropyridine-1,2(2H)-dicarboxylate as a white solid (410 mg, 93%).

[0445] TIFF2025131710000266.tif39128 Project 4 A solution of di-tert-butyl (R)-4-(4-fluorophenyl)-6-oxo-3,6-dihydropyridine-1,2(2H)-dicarboxylate (410 mg, 1 mmol) and 10% Pd / C (41 mg) in ethyl acetate (5 mL, 0.2 M) was sparged with argon for 10 minutes, followed by hydrogen for 10 minutes. The reaction mixture was stirred under H2 overnight. The reaction mixture was then sparged with argon for 10 minutes and filtered through Celite. The filtrate was then concentrated under reduced pressure to provide di-tert-butyl (2R,4R)-4-(4-fluorophenyl)-6-oxopiperidine-1,2-dicarboxylate as a white solid, which was carried on without further purification.

[0446] TIFF2025131710000267.tif39128 Project 5 To a solution of the crude product, di-tert-butyl (2R,4R)-4-(4-fluorophenyl)-6-oxopiperidine-1,2-dicarboxylate (395 mg, 1 mmol) in anhydrous THF (6.3 mL, 0.16 M) was added borane-dimethyl sulfide (2 M in THF, 2.6 mL, 5.2 mmol) dropwise at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then cooled to 0 °C, and 1 mL of methanol was added to quench the reaction. After stirring for 10 min, the reaction mixture was concentrated and purified on a silica column using ethyl acetate / heptane to give di-tert-butyl (2R,4S)-4-(4-fluorophenyl)piperidine-1,2-dicarboxylate (260 mg, 66% over two steps) as a white solid.

[0447] TIFF2025131710000268.tif39128 Project 6 To a solution of di-tert-butyl (2R,4S)-4-(4-fluorophenyl)piperidine-1,2-dicarboxylate (260 mg, 0.69 mmol), HCl (4 M in dioxane, 3.4 mL) was added, and the reaction mixture was stirred until the reaction was complete, as monitored by LCMS. The reaction mixture was then concentrated and redissolved in dioxane (1.3 mL, 0.5 M) and aqueous sodium hydroxide (1 N, 2.8 mL, 0.25 M). BocO (160 mg, 0.72 mmol) was added, and the mixture was stirred overnight. The reaction mixture was acidified with 1 M potassium hydrogen sulfate and extracted three times with ethyl acetate. The organic layer was then concentrated under reduced pressure to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidine-2-carboxylic acid (159 mg, 71% over two steps) as a white solid.

[0448] TIFF2025131710000269.tif55147 Project 7 To a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidine-2-carboxylic acid (100 mg, 0.3 mmol) and (S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-aminium chloride (145 mg, 0.37 mmol, prepared according to steps 5-11 of compound I-13) in anhydrous N,N-dimethylformamide (7.4 mL, 0.05 M) was added diisopropylethylamine (220 μL, 1.2 mmol), followed by hydroxybenzotriazole (50 mg, 0.37 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (71 mg, 0.37 mmol). After stirring overnight, the reaction mixture was diluted with ethyl acetate and then extracted with saturated NH4Cl, saturated NaHCO3, water (twice), and brine. The organic layer was then concentrated and purified on a silica column using ethyl acetate / heptane to give tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (110 mg, 54%).

[0449] TIFF2025131710000270.tif45147 Project 8 To a solution of tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (55 mg, 0.08 mmol) in dichloromethane (400 μL, 0.2 M) was added trifluoroacetic acid (130 μL, 1.7 mmol). After stirring for 1-3 h, the reaction was complete as monitored by LCMS. The reaction mixture was concentrated to dryness and redissolved in anhydrous methanol (800 μL, 0.1 M), to which was added 10% Pd / C (20 mg). The reaction mixture was sparged with argon for 10 min, followed by H2 for 10 min. The reaction mixture was stirred under H2 for approximately 30 min until the reaction was complete as monitored by LCMS. The reaction mixture was then sparged with argon for 10 minutes and filtered through Celite, and the filtrate was then concentrated under reduced pressure to give di-tert-butyl (2R,4R)-4-(4-fluorophenyl)-6-oxopiperidine-1,2-dicarboxylate (53.6 mg, quantitative over two steps) as a white solid powder after lyophilization.

