MASP-2 inhibitors and methods of use

Abstract

The present disclosure provides, inter alia, compounds having MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.

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_422WO_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): TIFF0007721143000001.tif34128In formula, R 1 , R 2 , R 3 , R 4 , R 5a , and R 5b is as defined herein.

[0009] Another aspect provides a compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000002.tif34128In formula, R 1 , R 2 , R 3 , R 4 , R 5a , and R 5b is as defined herein.

[0010] Yet another aspect provides a compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000003.tif44128In formula, R 1 , R 2 , R 3 , R 4 , R 5a , R5b , and n is as defined herein.

[0011] A further aspect of the present disclosure provides a pharmaceutical composition comprising a compound of Structure (I), Structure (II), or Structure (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0012] Compounds of structure (I), (II) and (III) 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), structure (II), or structure (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0013] [The present invention 1001] A compound having the following structure (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000004.tif34128 During the ceremony, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, 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 5a is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR6 , or C(=O)NR 6 R 7 and; R 5b is an electron pair or alkyl; R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; R 8 is alkyl, haloalkyl, aminylalkyl, substituted or unsubstituted arylalkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; however, R 2 and R 3 provided that they do not, together with the carbon and nitrogen to which they are respectively attached, form an optionally substituted 4- to 7-membered heterocyclyl. (A) R 5a is alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 or R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 and is substituted with one or more substituents selected from the group consisting of: (B) R 5a is alkyl or (CH 2 ) n C(=O)OR 6 If R 1 has the following structure: TIFF0007721143000005.tif14128 does not have. [The present invention 1002] R 1 1001. The compound of the present invention, wherein is substituted or unsubstituted aryl. [The present invention 1003] R 1 substituted or unsubstituted C 6 ~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 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 R 1a 、R 1b 、R 1c 、R 1d , and 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, nitro, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR9 ,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 9R 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; 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)R13 , 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, C2~6 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 But, OR 9 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 The compound of any one of 1001 to 1007 of the present invention, which is a phenyl substituted with at least one substituent selected from the group consisting of: [The present invention 1009] R 1 However, C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 The compound of any one of 1001 to 1008 of the present invention, which is substituted with at least one substituent selected from the group consisting of: [The present invention 1010] R 1 However, there is at least one C(=NR 9 )NR 10 R 11 1009 compounds of the present invention, substituted with [The present invention 1011] R 1 But there is at least one -C(=NH)NH 2 The compound of claim 1009 or 1010, wherein the compound is substituted with [The present invention 1012] R 1 But the following structure: TIFF0007721143000006.tif182145 The compound of any one of 1007 to 1011 of the present invention, having one of the following: [The present invention 1013] R 1 But the following structure: TIFF0007721143000007.tif105157 The compound of any one of 1001 to 1012 of the present invention, having one of the following: [The present invention 1014] R 1 But the following structure: TIFF0007721143000008.tif107144 The compound of the present invention 1007, having one of the following: [The present invention 1015] R 9 But C 1~6 Alkyl or C 1~6 1014. The compound of the present invention, which is haloalkyl. [The present invention 1016] R 9 The compound of the present invention 1015, wherein is methyl. [The present invention 1017] R 9 The compound of the present invention 1015, wherein is trifluoromethyl. [The present invention 1018] R 1 The compound of any one of 1001 to 1004 of the present invention, wherein is unsubstituted phenyl. [The present invention 1019] R 1 is a substituted or unsubstituted heteroaryl. [The present invention 1020] R 1 is a substituted or unsubstituted 5- to 10-membered heteroaryl. [The present invention 1021] R 1 The compound of any one of claims 1001 and 1019 to 1020, wherein is substituted or unsubstituted pyridinyl, pyrrolopyridinyl, thiophenyl, or benzimidazolyl. [The present invention 1022] R 1 The compound of any one of claims 1001 and 1019 to 1021, wherein is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl. [The present invention 1023] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl 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, nitro, 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 5-10 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; The compound of the present invention 1001 or any one of 1019 to 1022. [The present invention 1024] 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)NR13 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, C1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1023 of the present invention. [The present invention 1025] R 1 But the following structure: TIFF0007721143000009.tif107149TIFF0007721143000010.tif230148TIFF0007721143000011.tif230145TIFF0007721143000012.tif41142 The compound of any one of 1001 and 1019 to 1023 of the present invention, having one of the following: [The present invention 1026] R 1a or R 1b But independently C 1~6 The compound of the present invention 1025, which is alkyl, amino, or halo. [The present invention 1027] R 1a or R 1b 1026. The compound of claim 1026, wherein is methyl or ethyl. [The present invention 1028] R 1a or R 1b 1026. The compound of claim 1026, wherein is F, Cl, or Br. [The present invention 1029] R attached to nitrogen 1a or R 1b are C 1~6 The compound of the present invention 1025, which is alkyl. [The present invention 1030] R 1a or R 1b The compound of the present invention 1029, wherein is methyl or ethyl. [The present invention 1031] R 1 But the following structure: TIFF0007721143000013.tif49128TIFF0007721143000014.tif226147TIFF0007721143000015.tif192147TIFF0007721143000016.tif47155 The compound of any one of 1001 and 1019 to 1020 of the present invention, having one of the following: [The present invention 1032] R 1 But the following structure: TIFF0007721143000017.tif95146 The compound of any one of 1001 and 1019 to 1020 of the present invention, having one of the following: [The present invention 1033] R 1 1001. A compound of the present invention wherein is substituted or unsubstituted cycloalkyl. [The present invention 1034] R 1 substituted or unsubstituted C 3 ~C 6 The compound of the present invention 1001 or 1033, which is cycloalkyl. [This invention 1035] R 1 But substitution C 3 ~C 6 The compound of any one of 1001 or 1033 to 1034 of the present invention, which is cycloalkyl. [The present invention 1036] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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, C1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, nitro, 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 5-10 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 1035 of the present invention. [This invention 1037] 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; Compound 1036 of the present invention. [The present invention 1038] R 1 But unsubstituted C 3 ~C 6 The compound of the present invention 1034, which is cycloalkyl. [This invention 1039] R 1 1001. A compound of the present invention, wherein is substituted or unsubstituted heterocyclyl. [The present invention 1040] R 1 is a substituted or unsubstituted 4- to 10-membered heterocyclyl. [This invention 1041] R 1 is a substituted 4- to 10-membered heterocyclyl. [The present invention 1042] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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, nitro, 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 R12 , 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 5-10 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 1041 of the present invention. [This invention 1043] 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 C6~10 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; Compound 1042 of the present invention. [This invention 1044] R 1 is unsubstituted 4-10 membered heterocyclyl. [This invention 1045] R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 The compound of any one of 1001 to 1005 of the present invention, which is substituted with one or more substituents selected from the group consisting of: [The present invention 1046] R 1 But the following structure: TIFF0007721143000018.tif18128 1045 compounds of the present invention, substituted with a substituted heteroaryl having one of the following: [This invention 1047] R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 1045. The compound of the present invention, wherein is substituted or unsubstituted arylalkyl. [This invention 1048] R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 But the following structure: TIFF0007721143000019.tif44128 The compound of the present invention 1045 or 1047, having one of the following: [This invention 1049] R 1 However, C(=NOC(=O)R 8 )NH 2 is substituted with R 8 The compound of the present invention 1045, wherein is aminyl alkyl. [The present invention 1050] R 1 However, C(=NOC(=O)R 8 )NH 2 is substituted with R 8 But the following structure: TIFF0007721143000020.tif20128 The compound of the present invention 1045 or 1049, having the formula: [This invention 1051] R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 1045. The compound of the present invention, wherein is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl. [This invention 1052] R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 But the following structure: TIFF0007721143000021.tif16130 The compound of the present invention 1045 or 1051, having one of the following: [This invention 1053] R 1 But C(=NOH)NH 2 1045 compounds of the present invention, substituted with [This invention 1054] R 1 But the following structure: TIFF0007721143000022.tif121146TIFF0007721143000023.tif168140 The compound of any one of 1045 to 1053 of the present invention, which has one of the following: [This invention 1055] R 2 is hydrogen or C 1 ~C 6 The compound of any one of 1001 to 1054 of the present invention, which is alkyl. [The present invention 1056] R 2 C 1 ~C 6 The compound of any one of 1001 to 1055 of the present invention, which is alkyl. [This invention 1057] R 2 Ga-CH 3 The compound of any one of claims 1001 to 1056 of the present invention, [This invention 1058] 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 1059] 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. [The present invention 1060] 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 1061] The following structures (IA1), (IB1), (IC1), (ID1), (IE1), (IF1), (IG1), or (IH1): TIFF0007721143000024.tif150128 The compound of any one of 1001 to 1057 of the present invention, which has one of the following: [The present invention 1062] The following structures (IA2), (IB2), (IC2), (ID2), (IE2), (IF2), (IG2), or (IH2): TIFF0007721143000025.tif154130 The compound of any one of 1001 to 1055 or 1058 to 1060 of the present invention, having one of the following: [This invention 1063] R 4 The compound of any one of claims 1001 to 1062, wherein is substituted or unsubstituted aryl. [This invention 1064] R 4 is substituted or unsubstituted C 6 ~C 10 The compound of any one of 1001 to 1063 of the present invention, which is aryl. [This invention 1065] R 4 The compound of any one of claims 1001 to 1064, wherein is substituted or unsubstituted phenyl. [The present invention 1066] R 4 The compound of any one of claims 1001 to 1065, wherein is unsubstituted phenyl. [This invention 1067] 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 R18 , 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 5-10 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 the compounds 1001 to 1065 of the present invention. [The present invention 1068] 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; Compound 1067 of the present invention. [The present invention 1069] R 4 But the following structure: TIFF0007721143000026.tif26128 The compound of any one of 1001 to 1068 of the present invention, which has one of the following: [The present invention 1070] R 5a is alkyl, C(=O)OR 6 , phosphonoalkyl, or (CH 2 ) n C(=O)OR 6 The compound of any one of claims 1001 to 1069 of the present invention, [This invention 1071] R 5a The compound of the present invention 1070, wherein is alkyl. [This invention 1072] R 5a The compound of claim 1070 or 1071, wherein is methyl. [This invention 1073] R 5a The compound of claim 1070 or 1071, wherein is ethyl. [This invention 1074] R 5a is C(=O)OR 6 The compound of the present invention 1070, [This invention 1075] R 5a But the following structure: TIFF0007721143000027.tif33137 The compound of the present invention 1070 or 1074, having one of the following: [This invention 1076] R 5a The compound of claim 1070, wherein is phosphonoalkyl. [This invention 1077] R 5a But the following structure: TIFF0007721143000028.tif17128 The compound of the present invention 1070 or 1076, having one of the following: [This invention 1078] R 5a (CH 2 ) n C(=O)OR 6 The compound of the present invention 1070, [This invention 1079] R 5a But the following structure: TIFF0007721143000029.tif13128 The compound of the present invention 1070 or 1078, having one of the following: [The present invention 1080] R 5b The compound of any one of claims 1001 to 1079 of the present invention, wherein is an electron pair. [This invention 1081] R 5b The compound of any one of claims 1001 to 1079, wherein is alkyl. [This invention 1082] R 5b C 1 ~C 6 The compound of the present invention 1081, which is alkyl. [This invention 1083] R 5b The compound of the present invention 1082, wherein is methyl. [This invention 1084] A compound having the following structure (II): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000030.tif34128 During the ceremony, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, 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 5a is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 and; R 5b is an electron pair or alkyl; R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; R 8 is alkyl, haloalkyl, aminylalkyl, substituted or unsubstituted arylalkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; however, (A) R 5a is alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 or R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 and is substituted with one or more substituents selected from the group consisting of: (B) The compound of structure (I) has the following structure: TIFF0007721143000031.tif226158 does not have one of the following: [This invention 1085] R 1 The compound of the present invention 1084, wherein is substituted or unsubstituted aryl. [This invention 1086] R 1 is substituted or unsubstituted C 6 ~C 10 The compound of the present invention 1084 or 1085, which is aryl. [This invention 1087] R 1 The compound of any one of claims 1084 to 1086, wherein is substituted or unsubstituted phenyl. [This invention 1088] R 1 The compound of any one of claims 1084 to 1087, wherein is substituted phenyl. [This invention 1089] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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, nitro, 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 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 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; Any of compounds 1084 to 1088 of the present invention. [The present invention 1090] 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 13R 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; Compound 1089 of the present invention. [This invention 1091] R 1 But, OR 9 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 The compound of any one of 1084 to 1090 of the present invention, which is a phenyl substituted with at least one substituent selected from the group consisting of: [This invention 1092] R 1 However, C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 The compound of any one of 1084 to 1091 of the present invention, which is substituted with at least one substituent selected from the group consisting of: [This invention 1093] R1 However, there is at least one C(=NR 9 )NR 10 R 11 1092. A compound of the present invention substituted with [This invention 1094] R 1 But there is at least one -C(=NH)NH 2 The compound of claim 1092 or 1093, wherein the compound is substituted with [This invention 1095] R 1 But the following structure: TIFF0007721143000032.tif180145 The compound of any one of 1090 to 1094 of the present invention, which has one of the following: [This invention 1096] R 1 But the following structure: TIFF0007721143000033.tif107157 The compound of any one of 1090 to 1095 of the present invention, which has one of the following: [This invention 1097] R 1 But the following structure: TIFF0007721143000034.tif107144 The compound of the present invention 1090, having one of the following: [This invention 1098] R 9 But C 1~6 Alkyl or C 1~6 The compound of the present invention 1097, which is haloalkyl. [This invention 1099] R 9 1098. The compound of the present invention, wherein is methyl. [The present invention 1100] R 9 1098. The compound of the present invention, wherein is trifluoromethyl. [The present invention 1101] R 1 The compound of any one of claims 1084 to 1087, wherein is unsubstituted phenyl. [The present invention 1102] R 1 1084. The compound of the present invention, wherein is substituted or unsubstituted heteroaryl. [The present invention 1103] R 1 is a substituted or unsubstituted 5- to 10-membered heteroaryl. [The present invention 1104] R 1 The compound of any one of claims 1084 to 1103, wherein R is a substituted or unsubstituted pyridinyl, pyrrolopyridinyl, thiophenyl, or benzimidazolyl. [This invention 1105] R 1 The compound of any one of claims 1084 and 1102 to 1104, wherein is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl. [The present invention 1106] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl 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, nitro, 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 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 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; The compound of the present invention is any one of compounds 1084 and 1102 to 1103. [This invention 1107] 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 13R 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; Compound 1106 of the present invention. [This invention 1108] R 1 But the following structure: TIFF0007721143000035.tif224149TIFF0007721143000036.tif209144TIFF0007721143000037.tif175145 The compound of any one of 1084 and 1102 to 1106 of the present invention, having one of the following: [This invention 1109] R 1a or R 1b But independently C 1~6 The compound of the present invention 1108, which is alkyl, amino, or halo. [The present invention 1110] R 1a or R 1b The compound of the present invention 1109, wherein is methyl or ethyl. [The present invention 1111] R 1a or R 1b 1109. The compound of claim 1109, wherein is F, Cl, or Br. [The present invention 1112] R attached to nitrogen 1a or R 1b are respectively, C 1~6 The compound of the present invention 1108, which is alkyl. [The present invention 1113] R 1a or R 1b The compound of the present invention 1112, wherein is methyl or ethyl. [This invention 1114] R 1 But the following structure: TIFF0007721143000038.tif173147TIFF0007721143000039.tif216147TIFF0007721143000040.tif126155 The compound of any one of 1084 and 1102 to 1103 of the present invention, having one of the following: [This invention 1115] R 1 But the following structure: TIFF0007721143000041.tif99146 The compound of any one of 1084 and 1102 to 1103 of the present invention, having one of the following: [The present invention 1116] R 1 1084. A compound of the present invention, wherein is substituted or unsubstituted cycloalkyl. [This invention 1117] R 1 substituted or unsubstituted C 3 ~C 6 The compound of the present invention 1084 or 1116, which is cycloalkyl. [This invention 1118] R 1 But substitution C 3 ~C 6 Compounds of any one of 1084 and 1116 to 1117 of the present invention, which are cycloalkyl. [This invention 1119] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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(=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, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, nitro, 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 R12 , 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 5-10 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 1118 of the present invention. [The present invention 1120] 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 C6~10 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 the present invention 1119. [This invention 1121] R 1 But unsubstituted C 3 ~C 6 The compound of the present invention 1117, which is cycloalkyl. [This invention 1122] R 1 1084. A compound of the present invention, wherein is substituted or unsubstituted heterocyclyl. [This invention 1123] R 1 The compound of the present invention 1084 or 1122, wherein is substituted or unsubstituted 4- to 10-membered heterocyclyl. [This invention 1124] R 1 The compound of any one of claims 1084 and 1122 to 1123, wherein is substituted 4- to 10-membered heterocyclyl. [Invention 1125] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and R 1e and R is a 4- to 10-membered heterocyclyl substituted with one or more of 1a 、R1b 、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, nitro, 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 )NR10 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 5-10 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 1124 of the present invention. [The present invention 1126] 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 )NR15 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; Compound 1125 of the present invention. [This invention 1127] R 1 The compound of the present invention 1122, wherein is unsubstituted 4-10 membered heterocyclyl. [This invention 1128] R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 The compound of any one of 1084 to 1088 of the present invention, which is substituted with one or more substituents selected from the group consisting of: [This invention 1129] R 1 But the following structure: TIFF0007721143000042.tif18128 1128 compounds of the present invention, which are substituted with a substituted heteroaryl having one of the following: [The present invention 1130] R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 1128. The compound of the present invention, wherein is substituted or unsubstituted arylalkyl. [This invention 1131] R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 But the following structure: TIFF0007721143000043.tif44128 The compound of the present invention 1128 or 1130, having one of the following: [This invention 1132] R 1 However, C(=NOC(=O)R 8 )NH 2 is substituted with R 8 1128. The compound of the present invention, wherein is aminylalkyl. [This invention 1133] R 1 However, C(=NOC(=O)R 8 )NH 2 is substituted with R 8 But the following structure: TIFF0007721143000044.tif20128 The compound of the present invention 1128 or 1132, [This invention 1134] R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 1128. The compound of the present invention, wherein is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl. [This invention 1135] R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 But the following structure: TIFF0007721143000045.tif16130 The compound of the present invention 1128 or 1134, having one of the following: [This invention 1136] R 1 C(=NOH)NH 2 1128 compounds of the present invention, substituted with [This invention 1137] R 1 But the following structure: TIFF0007721143000046.tif231146TIFF0007721143000047.tif59140 The compound of any one of 1128 to 1136 of the present invention, which has one of the following: [This invention 1138] R 2 is hydrogen or C 1 ~C 6 The compound of any one of claims 1084 to 1137, wherein the compound is alkyl. [This invention 1139] R 2 C 1 ~C 6 The compound of any one of 1084 to 1138 of the present invention, wherein the compound is alkyl. [This invention 1140] R 2 Ga-CH 3 The compound of any one of claims 1084 to 1139 of the present invention, [This invention 1141] 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 1142] 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 1143] R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached to form an optionally substituted 4-membered heterocyclyl. [This invention 1144] The following structures (IIA1), (IIB1), (IIC1), (IID1), (IIE1), (IIF1), (IIG1), or (IIH1): TIFF0007721143000048.tif144128 The compound of any one of 1084 to 1140 of the present invention, which has one of the following: [Invention 1145] The following structures (IIA2), (IIB2), (IIC2), (IID2), (IIE2), (IIF2), (IIG2), or (IIH2): TIFF0007721143000049.tif155130 The compound of any one of 1084 to 1138 or 1141 to 1143 of the present invention, having one of the following: [Invention 1146] R 4 The compound of any one of 1084 to 1145 of the present invention, wherein is substituted or unsubstituted aryl. [This invention 1147] R 4 is substituted or unsubstituted C 6 ~C 10 The compound of any one of 1084 to 1146 of the present invention, which is aryl. [This invention 1148] R 4 The compound of any one of claims 1084 to 1147, wherein is substituted or unsubstituted phenyl. [This invention 1149] R 4 The compound of any one of 1084 to 1148 of the present invention, wherein is unsubstituted phenyl. [This invention 1150] 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)R17 , 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) 2R 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 5-10 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 the compounds 1084 to 1148 of the present invention. [This invention 1151] 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; Compound 1150 of the present invention. [This invention 1152] R 4 But the following structure: TIFF0007721143000050.tif26128 The compound of any one of 1084 to 1151 of the present invention, which has one of the following: [This invention 1153] R 5a is alkyl, C(=O)OR 6 , phosphonoalkyl, or (CH 2 ) n C(=O)OR 6 The compound of any one of claims 1084 to 1152 of the present invention, [This invention 1154] R 5a The compound of the present invention 1153, wherein is alkyl. [This invention 1155] R 5a The compound of the present invention 1153 or 1154, wherein is methyl. [Invention 1156] R 5a The compound of the present invention 1153 or 1154, wherein is ethyl. [This invention 1157] R 5a is C(=O)OR 6 The compound of the present invention 1153, [This invention 1158] R 5a But the following structure: TIFF0007721143000051.tif33137 The compound of the present invention 1153 or 1157, having one of the following: [This invention 1159] R 5a The compound of the present invention 1153, wherein is phosphonoalkyl. [The present invention 1160] R 5a But the following structure: TIFF0007721143000052.tif17128 The compound of the present invention 1153 or 1159, having one of the following: [This invention 1161] R 5a (CH 2 ) n C(=O)OR 6 The compound of the present invention 1153, [This invention 1162] R 5a But the following structure: TIFF0007721143000053.tif13128 The compound of the present invention 1153 or 1161, having one of the following: [This invention 1163] R 5b The compound of any one of claims 1084 to 1162 of the present invention, wherein is an electron pair. [Invention 1164] R 5b The compound of any one of claims 1084 to 1162, wherein is alkyl. [This invention 1165] R 5b C 1 ~C 6 The compound of the present invention 1164, which is alkyl. [Invention 1166] R 5b The compound of the present invention 1165, wherein is methyl. [This invention 1167] A compound having one of the structures in Table 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. [Invention 1168] A compound having the following structure (III): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000054.tif44128 During the ceremony, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, 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 5a and R 5b independently for each occurrence, the structure: TIFF0007721143000055.tif20143 have one of the following: Alternatively, R 5a and R 5b together with the phosphorus atom to which they are attached form an optionally substituted 4- to 7-membered heterocyclyl; R 6a is alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 6b is independently at each occurrence hydrogen or alkyl; R 7 is independently at each occurrence alkyl, haloalkyl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; R 8 is an amino acid side chain; n is 1, 2, 3, 4, 5, 6, 7, or 8. [This invention 1169] R 1 1168. The compound of the present invention, wherein is substituted or unsubstituted aryl. [This invention 1170] R 1 is substituted or unsubstituted C 6 ~C 10 The compound of the present invention 1168 or 1169, which is aryl. [This invention 1171] R 1 The compound of any one of claims 1168 to 1170, wherein is substituted or unsubstituted phenyl. [This invention 1172] R 1 The compound of any one of claims 1168 to 1171, wherein is substituted phenyl. [This invention 1173] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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, nitro, 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(R9 )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 5-10 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; Any of the compounds of the present invention 1168 to 1172. [This invention 1174] 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; Compound 1173 of the present invention. [Invention 1175] R 1 But, OR 9 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 The compound of any one of claims 1168 to 1174 of the present invention, which is a phenyl substituted with at least one substituent selected from the group consisting of: [Invention 1176] R 1 However, C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 The compound of any one of 1168 to 1175 of the present invention, which is substituted with at least one substituent selected from the group consisting of: [This invention 1177] R 1 However, there is at least one C(=NR 9 )NR 10 R 11 1176. A compound of the present invention substituted with: [This invention 1178] R 1 But there is at least one -C(=NH)NH 2 The compound of claim 1176 or 1177, wherein the compound is substituted with [This invention 1179] R 1 But the following structure: TIFF0007721143000056.tif178145 The compound of any one of 1174 to 1178 of the present invention, which has one of the following: [This invention 1180] R 1 But the following structure: TIFF0007721143000057.tif105157 The compound of any one of claims 1168 to 1179 of the present invention, which has one of the following: [This invention 1181] R 1 But the following structure: TIFF0007721143000058.tif110144 The compound of the present invention 1007, having one of the following: [This invention 1182] R 9 But C 1~6 Alkyl or C 1~6 The compound of the present invention 1174, which is haloalkyl. [This invention 1183] R 9 The compound of the present invention 1182, wherein is methyl. [This invention 1184] R 9 The compound of the present invention 1182, wherein is trifluoromethyl. [This invention 1185] R 1 The compound of any one of claims 1168 to 1171, wherein is unsubstituted phenyl. [Invention 1186] R 1 1168. The compound of the present invention, wherein is substituted or unsubstituted heteroaryl. [This invention 1187] R 1 is a substituted or unsubstituted 5- to 10-membered heteroaryl. [This invention 1188] R 1 The compound of any one of claims 1168 to 1187, wherein is substituted or unsubstituted pyridinyl, pyrrolopyridinyl, thiophenyl, or benzimidazolyl. [This invention 1189] R 1 The compound of any one of claims 1168 and 1186 to 1188, wherein is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl. [This invention 1190] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl 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, nitro, 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 5-10 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; The compound of the present invention is any one of compounds 1168 and 1186 to 1189. [This invention 1191] 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)NR14 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; Compound 1190 of the present invention. [This invention 1192] R 1 But the following structure: TIFF0007721143000059.tif133149TIFF0007721143000060.tif227148TIFF0007721143000061.tif207145TIFF0007721143000062.tif41142 The compound of any one of 1168 and 1186 to 1190 of the present invention, having one of the following: [This invention 1193] R 1a or R 1b But independently C 1~6 The compound of the present invention 1192, which is alkyl, amino, or halo. [This invention 1194] R 1a or R 1b is methyl or ethyl. [This invention 1195] R 1a or R 1b 1193. The compound of claim 1193, wherein is F, Cl, or Br. [This invention 1196] R attached to nitrogen 1a or R 1b are respectively, C 1~6 The compound of the present invention 1193, which is alkyl. [This invention 1197] R 1a or R 1b 1196. The compound of the present invention, wherein is methyl or ethyl. [This invention 1198] R 1 But the following structure: TIFF0007721143000063.tif49128TIFF0007721143000064.tif226148TIFF0007721143000065.tif226149 The compound of any one of 1168 and 1186 to 1187 of the present invention, which has one of the following: [This invention 1199] R 1 But the following structure: TIFF0007721143000066.tif95146 The compound of any one of 1168 and 1186 to 1187 of the present invention, which has one of the following: [The present invention 1200] R 1 1001. A compound of the present invention wherein is substituted