[0450] Example 63 Preparation of (2R,4S)-4-([1,1'-biphenyl]-3-yl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide bistrifluoroacetate (compound I-68) (2R,4S)-4-([1,1′-biphenyl]-3-yl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-67.

[0451] Example 64 Preparation of (2R,4S)-4-([1,1'-biphenyl]-4-yl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide bistrifluoroacetate (compound I-69) (2R,4S)-4-([1,1′-biphenyl]-4-yl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-67.

[0452] Example 65 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(naphthalen-2-yl)piperidine-2-carboxamide bistrifluoroacetate (compound I-70) (2R,4S)—N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(naphthalen-2-yl)piperidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-67.

[0453] Example 66 Preparation of (2R,4S)-4-(benzo[b]thiophen-2-yl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide bistrifluoroacetate (compound I-71) (2R,4S)-4-(benzo[b]thiophen-2-yl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-67.

[0454] Example 67 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-(pyridin-3-yl)phenyl)piperidine-2-carboxamide bistrifluoroacetate (compound I-72) (2R,4S)—N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-(pyridin-3-yl)phenyl)piperidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-67.

[0455] Example 68 Preparation of (2R,4S)—N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-(4-(pyridin-3-yl)phenyl)piperidine-2-carboxamide trifluoroacetate (Compound I-73) (2R,4S)—N—((S)-1-(((1H-Pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-(4-(pyridin-3-yl)phenyl)piperidine-2-carboxamide tritrifluoroacetate was synthesized according to the procedure for compound I-67, except that (S)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-aminopropanamide ditrifluoroacetate (prepared according to steps 1-6 of the procedure for synthesizing compound I-2) was used as the amine coupling partner in step 7. Additionally, hydrogenation was not performed in step 8.

[0456] Example 69 Preparation of (2R,4S)—N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-([1,1′-biphenyl]-4-yl)piperidine-2-carboxamide bistrifluoroacetate (compound I-74) (2R,4S)—N—((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-([1,1′-biphenyl]-4-yl)piperidine-2-carboxamide bistrifluoroacetate was synthesized according to the procedure for compound I-73.

[0457] Example 70 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)piperidine-2-carboxamide dihydrochloride (compound I-75) (2R,4S)—N—((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedure for compound I-67, except that in step 8, a solution of HCl in isopropanol was used instead of trifluoroacetic acid and anhydrous methanol was used as the solvent.

[0458] Example 71 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-morpholinophenyl)piperidine-2-carboxamide dihydrochloride (compound I-76) (2R,4S)—N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-4-(4-morpholinophenyl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedure for compound I-67.

[0459] Example 72 Preparation of (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride (compound I-77) (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedure for compound I-67.

[0460] Example 73 Preparation of (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride (Compound I-78) (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedure for Compound I-67, except that (S)-2-amino-N-((6-amino-2-methylpyridin-3-yl)methyl)propanamide ditrifluoroacetate (prepared according to Step 4 of the procedure for Compound I-44 and Step 7 of the procedure for Compound I-1) was used as the amine coupling partner in Step 7. Furthermore, hydrogenation was not performed in Step 8.

[0461] Example 74 Preparation of (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride (Compound I-79) (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedure for compound I-67, except that (S)-2-amino-N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)propanamide ditrifluoroacetate was used as the amine coupling partner in step 7. Additionally, hydrogenation was not performed in step 8.

[0462] Example 75 Preparation of (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride (Compound I-80) (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-N-((S)-1-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedure of compound I-67, except that (S)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-2-aminopropanamide ditrifluoroacetate (prepared according to steps 1 to 6 of compound I-2) was used as the amine coupling partner in step 7. Additionally, hydrogenation was not performed in step 8.

[0463] Example 76 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-1-((2R,4S)-4-phenylpiperidine-2-carbonyl)azetidine-2-carboxamide bistrifluoroacetate (compound I-63) (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-1-((2R,4S)-4-phenylpiperidine-2-carbonyl)azetidine-2-carboxamide bistrifluoroacetate was synthesized according to the ...