or unsubstituted cycloalkyl. [The present invention 1201] R 1 substituted or unsubstituted C 3 ~C 6 The compound of claim 1168 or 1200, which is cycloalkyl. [This invention 1202] R 1 But substitution C 3 ~C 6 Compounds of any one of 1168 and 1200 to 1201 of the present invention, which are cycloalkyl. [This invention 1203] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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, nitro, 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 5-10 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 1202 of the present invention. [The present invention 1204] 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)OR13 ,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, C1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1203 of the present invention. [This invention 1205] R 1 But unsubstituted C 3 ~C 6 The compound of the present invention 1201, which is cycloalkyl. [The present invention 1206] R 1 1168. A compound of the invention, wherein is substituted or unsubstituted heterocyclyl. [This invention 1207] R 1 The compound of the present invention 1168 or 1206, wherein is substituted or unsubstituted 4- to 10-membered heterocyclyl. [This invention 1208] R 1 The compound of any one of claims 1168 and 1206 to 1207, wherein is a substituted 4- to 10-membered heterocyclyl. [This invention 1209] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and 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, nitro, 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 NR9 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 1208 of the present invention. [The present invention 1210] 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; Compound 1209 of the present invention. [The present invention 1211] R 1 is unsubstituted 4-10 membered heterocyclyl. [The present invention 1212] R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 The compound of any one of 1168 to 1172 of the present invention, which is substituted with one or more substituents selected from the group consisting of: [This invention 1213] R 1 But the following structure: TIFF0007721143000067.tif18128 The compound of the present invention 1212, which is substituted with a substituted heteroaryl having one of the following: [This invention 1214] R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 The compound of the present invention 1212, wherein is substituted or unsubstituted arylalkyl. [This invention 1215] R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 But the following structure: TIFF0007721143000068.tif44128 The compound of the present invention 1212 or 1214, having one of the following: [This invention 1216] R 1 However, C(=NOC(=O)R8 )NH 2 is substituted with R 8 The compound of the present invention 1212, wherein is aminyl alkyl. [This invention 1217] R 1 However, C(=NOC(=O)R 8 )NH 2 is substituted with R 8 But the following structure: TIFF0007721143000069.tif20128 The compound of the present invention 1212 or 1216, having the formula: [This invention 1218] R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl. [This invention 1219] R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 But the following structure: TIFF0007721143000070.tif16130 The compound of the present invention 1212 or 1218, having one of the following: [The present invention 1220] R 1 But C(=NOH)NH 2 The compound of the present invention 1212, substituted with [This invention 1221] R 1 But the following structure: TIFF0007721143000071.tif231146TIFF0007721143000072.tif59140 The compound of any one of 1212 to 1220 of the present invention, which has one of the following: [This invention 1222] R 2 is hydrogen or C 1 ~C 6 The compound of any one of claims 1168 to 1221 of the present invention, which is alkyl. [This invention 1223] R 2 C 1 ~C 6 The compound of any one of claims 1168 to 1222 of the present invention, which is alkyl. [This invention 1224] R 2 Ga-CH 3 The compound of any one of claims 1168 to 1223 of the present invention, [This invention 1225] 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 1226] 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 1227] 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. [This invention 1228] The following structures (IIIA1), (IIIB1), (IIIC1), (IIID1), (IIIE1), (IIIF1), (IIIG1), or (IIIH1): TIFF0007721143000073.tif185138 The compound of any one of claims 1168 to 1224 of the present invention, which has one of the following: [This invention 1229] The following structures (IIIA2), (IIIB2), (IIIC2), (IIID2), (IIIE2), (IIIF2), (IIIG2), or (IIIH2): TIFF0007721143000074.tif185140 The compound of any one of 1168 to 1222 or 1225 to 1227 of the present invention, which has one of the following. [This invention 1230] R 4 The compound of any one of claims 1168 to 1229 of the present invention, wherein is substituted or unsubstituted aryl. [This invention 1231] R 4 is substituted or unsubstituted C 6 ~C 10 The compound of any one of 1168 to 1230 of the present invention, which is aryl. [This invention 1232] R 4 The compound of any one of claims 1168 to 1231, wherein is substituted or unsubstituted phenyl. [This invention 1233] R 4 The compound of any one of claims 1168 to 1232, wherein is unsubstituted phenyl. [This invention 1234] 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 5-10 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 the compounds 1168 to 1232 of the present invention. [This invention 1235] 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)OR22 , 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; Compound 1234 of the present invention. [This invention 1236] R 4 But the following structure: TIFF0007721143000075.tif26128 The compound of any one of 1168 to 1235 of the present invention, which has one of the following: [This invention 1237] The following structure (IIIa): TIFF0007721143000076.tif48128 The compound of any one of claims 1168 to 1236 of the present invention, [This invention 1238] The following structure (IIIb): TIFF0007721143000077.tif48128 The compound of any one of claims 1168 to 1236 of the present invention, [This invention 1239] The following structure (IIIc): TIFF0007721143000078.tif48128 The compound of any one of claims 1168 to 1236 of the present invention, [This invention 1240] The following structure (IIId): TIFF0007721143000079.tif61128 The compound of any one of claims 1168 to 1236 of the present invention, [This invention 1241] The following structure (IIIe): TIFF0007721143000080.tif53128 and wherein R' is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Any of the compounds 1168 to 1236 of the present invention. [This invention 1242] R 6a is aryl, heteroaryl, cycloalkyl, or heterocyclyl. [This invention 1243] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1242 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. [This invention 1244] A method for treating or preventing a MASP-2-related disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of any of compounds 1001 to 1242 of the present invention or a pharmaceutical composition of compound 1243 of the present invention. [Invention 1245] The method of claim 1244, wherein the compound is administered in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. [Invention 1246] The method of claim 1169, wherein said subject has been diagnosed with a condition in need of treatment for a lectin complement-associated disease or disorder. [This invention 1247] The method of claim 1244, 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. [Invention 1248] 1244. The method of claim 1244, 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. [Invention 1249] The method of claim 1244, wherein the disease or disorder is graft-versus-host disease. [This invention 1250] The method of claim 1244, wherein the disease or disorder is diffuse alveolar hemorrhage (DAH). [This invention 1251] The method of claim 1244, wherein the disease or disorder is veno-occlusive disease (VOD). [This invention 1252] The method of claim 1244, wherein the disease or disorder is a renal condition. [This invention 1253] The method of claim 1244, 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. [Invention 1254] The method of claim 1244, wherein the disease or disorder is renal fibrosis, proteinuria, or a combination thereof. [Invention 1255] The method of claim 1244, wherein the disease or disorder is an inflammatory response due to tissue transplantation or solid organ transplantation. [Invention 1256] The method of claim 1244, wherein the disease or disorder is ischemia-reperfusion injury (I / R). [Invention 1257] The method of claim 1244, 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. [Invention 1258] The method of claim 1244, wherein the disease or disorder is a cardiovascular disease or disorder. [Invention 1259] The method of claim 1244, wherein the disease or disorder is an inflammatory gastrointestinal disorder. [This invention 1260] The method of claim 1244, wherein the disease or disorder is a pulmonary disorder. [This invention 1261] The method of claim 1244, wherein the disease or disorder is an in vitro exposure-induced inflammatory response. [This invention 1262] The method of claim 1261, further comprising treating a subject undergoing extracorporeal circulation treatment. [This invention 1263] The method of claim 1244, wherein the disease or disorder is inflammatory arthritis, non-inflammatory arthritis, a musculoskeletal disorder, or a combination thereof. [Invention 1264] The method of claim 1244, wherein the disease or disorder is a skin disorder. [Invention 1265] The method of claim 1244, 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. [Invention 1266] The method of claim 1244, wherein the disease or disorder is sepsis or a septic state. [Invention 1267] The method of claim 1244, wherein the disease or disorder is a genitourinary disorder. [Invention 1268] The method of claim 1244, wherein the disease or disorder is an inflammatory response in a subject being treated with a chemotherapeutic agent, radiation therapy, or a combination thereof. [Invention 1269] The method of claim 1244, wherein the disease or disorder is an angiogenesis-dependent cancer. [Invention 1270] The method of claim 1244, wherein the disease or disorder is an angiogenesis-dependent benign tumor. [This invention 1271] The method of claim 1244, wherein the disease or disorder is an endocrine disorder. [This invention 1272] The method of claim 1244, wherein the disease or disorder is an ocular disease or disorder. [This invention 1273] The method of claim 1244, wherein the disease or disorder is an intraocular neovascular disease or condition. [Invention 1274] The method of claim 1244, wherein the disease or disorder is disseminated intravascular coagulation (DIC), a complement-mediated coagulopathy, or a combination thereof. [Invention 1275] The method of the present invention 1244, 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. [Invention 1276] The method of claim 1244, wherein the disease or disorder is atypical hemolytic uremic syndrome (aHUS). [Invention 1277] The method of claim 1244, wherein the disease or disorder is hematopoietic stem cell transplantation-associated TMA. [Invention 1278] The method of claim 1244, wherein the disease or disorder is immunoglobulin A nephropathy (IgAN). [This invention 1279] The method of claim 1244, wherein the disease or disorder is lupus nephritis (LN). These and other aspects, objects and embodiments will become more apparent from the following detailed description and drawings. DETAILED DESCRIPTION OF THE INVENTION

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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."

[0018] 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.

[0019] 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

[0020] The term "MASP-2-dependent complement-associated disease or disorder" refers to a disease or disorder associated with MASP-2-dependent complement activation.

[0021] 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.

[0022] 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).

[0023] 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.

[0024] 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).

[0025] 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.

[0026] 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.

[0027] 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.

[0028] "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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The term "subcutaneous administration" refers to administration of a formulation below all layers of a subject's skin.

[0033] The term "histidine" specifically includes L-histidine unless otherwise specified.

[0034] 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.

[0035] The term "hypertonic" refers to a formulation whose osmolality is higher than that of humans (ie, greater than 350 mOsm / L).

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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)).

[0041] 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.

[0042] 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).

[0043] The group "A or B" is equivalent to the group "selected from the group consisting of A and B."

[0044] 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.

[0045] The term "hypertonic" refers to a formulation having an osmolality greater than that of humans (ie, greater than 350 mOsm / KglHhO).

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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 (but not be limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0050] 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.

[0051] "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 ".

[0052] 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 or piperidinyl are examples of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0053] "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)R102 , -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.

[0054] "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 R102 (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.

[0055] "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.

[0056] "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.

[0057] 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.

[0058] "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.

[0059] "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.

[0060] "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.

[0061] "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: TIFF0007721143000081.tif24128

[0062] "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.

[0063] "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).

[0064] "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).

[0065] "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.

[0066] "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.

[0067] "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.

[0068] "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.

[0069] "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.

[0070] "Sulfide" refers to the group =S.

[0071] "Amino" refers to the group -NH2.

[0072] "Carbamyl" refers to the group -C(O)NH2.

[0073] "Carboxy" refers to the group --C(O)OH.

[0074] "Carbonyl" refers to the group C(=O), which may also be written as C(O).

[0075] "Cyano" or "nitrile" refers to the group -C≡N, which may also be written as -CN.

[0076] "Nitro" refers to the -NO2 group.

[0077] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0078] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0079] "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.

[0080] 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.

[0081] "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.

[0082] "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.

[0083] "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: TIFF0007721143000082.tif23128

[0084] "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.

[0085] "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.

[0086] The compounds and methods of the present disclosure are also meant to encompass all pharmaceutically acceptable compounds of structures (I), (II), and (III) that are isotopically labeled by replacing one or more atoms with an atom having a different atomic mass or mass number.

[0087] 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 Radiolabeled compounds 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), (II), or (III), 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.

[0088] 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, a compound of structure (I), (II), or (III) 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.

[0089] 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), (II), or (III) 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.

[0090] 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.

[0091] "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.

[0092] "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.

[0093] 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.

[0094] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0095] "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.

[0096] "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.

[0097] Crystallization often produces solvates of the disclosed compounds (e.g., compounds of structure (I), (II), or (III)). 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.

[0098] 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.

[0099] 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:

[0100] 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).

[0101] 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.

[0102] "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).

[0103] "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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] The following abbreviations may be used herein and, unless otherwise specified, have the meanings indicated below: μ (micro); °C (degrees Celsius); Ac (acetyl); ACN (acetonitrile); anhyd (anhydrous); aq (aqueous solution); atm (atmosphere); Bn (benzyl); Boc (tert-butoxycarbonyl); Bu (butyl); calcd (calculated value); Cbz (benzyloxycarbonyl); chrom.(chromatography); CPME (cyclopentyl methyl ether); CHCl(dichloromethane); concd (concentrated); conc (concentration); DCC(N,N'-dicyclohexylcarbodiimide); DIAD (diisopropyl azodicarboxylate); 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); EtO (diethyl ether); g (gram); h (hour); 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); HOBt (1-hydroxybenzotriazole hydrate); L (liter); m (milli); m- (meta); M (molar concentration); MeCN (acetonitrile); min (minute); mL (milliliter); mol (mole; molecule (as in "molecular weight (mol wt)")); Ms (methanesulfonyl); MS (mass spectrometry); MW (molecular weight); NBS (N-bromosuccinimide); NCS (N-chlorosuccinimide); NIS (N-iodosuccinimide); NHS (N-hydroxysuccinimide); NMM (4-methylmorpholine); NMR (nuclear magnetic resonance); o- (ortho); obsd (observed); p- (para); Ph (phenyl); Phth (phthalimide); ppt (precipitate); Pr (propyl); psi (pounds per square inch); temp (temperature); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TPP (triphenylphosphine); and Tr (trityl). Other abbreviations may be used and have meanings that will be understood by those skilled in the art.