Claims

1. A compound having the following structure (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: During the ceremony, represents independently at each occurrence a double bond or a single bond; R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or cycloalkyl; R 3 is hydrogen, alkyl, haloalkyl, or cycloalkyl, or R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl; R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 5 is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) m C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , (CH 2 ) m NR 6 S(O) 2 R 7 , or C(=O)NR 6 R 7 and R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; L 1 is a direct bond, -CR 8a R 8b -, -S(O) t -, NR 8c or -O-; R 8a and R 8b are each independently hydrogen, alkyl, or R 8a and R 8b taken together with the carbon to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl; R 8c is hydrogen, alkyl, haloalkyl, (C=O)alkyl, (C=O)Oalkyl, (C=O)cycloalkyl, (C=O)Ocycloalkyl, (C=O)aryl, (C=O)Oaryl, (C=O)heteroaryl, (C=O)Oheteroaryl, (C=O)heterocyclyl, (C=O)Oheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heterocyclylalkyl; n is 1 or 2; m is 1, 2, 3, 4, 5, or 6; and t is 0, 1, or 2; However, the compound of structure (I) does not have the structure in Table A.

2. R 1 2. The compound of claim 1, wherein is substituted or unsubstituted aryl.

3. R 1 substituted or unsubstituted C 6 ~C 10 3. The compound of claim 1 or 2, which is aryl.

4. R 1 4. The compound of any one of claims 1 to 3, wherein is substituted or unsubstituted phenyl.

5. R 1 5. The compound of any one of claims 1 to 4, wherein is substituted phenyl.

6. R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e and wherein R is a phenyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , C(=NOH)NH 2 , C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Halo, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The compound of any one of claims 1 to 5.

7. R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; The compound of claim 6.

8. R 1 Halo, haloalkyl, C(=NR 9 )NR 10 R 11 , C(=NR 9 )NR 10 C(O)OR 11 8. The compound of any one of claims 1 to 7, wherein the phenyl is substituted with at least one substituent selected from the group consisting of:

9. R 1 But -C(=NH)NH 2 , chloro, fluoro, -CHF 2 , and 9. The compound of claim 8, substituted with at least one substituent selected from the group consisting of:

10. R 1 has the following structure:

10. The compound of any one of claims 7 to 9, having one of:

11. R 1 has the following structure:

11. The compound of any one of claims 1 to 10, having one of:

12. R 1 has the following structure:

8. The compound of claim 7, having one of:

13. R 9 But C 1～6 Alkyl or C 1～6 13. The compound of claim 12, which is haloalkyl.

14. R 9 14. The compound of claim 13, wherein is methyl.

15. R 9 14. The compound of claim 13, wherein is trifluoromethyl.

16. R 1 5. The compound of any one of claims 1 to 4, wherein is unsubstituted phenyl.

17. R 1 10. The compound of claim 1, wherein is substituted or unsubstituted heteroaryl.

18. R 1 20. The compound of claim 1 or 17, wherein is a substituted or unsubstituted 5-10 membered heteroaryl.

19. R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted thienopyridinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoindolinyl, or substituted or unsubstituted benzothiazolyl.

20. R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e and heteroaryl substituted with one or more of the following: 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Halo, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 20. The compound of any one of claims 1 or 17-19.

21. R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 21. The compound of claim 20.

22. R 1 has the following structure:

22. The compound of any one of claims 1 or 17-21, having one of:

23. R 1a or R 1b independently, C 1～6 Alkyl, C 1～6 23. The compound of claim 22, which is a deuterated alkyl, amino, or halo.

24. R 1a or R 1b is methyl or CD 3 24. The compound of claim 23, wherein:

25. R 1a or R 1b 24. The compound of claim 23, wherein is F, Cl, or Br.

26. R attached to nitrogen 1a or R 1b are respectively, C 1～6 24. The compound of claim 23, which is alkyl.

27. R 1a or R 1b 27. The compound of claim 26, wherein is methyl or ethyl.

28. R 1 has the following structure:

20. The compound of any one of claims 1 or 17-19, having one of:

29. R 1 has the following structure:

20. The compound of any one of claims 1 or 17-19, having one of:

30. R 1 has the following structure:

20. The compound of any one of claims 1 or 17-19, having one of:

31. R 1 2. The compound of claim 1, wherein is substituted or unsubstituted cycloalkyl.

32. R 1 substituted or unsubstituted C 3 ~C 6 32. The compound of claim 1 or 31, which is cycloalkyl.

33. R 1 But substitution C 3 ~C 6 33. The compound of any one of claims 1 or 31-32, which is cycloalkyl.

34. R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e C substituted with one or more of 3 ~C 6 cycloalkyl, where R 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 34. The compound of claim 33.

35. R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, Halo, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 35. The compound of claim 34.

36. R 1 But unsubstituted C 3 ~C 6 33. The compound of claim 32, which is cycloalkyl.

37. R 1 2. The compound of claim 1, wherein is substituted or unsubstituted heterocyclyl.

38. R 1 40. The compound of claim 1 or 37, wherein is a substituted or unsubstituted 4- to 10-membered heterocyclyl.

39. R 1 39. The compound of any one of claims 1 or 37-38, wherein is a substituted 4-10 membered heterocyclyl.

40. R 1 But R 1a , R 1b , R 1c , R 1d , or R 1e and R is a 4- to 10-membered heterocyclyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1e are each independently, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Halo, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 , R 10 , R 11 , and R 12 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 40. The compound of claim 39.

41. R 1a , R 1b , R 1c , R 1d , or R 1e But substitution C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 1a , R 1b , R 1c , R 1d , or R 1e But, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, where R 13 , R 14 , R 15 , and R 16 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 41. The compound of claim 40.

42. R 1 38. The compound of claim 37, wherein is unsubstituted 4-10 membered heterocyclyl.

43. R 2 But hydrogen, C 1 ~C 6 alkyl or R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4- to 7-membered heterocyclyl.

44. R 2 C 1 ~C 6 44. The compound of any one of claims 1 to 43, which is alkyl.

45. R 2 Ga-CH 3 45. The compound of any one of claims 1 to 44, wherein

46. R 2 Ga-CH 2 45. The compound of any one of claims 1 to 44, wherein said compound is OH.

47. R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4- to 7-membered heterocyclyl.

48. R 2 and R 3 48. The compound of claim 47, wherein: taken together with the carbon and nitrogen to which they are respectively attached, form an optionally substituted 4-, 5-, or 6-membered heterocyclyl.

49. R 2 and R 3 49. The compound of claim 47 or 48, wherein, together with the carbon and nitrogen to which they are respectively attached, form an optionally substituted 4-membered heterocyclyl.

50. The following structure (IA1a), (IB1a), (IC1a), (ID1a), (IE1a), (IF1a), (IG1a), or (IH1a):

46. ​​The compound of any one of claims 1 to 45, having one of:

51. The following structure (IA1b), (IB1b), (IC1b), (ID1b), (IE1b), (IF1b), (IG1b), or (IH1b):

46. ​​The compound of any one of claims 1 to 45, having one of:

52. The following structure (IA2a), (IB2a), (IC2a), (ID2a), (IE2a), (IF2a), (IG2a), or (IH2a):

50. The compound of any one of claims 1-43 or 47-49, having one of:

53. The following structure (IA2b), (IB2b), (IC2b), (ID2b), (IE2b), (IF2b), (IG2b), or (IH2b):

50. The compound of any one of claims 1-43 or 47-49, having one of:

54. The following structure (IA3a), (IB3a), (IC3a), (ID3a), (IE3a), (IF3a), (IG3a), or (IH3a):

49. The compound of any one of claims 1-43 or 47-48, having one of:

55. The following structure (IA3b), (IB3b), (IC3b), (ID3b), (IE3b), (IF3b), (IG3b), or (IH3b):

49. The compound of any one of claims 1-43 or 47-48, having one of:

56. The following structure (IA4a), (IB4a), (IC4a), (ID4a), (IE4a), (IF4a), (IG4a), or (IH4a):

49. The compound of any one of claims 1-43 or 47-48, having one of:

57. The following structure (IA4b), (IB4b), (IC4b), (ID4b), (IE4b), (IF4b), (IG4b), or (IH4b):

49. The compound of any one of claims 1-43 or 47-48, having one of:

58. The following structure (IA5a), (IB5a), (IC5a), (ID5a), (IE5a), (IF5a), (IG5a), or (IH5a): and In the formula, R 2a and R 2b are each independently hydrogen or halo; 49. The compound of any one of claims 1-43 or 47-48.

59. The following structure (IA5b), (IB5b), (IC5b), (ID5b), (IE5b), (IF5b), (IG5b), or (IH5b): and In the formula, R 2a and R 2b are each independently hydrogen or halo; 49. The compound of any one of claims 1-43 or 47-48.

60. R 2a and R 2b and R are both halo.

61. R 2a and R 2b 61. The compound of claim 60, wherein each of

62. R 4 62. The compound of any one of claims 1-61, wherein is substituted or unsubstituted aryl.

63. R 4 substituted or unsubstituted C 6 ~C 10 63. The compound of any one of claims 1 to 62, which is aryl.

64. R 4 64. The compound of any one of claims 1-63, wherein is substituted or unsubstituted phenyl.

65. R 4 65. The compound of any one of claims 1-64, wherein is unsubstituted phenyl.

66. R 4 But R 4a , R 4b , R 4c , R 4d , or R 4e and wherein R is a phenyl substituted with one or more of 4a , R 4b , R 4c , R 4d , and R 4e are each independently, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Halo, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , S.R. 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 ,OC(O)R 17 ,OC(O)OR 17 , OC(O)NR 17 R 18 , N.R. 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(=NR 17 )NR 18 R 19 , C(=NOR 17 )NR 18 R 19 , C(=NOC(O)R 17 )NR 18 R 19 , C(=NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(=NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O) 2 R 17 , N(R 17 )S(O) 2 R 18 , S(O) 2 NR 17 R 18 , oxo, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 17 , R 18 , R 19 , and R 20 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 65. The compound of any one of claims 1 to 64.

67. R 4a , R 4b , R 4c , R 4d , or R 4e But substitution C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 4a , R 4b , R 4c , R 4d , or R 4e But, OR 21 , S.R. 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 ,OC(O)R 21 , OC(O)NR 21 R 22 , N.R. 21 R 22 , N.R. 21 C(O)R 22 , N.R. 21 C(O)NR 22 R 23 , N.R. 21 C(O)OR 22 , C(=NR 21 )NR 22 R 23 , N.R. 21 C(=NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O) 2 R 21 , N.R. 21 S(O) 2 R 22 , S(O) 2 NR 21 R 22 and oxo, where R 21 , R 22 , R 23 , and R 24 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 67. The compound of claim 66.

68. R 4 has the following structure:

64. The compound of any one of claims 1 to 63, having one of:

69. R 4 62. The compound of any one of claims 1-61, wherein is substituted or unsubstituted heteroaryl.

70. R 4 70. The compound of any one of claims 1-61 or 69, wherein is a 4-10 membered heteroaryl.

71. R 4 71. The compound of any one of claims 1-61 or 69-70, wherein is unsubstituted 4-10 membered heteroaryl.

72. R 4 But R 4a , R 4b , R 4c , R 4d , or R 4e and R is a 4- to 10-membered heteroaryl substituted with one or more of 4a , R 4b , R 4c , R 4d , and R 4e are each independently, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Halo, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, OR 17 , S.R. 17 , C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 ,OC(O)R 17 ,OC(O)OR 17 , OC(O)NR 17 R 18 , N.R. 17 R 18 , N(R 17 )C(O)R 18 , N(R 17 )C(O)NR 18 R 19 , N(R 17 )C(O)OR 18 , C(=NR 17 )NR 18 R 19 , C(=NOR 17 )NR 18 R 19 , C(=NOC(O)R 17 )NR 18 R 19 , C(=NR 17 )N(R 18 )C(O)OR 19 , N(R 17 )C(=NR 18 )NR 19 R 20 , S(O)R 17 , S(O)NR 17 R 18 , S(O) 2 R 17 , N(R 17 )S(O) 2 R 18 , S(O) 2 NR 17 R 18 , oxo, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 17 , R 18 , R 19 , and R 20 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 62. The compound of any one of claims 1 to 61.