[0111] II. compound In certain aspects, the present disclosure provides compounds of structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000083.tif34128In formula, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, 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 5a is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH2) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 and; R 5b is an electron pair or alkyl; R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; R 8 is alkyl, haloalkyl, aminylalkyl, substituted or unsubstituted arylalkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; however, R 2 and R 3 provided that they do not, together with the carbon and nitrogen to which they are respectively attached, form an optionally substituted 4- to 7-membered heterocyclyl. (A) R 5a is alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH2) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 or R 1 is substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 )NH2, and C(=NOH)NH2; (B) R 5a is alkyl or (CH2) n C(=O)OR 6 If R 1 has the following structure: Does not have TIFF0007721143000084.tif14128.

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

[0113] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1eand phenyl substituted with one or more of the following, where R 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, nitro, 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)2R9 , 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, and heteroaryl.

[0114] In certain embodiments, 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)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.

[0115] In some embodiments, R 1 is OR 9 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 In certain embodiments, R is phenyl substituted with at least one substituent selected from the group consisting of 1 is C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 In some more specific embodiments, R 1 must contain at least one C(=NR 9 )NR 10 R 11 In some more specific embodiments, R 1 is substituted with at least one -C(=NH)NH2.

[0116] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721143000085.tif181145.

[0117] In certain embodiments, R 1 has the following structure: I have one of the following: TIFF0007721143000086.tif105154.

[0118] In some more specific embodiments, R 1 has the following structure: I have one of the following: TIFF0007721143000087.tif107141.

[0119] In some of the foregoing embodiments, R 9 is C 1~6 Alkyl or C 1~6 In certain more particular embodiments, R 9 is methyl. In some specific embodiments, R 9 is trifluoromethyl.

[0120] In certain embodiments, R 1 is unsubstituted phenyl.

[0121] In certain other 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, pyrrolopyridinyl, thiophenyl, or benzimidazolyl. In some more specific embodiments, R 1 is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl.

[0122] In certain embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl 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, nitro, 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 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0123] In some embodiments, 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)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.

[0124] In some embodiments, R 1 has the following structure: It has one of the following: TIFF0007721143000088.tif57149TIFF0007721143000089.tif227148TIFF0007721143000090.tif209145TIFF0007721143000091.tif115142.

[0125] In some embodiments, R 1a or R 1b independently, C 1~6 In certain embodiments, R is alkyl, amino, or halo. 1a or R 1b is methyl or ethyl. In some more specific embodiments, R 1a or R 1b is F, Cl, or Br. In some embodiments, each R attached to a nitrogen 1a or R 1bis C 1~6 In some more specific embodiments, R 1a or R 1b is methyl or ethyl. In certain more specific embodiments, R 1 has the following structure: It has one of the following: TIFF0007721143000092.tif49128TIFF0007721143000093.tif226147TIFF0007721143000094.tif192147TIFF0007721143000095.tif47153

[0126] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721143000096.tif95146.

[0127] In certain embodiments, R 1 is substituted or unsubstituted cycloalkyl. In certain embodiments, R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some more specific embodiments, R 1 is a substituted C3-C6 cycloalkyl.

[0128] In some more specific embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1e and C3-C6 cycloalkyl 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 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, nitro, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR9 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 1~6Alkyl, 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.

[0129] In some embodiments, 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.

[0130] In some embodiments, R 1 is an unsubstituted C3-C6 cycloalkyl.

[0131] In certain embodiments, R 1 is substituted or unsubstituted heterocyclyl. In some more specific embodiments, R 1 is a substituted or unsubstituted 4-10 membered heterocyclyl. In certain more specific embodiments, R 1 is a substituted 4- to 10-membered heterocyclyl.

[0132] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and 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 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Halo, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, nitro, 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 6~10Arylalkoxy, 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.

[0133] In certain embodiments, 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 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 14R 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.

[0134] In some embodiments, R 1 is unsubstituted 4-10 membered heterocyclyl. In certain embodiments, R 1 is substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 In some more specific embodiments, R is substituted with one or more substituents selected from the group consisting of C(=NOH)NH, and C(=NOH)NH. 1 is substituted with a substituted heteroaryl having one of the following structures: TIFF0007721143000097.tif18128

[0135] In some embodiments, R 1 is C(=NH)NHC(=O)OR 8 is substituted with R 8 is substituted or unsubstituted arylalkyl. In certain embodiments, R 1 is C(=NH)NHC(=O)OR 8 is substituted with R 8 has one of the following structures: TIFF0007721143000098.tif44128

[0136] In some embodiments, R 1 is C(=NOC(=O)R 8 ) substituted with NH2 and R 8 is aminylalkyl. In certain more specific embodiments, R 1 is C(=NOC(=O)R 8 ) substituted with NH2 and R 8 has the following structure: TIFF0007721143000099.tif20128

[0137] In certain embodiments, R 1 is C(=NOC(=O)OR 8 ) substituted with NH2 and R 8 is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl. In some embodiments, R 1 is C(=NOC(=O)OR 8 ) substituted with NH2 and R 8 has one of the following structures: TIFF0007721143000100.tif16130

[0138] In some more specific embodiments, R 1 is substituted with C(=NOH)NH. In some embodiments, R 1 has one of the following structures: TIFF0007721143000101.tif231146TIFF0007721143000102.tif59140

[0139] In some embodiments, R 2 is hydrogen or C1-C6 alkyl. In certain embodiments, R 2 is C1-C6 alkyl. In some more specific embodiments, R 2 is -CH3.

[0140] 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.

[0141] In some embodiments, the compound has one of the following structures: (IA1), (IB1), (IC1), (ID1), (IE1), (IF1), (IG1), or (IH1). TIFF0007721143000103.tif151128

[0142] In some embodiments, the compound has one of the following structures: (IA2), (IB2), (IC2), (ID2), (IE2), (IF2), (IG2), or (IH2). TIFF0007721143000104.tif158130

[0143] In some 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 4is substituted or unsubstituted phenyl. In certain embodiments, R 4 is unsubstituted phenyl.

[0144] In some more specific embodiments, R 4 is 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)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.

[0145] 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.

[0146] In some embodiments, R 4has one of the following structures: TIFF0007721143000105.tif145148

[0147] In some embodiments, R 4 has one of the following structures: TIFF0007721143000106.tif26128

[0148] In some embodiments, R 5a is alkyl, C(=O)OR 6 , phosphonoalkyl, or (CH2) n C(=O)OR 6 In certain embodiments, R 5a is alkyl. In some particular embodiments, R 5a is methyl. In certain more specific embodiments, R 5a is ethyl. In some embodiments, R 5a is C(=O)OR 6 In some more specific embodiments, R 5a has one of the following structures: TIFF0007721143000107.tif33137

[0149] In certain embodiments, R 5a is phosphonoalkyl. In some particular embodiments, R 5a has one of the following structures: TIFF0007721143000108.tif17128

[0150] In certain embodiments, R 5a (CH2) n C(=O)OR 6 In some more specific embodiments, R 5a has one of the following structures: TIFF0007721143000109.tif13128

[0151] In certain specific embodiments, R 5b is an electron pair. In other embodiments, R 5bis alkyl (e.g., C1-C6 alkyl). In some embodiments, R 5b is methyl.