73. R 4a , R 4b , R 4c , R 4d , or R 4e But substitution C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 cycloalkyl, and substituted 4- to 10-membered heterocyclyl, R 4a , R 4b , R 4c , R 4d , or R 4e But, Halo, CN, OR 21 , S.R. 21 , C(O)R 21 , C(O)NR 21 R 22 , C(O)OR 21 ,OC(O)R 21 , OC(O)NR 21 R 22 , N.R. 21 R 22 , N.R. 21 C(O)R 22 , N.R. 21 C(O)NR 22 R 23 , N.R. 21 C(O)OR 22 , C(=NR 21 )NR 22 R 23 , N.R. 21 C(=NR 22 )NR 23 R 24 , S(O)R 21 , S(O)NR 21 R 22 , S(O) 2 R 21 , N.R. 21 S(O) 2 R 22 , S(O) 2 NR 21 R 22 and oxo, where R 21 , R 22 , R 23 , and R 24 Each occurrence of is independently hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 73. The compound of claim 72.

74. R 4 has the following structure:

62. The compound of any one of claims 1 to 61, having one of:

75. R 5 75. The compound of any one of claims 1-74, wherein is hydrogen.

76. R 5 is alkyl, phosphonoalkyl, (CH 2 ) m NR 6 S(O) 2 R 7 , or (CH 2 ) m C(=O)OR 6 75. The compound of any one of claims 1 to 74, wherein:

77. R 5 77. The compound of claim 76, wherein is alkyl.

78. R 5 78. The compound of claim 76 or 77, wherein is methyl.

79. R 5 78. The compound of claim 76 or 77, wherein is ethyl.

80. R 5 (CH 2 ) m C(=O)OR 6 77. The compound of claim 76, wherein:

81. R 5 has the following structure:

81. The compound of claim 76 or 80, having one of:

82. R 5 77. The compound of claim 76, wherein is phosphonoalkyl.

83. R 5 has the following structure:

83. The compound of claim 82, having one of:

84. R 5 (CH 2 ) m NR 6 S(O) 2 R 7 77. The compound of claim 76, wherein:

85. R 5 has the following structure:

85. The compound of claim 84, having the formula:

86. The compound of any one of claims 1 to 85, wherein each occurrence represents a single bond.

87. The compound of any one of claims 1 to 86, wherein at least one occurrence represents a double bond.

88. L 1 88. The compound of any one of claims 1-87, wherein is a direct bond.

89. L 1 88. The compound of any one of claims 1-87, wherein is -O-.

90. L 1 Ga-CH 2 88. The compound of any one of claims 1 to 87, wherein:

91. L 1 Ga-CR 8a R 8b - and R 8a and R 8b together with the carbon to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl.

92. R 8a and R 8b 88. The compound of claim 87, wherein: together with the carbon to which they are attached form an optionally substituted 3-, 4-, or 5-membered cycloalkyl.

93. R 8a and R 8b 88. The compound of claim 87, wherein: together with the carbon to which they are attached form an optionally substituted 3-membered cycloalkyl.

94. 94. The compound of claim 93, wherein the 3-membered cycloalkyl is unsubstituted.

95. A compound having one of the structures in Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

96. 96. A pharmaceutical composition comprising a compound of any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

97. A method for treating a MASP-2-related disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described in any one of claims 1 to 95 or a pharmaceutical composition described in claim 96.

98. The method of claim 97, wherein the compound is administered in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject.

99. 98. The method of claim 97, wherein the subject has been diagnosed with a need for treatment of a lectin complement-associated disease or disorder.