[0152] A further embodiment provides a compound having the following structure (II): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000110.tif34128In formula, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, 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 5a is hydrogen, alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH2) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 and; R 5b is an electron pair or alkyl; R 6 and R 7 is independently at each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, or arylalkyl; R 8is alkyl, haloalkyl, aminylalkyl, substituted or unsubstituted arylalkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; however, (A) R 5a is alkyl, haloalkyl, cycloalkyl, phosphonoalkyl, (CH2) n C(=O)OR 6 , C(=O)R 6 , C(=O)OR 6 , or C(=O)NR 6 R 7 or R 1 is substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 )NH2, and C(=NOH)NH2; (B) Compounds of structure (I) have the following structure: It does not have one of TIFF0007721143000111.tif222158.

[0153] In some embodiments, R 1 is substituted or unsubstituted aryl. In certain embodiments, R 1 is substituted or unsubstituted C6-C 10 In some more specific embodiments, R 1 is substituted or unsubstituted phenyl. In certain more specific embodiments, R 1 is a substituted phenyl.

[0154] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1e and wherein R is a phenyl substituted with one or more of 1a , R 1b , R 1c , R 1d , and R 1eare 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, nitro, 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 6~10Aryl, 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.

[0155] In certain embodiments, 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 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.

[0156] In some embodiments, R 1 is OR 9 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10C(O)OR 11 In certain embodiments, R is phenyl substituted with at least one substituent selected from the group consisting of 1 is C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 In some more specific embodiments, R 1 has at least one C(=NR 9 )NR 10 R 11 In some more specific embodiments, R 1 is substituted with at least one -C(=NH)NH2.

[0157] In some embodiments, R 1 has one of the following structures: TIFF0007721143000112.tif182145

[0158] In certain embodiments, R 1 has one of the following structures: TIFF0007721143000113.tif106157

[0159] In some more specific embodiments, R 1 has one of the following structures: TIFF0007721143000114.tif107143

[0160] In some of the above embodiments, R 9 is C 1~6 Alkyl or C 1~6 In certain more particular embodiments, R 9is methyl. In some particular embodiments, R 9 is trifluoromethyl.

[0161] In certain embodiments, R 1 is unsubstituted phenyl.

[0162] In certain other 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, pyrrolopyridinyl, thiophenyl, or benzimidazolyl. In some more specific embodiments, R 1 is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl.

[0163] In certain embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl 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, nitro, 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 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 1~6Alkoxy, 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.

[0164] In some embodiments, 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 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.

[0165] In some embodiments, R 1 has one of the following structures: TIFF0007721143000115.tif57149TIFF0007721143000116.tif227148TIFF0007721143000117.tif209145TIFF0007721143000118.tif115142

[0166] In some embodiments, R 1a or R 1b is independently C 1~6 In certain embodiments, R is alkyl, amino, or halo. 1a or R 1b is methyl or ethyl. In some more specific embodiments, R 1a or R 1b is F, Cl, or Br. In some embodiments, the R bonded to the nitrogen 1a or R 1b are C 1~6 In some more specific embodiments, R 1a or R 1b is methyl or ethyl. In certain more specific embodiments, R 1has one of the following structures: TIFF0007721143000119.tif49128TIFF0007721143000120.tif226148TIFF0007721143000121.tif222149

[0167] In some embodiments, R 1 has one of the following structures: TIFF0007721143000122.tif95146

[0168] In certain embodiments, R 1 is substituted or unsubstituted cycloalkyl. In certain embodiments, R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some more specific embodiments, R 1 is a substituted C3-C6 cycloalkyl.

[0169] In some more specific embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and 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, nitro, 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(R9 )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.

[0170] In some embodiments, R 1a , R 1b , R 1c , R 1d , or R 1e is a 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)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.

[0171] In some embodiments, R 1 is an unsubstituted C3-C6 cycloalkyl.

[0172] In certain embodiments, R 1 is substituted or unsubstituted heterocyclyl. In some more specific embodiments, R 1 is substituted or unsubstituted 4-10 membered heterocyclyl. In certain more specific embodiments, R 1 is a substituted 4- to 10-membered heterocyclyl.

[0173] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and 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, nitro, 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 12are 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.

[0174] In certain embodiments, 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 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.

[0175] In some embodiments, R 1 is unsubstituted 4-10 membered heterocyclyl. In certain embodiments, R 1 is substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 In some more specific embodiments, R is substituted with one or more substituents selected from the group consisting of C(=NOH)NH, and C(=NOH)NH. 1 is substituted with a substituted heteroaryl having one of the following structures: TIFF0007721143000123.tif18128

[0176] In some embodiments, R 1 is C(=NH)NHC(=O)OR 8 is substituted with R 8 is substituted or unsubstituted arylalkyl. In certain embodiments, R 1 is C(=NH)NHC(=O)OR8 is substituted with R 8 has one of the following structures: TIFF0007721143000124.tif44128

[0177] In some embodiments, R 1 is C(=NOC(=O)R 8 ) substituted with NH2 and R 8 is aminylalkyl. In certain more specific embodiments, R 1 is C(=NOC(=O)R 8 ) substituted with NH2 and R 8 has the following structure: TIFF0007721143000125.tif20128

[0178] In certain embodiments, R 1 is C(=NOC(=O)OR 8 ) substituted with NH2 and R 8 is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl. In some embodiments, R 1 is C(=NOC(=O)OR 8 ) substituted with NH2 and R 8 has one of the following structures: TIFF0007721143000126.tif16130

[0179] In some more specific embodiments, R 1 is substituted with C(=NOH)NH2. In some embodiments, R 1 has one of the following structures: TIFF0007721143000127.tif82146TIFF0007721143000128.tif208140

[0180] In some embodiments, R 2 is hydrogen or C1-C6 alkyl. In certain embodiments, R 2 is C1-C6 alkyl. In some more specific embodiments, R 2 is -CH3.

[0181] 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.

[0182] In some embodiments, the compound has one of the following structures: (IA1), (IB1), (IC1), (ID1), (IE1), (IF1), (IG1), or (IH1). TIFF0007721143000129.tif144128

[0183] In some embodiments, the compound has one of the following structures: (IA2), (IB2), (IC2), (ID2), (IE2), (IF2), (IG2), or (IH2). TIFF0007721143000130.tif154130

[0184] In some 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.

[0185] In some more specific embodiments, R 4 is R 4a , R 4b , R 4c , R4d , 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)2R 17 , N(R 17 )S(O)2R 18 , S(O)NR 17 R18 , 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.

[0186] 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 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.

[0187] In some embodiments, R 4 has one of the following structures: TIFF0007721143000131.tif149148

[0188] In some embodiments, R 4 has one of the following structures: TIFF0007721143000132.tif26128

[0189] In some embodiments, R 5a is alkyl, C(=O)OR 6 , phosphonoalkyl, or (CH2) n C(=O)OR 6 In certain embodiments, R 5a is alkyl. In some particular embodiments, R 5a is methyl. In certain more specific embodiments, R 5a is ethyl. In some embodiments, R 5a is C(=O)OR 6 In some more specific embodiments, R 5a has one of the following structures: TIFF0007721143000133.tif33137

[0190] In certain embodiments, R 5a is phosphonoalkyl. In some particular embodiments, R 5a has one of the following structures: TIFF0007721143000134.tif17128

[0191] In certain embodiments, R 5a (CH2) n C(=O)OR 6 In some more specific embodiments, R 5a has one of the following structures: TIFF0007721143000135.tif13128

[0192] In certain specific embodiments, R 5b is an electron pair. In other embodiments, R 5b is alkyl (e.g., C1-C6 alkyl). In some embodiments, R 5b is methyl.

[0193] Yet another embodiment provides a compound having the following structure (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721143000136.tif44128In formula, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2 is hydrogen, alkyl, alkoxy, haloalkyl, 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 5a and R 5b has, independently at each occurrence, one of the following structures: TIFF0007721143000137.tif20143; Alternatively, R 5a and R 5b together with the phosphorus atom to which they are attached form an optionally substituted 4- to 7-membered heterocyclyl; R 6a is alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; R 6b is independently at each occurrence hydrogen or alkyl; R 7 is independently at each occurrence alkyl, haloalkyl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; R 8 is an amino acid side chain; n is 1, 2, 3, 4, 5, 6, 7, or 8.