100. 98. The method of claim 97, wherein the disease or disorder is thrombotic microangiopathy (TMA), a renal condition, an inflammatory response due to tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ocular disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, venous occlusive disease, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome, fluid overload, or a combination thereof.

101. 98. The method of claim 97, wherein the disease or disorder is thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), factor H-independent atypical hemolytic uremic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplantation, TMA associated with hematopoietic stem cell transplantation, or a combination thereof.

102. 98. The method of claim 97, wherein the disease or disorder is graft-versus-host disease.

103. 98. The method of claim 97, wherein the disease or disorder is diffuse alveolar hemorrhage (DAH).

104. 98. The method of claim 97, wherein the disease or disorder is veno-occlusive disease (VOD).

105. 98. The method of claim 97, wherein the disease or disorder is a renal condition.

106. 98. The method of claim 97, wherein the renal condition is mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, microimmune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, or a combination thereof.

107. 98. The method of claim 97, wherein the disease or disorder is renal fibrosis, proteinuria, or a combination thereof.

108. 98. The method of claim 97, wherein the disease or disorder is an inflammatory response due to tissue transplantation or solid organ transplantation.

109. 98. The method of claim 97, wherein the disease or disorder is ischemia-reperfusion injury (I / R).

110. 98. The method of claim 97, wherein the disease or disorder is a complication associated with non-obese diabetes, type 1 diabetes, a complication associated with type 2 (adult-onset) diabetes, or a combination thereof.

111. 98. The method of claim 97, wherein the disease or disorder is a cardiovascular disease or disorder.

112. 98. The method of claim 97, wherein the disease or disorder is an inflammatory gastrointestinal disorder.

113. 98. The method of claim 97, wherein the disease or disorder is a pulmonary disorder.

114. 98. The method of claim 97, wherein the disease or disorder is an in vitro exposure-induced inflammatory response.

115. 115. The method of claim 114, further comprising treating a subject undergoing extracorporeal circulation treatment.

116. 98. The method of claim 97, wherein the disease or disorder is inflammatory arthritis, non-inflammatory arthritis, a musculoskeletal disorder, or a combination thereof.

117. 98. The method of claim 97, wherein the disease or disorder is a skin disorder.

118. 98. The method of claim 97, wherein the disease or disorder is a peripheral nervous system (PNS) disorder or injury, a central nervous system (CNS) disorder or injury, or a combination thereof.

119. 98. The method of claim 97, wherein the disease or disorder is sepsis or a septic condition.

120. 98. The method of claim 97, wherein the disease or disorder is a genitourinary disorder.

121. 98. The method of claim 97, wherein the disease or disorder is an inflammatory response in a subject being treated with a chemotherapeutic agent, radiation therapy, or a combination thereof.

122. 98. The method of claim 97, wherein the disease or disorder is an angiogenesis-dependent cancer.

123. 98. The method of claim 97, wherein the disease or disorder is an angiogenesis-dependent benign tumor.

124. 98. The method of claim 97, wherein the disease or disorder is an endocrine disorder.

125. 98. The method of claim 97, wherein the disease or disorder is an ocular disease or disorder.

126. 98. The method of claim 97, wherein the disease or disorder is an intraocular neovascular disease or condition.

127. 98. The method of claim 97, wherein the disease or disorder is disseminated intravascular coagulation (DIC), a complement-mediated coagulopathy, or a combination thereof.

128. 98. The method of claim 97, wherein the disease or disorder is acute radiation syndrome, dense deposit disease, Degos disease, fulminant antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia, paroxysmal nocturnal hemoglobinuria ("PNH"), cold agglutinin disease, or a combination thereof.

129. 98. The method of claim 97, wherein the disease or disorder is atypical hemolytic uremic syndrome (aHUS).

130. 98. The method of claim 97, wherein the disease or disorder is hematopoietic stem cell transplantation-associated TMA.

131. 98. The method of claim 97, wherein the disease or disorder is immunoglobulin A nephropathy (IgAN).

132. 98. The method of claim 97, wherein the disease or disorder is lupus nephritis (LN).

133. R 1 has the following structure:

2. The compound of claim 1, having one of:

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