[0194] In some embodiments, R 1 is substituted or unsubstituted aryl. In certain embodiments, R 1 is substituted or unsubstituted C6-C 10 In some more specific embodiments, R 1 is substituted or unsubstituted phenyl. In certain more specific embodiments, R 1 is a substituted phenyl.

[0195] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and 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, nitro, 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)R10 , 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.

[0196] In certain embodiments, R 1a , R 1b , R 1c , R 1d , or R 1e is a 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)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.

[0197] In some embodiments, R 1 is OR 9 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 In certain embodiments, R is phenyl substituted with at least one substituent selected from the group consisting of 1 is C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , and C(=NR 9 )NR 10 C(O)OR 11 In some more specific embodiments, R 1 has at least one C(=NR 9 )NR 10 R11 In some more specific embodiments, R 1 is substituted with at least one -C(=NH)NH2.

[0198] In some embodiments, R 1 has one of the following structures: TIFF0007721143000138.tif181145

[0199] In certain embodiments, R 1 has one of the following structures: TIFF0007721143000139.tif105157

[0200] In some more specific embodiments, R 1 has one of the following structures: TIFF0007721143000140.tif107144

[0201] In some of the above embodiments, R 9 is C 1~6 Alkyl or C 1~6 In certain more particular embodiments, R 9 is methyl. In some particular embodiments, R 9 is trifluoromethyl.

[0202] In certain embodiments, R 1 is unsubstituted phenyl.

[0203] In certain other 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, pyrrolopyridinyl, thiophenyl, or benzimidazolyl. In some more specific embodiments, R 1is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl.

[0204] In certain embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, thiophen-2-yl, or 1H-benzo[d]imidazol-6-yl 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, nitro, 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(=NR9 )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, and heteroaryl.

[0205] In some embodiments, R 1a , R 1b , R 1c , R 1d , or R 1e is a 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 C3~10 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 1~6 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.

[0206] In some embodiments, R 1 has one of the following structures: TIFF0007721143000141.tif57149TIFF0007721143000142.tif227148TIFF0007721143000143.tif209145TIFF0007721143000144.tif115142

[0207] In some embodiments, R 1a or R 1b is independently C 1~6 In certain embodiments, R is alkyl, amino, or halo. 1a or R 1b is methyl or ethyl. In some more specific embodiments, R 1a or R 1b is F, Cl, or Br. In some embodiments, the R bonded to the nitrogen 1a or R 1b are C 1~6 In some more specific embodiments, R 1a or R 1b is methyl or ethyl. In certain more specific embodiments, R 1 has one of the following structures: TIFF0007721143000145.tif49128TIFF0007721143000146.tif226147TIFF0007721143000147.tif192147TIFF0007721143000148.tif47155

[0208] In some embodiments, R 1 has one of the following structures: TIFF0007721143000149.tif95146

[0209] In certain embodiments, R 1is substituted or unsubstituted cycloalkyl. In certain embodiments, R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some more specific embodiments, R 1 is a substituted C3-C6 cycloalkyl.

[0210] In some more specific embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and 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, nitro, 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(R10 )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, and heteroaryl.

[0211] In some embodiments, R 1a , R 1b , R 1c , R 1d , or R 1e is a 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 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 1~6 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.

[0212] In some embodiments, R 1 is an unsubstituted C3-C6 cycloalkyl.

[0213] In certain embodiments, R 1 is substituted or unsubstituted heterocyclyl. In some more specific embodiments, R 1 is substituted or unsubstituted 4-10 membered heterocyclyl. In certain more specific embodiments, R 1 is a substituted 4- to 10-membered heterocyclyl.

[0214] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and 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, nitro, 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 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0215] In certain embodiments, R 1a , R1b , 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 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, C2~6 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.

[0216] In some embodiments, R 1 is unsubstituted 4-10 membered heterocyclyl. In certain embodiments, R 1 is substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 In some more specific embodiments, R is substituted with one or more substituents selected from the group consisting of C(=NOH)NH, and C(=NOH)NH. 1 is substituted with a substituted heteroaryl having one of the following structures: TIFF0007721143000150.tif18128

[0217] In some embodiments, R 1 is C(=NH)NHC(=O)OR 8 is substituted with R 8 is substituted or unsubstituted arylalkyl. In certain embodiments, R 1 is C(=NH)NHC(=O)OR 8 is substituted with R 8 has one of the following structures: TIFF0007721143000151.tif44128

[0218] In some embodiments, R 1 is C(=NOC(=O)R 8 ) substituted with NH2 and R 8 is aminylalkyl. In certain more specific embodiments, R 1 is C(=NOC(=O)R 8 ) substituted with NH2 and R8 has the following structure: TIFF0007721143000152.tif20128

[0219] In certain embodiments, R 1 is C(=NOC(=O)OR 8 ) substituted with NH2 and R 8 is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl. In some embodiments, R 1 is C(=NOC(=O)OR 8 ) substituted with NH2 and R 8 has one of the following structures: TIFF0007721143000153.tif16130

[0220] In some more specific embodiments, R 1 is substituted with C(=NOH)NH2. In some embodiments, R 1 has one of the following structures: TIFF0007721143000154.tif231146TIFF0007721143000155.tif59140

[0221] In some embodiments, R 2 is hydrogen or C1-C6 alkyl. In certain embodiments, R 2 is C1-C6 alkyl. In some more specific embodiments, R 2 is -CH3.

[0222] 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 3taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4-membered heterocyclyl.

[0223] In some embodiments, the compound has one of the following structures: (IIIA1), (IIIB1), (IIIC1), (IIID1), (IIIE1), (IIIF1), (IIIG1), or (IIIH1). TIFF0007721143000156.tif191138

[0224] In certain specific embodiments, the compound has one of the following structures: (IIIA2), (IIIB2), (IIIC2), (IIID2), (IIIE2), (IIIF2), (IIIG2), or (IIIH2). TIFF0007721143000157.tif189140

[0225] In some 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 some embodiments, R 4 is unsubstituted phenyl.

[0226] In some more specific embodiments, R 4 is 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 1~6Haloalkyl, 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 3~10cycloalkyl, 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.

[0227] 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)OR22 , 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.

[0228] In some embodiments, R 4 has one of the following structures: TIFF0007721143000158.tif149148

[0229] In some particular embodiments, R 4 has one of the following structures: TIFF0007721143000159.tif26128

[0230] In certain specific embodiments, the compound has the following structure (IIIa): TIFF0007721143000160.tif48128

[0231] In another embodiment, the compound has the following structure (IIIb): TIFF0007721143000161.tif48128

[0232] In yet another embodiment, the compound has the following structure (IIIc): TIFF0007721143000162.tif48128

[0233] In some embodiments, the compound has the following structure (IIId): TIFF0007721143000163.tif61128

[0234] In certain embodiments, the compound has the following structure (IIIe): TIFF0007721143000164.tif53128In formula, R' is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0235] In some of the above embodiments, R 6a is aryl, heteroaryl, cycloalkyl, or heterocyclyl.

[0236] In some embodiments, compounds of structure (I), (II), or (III) and embodiments thereof may be in the form of a salt, such as a pharmaceutically acceptable salt.

[0237] Compounds of structure (I), (II), or (III), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. Compounds of structure (I), (II), or (III), 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), (II), or (III), or an embodiment thereof, optionally in the form of a salt.

[0238] In some embodiments, structure (I), (II), or (III), or embodiments 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.

[0239] In certain aspects, the compound is one or more selected from compounds of structure (I), (II) or (III) (e.g., compounds having selectivity for MASP-2 over thrombin) described in the Examples, including the compounds listed in Table 1. In certain aspects, one or more of the variables defining a compound of structure (I), (II) or (III) are selected from the corresponding substituents in compounds of structure (I), (II) or (III) in the Examples, including the compounds listed in Table 1, preferably compounds having selectivity for MASP-2 over thrombin.

[0240] 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.

[0241] 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).

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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).

[0247] 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 13 C), 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).

[0248] 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.

[0249] 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.

[0250] 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.

[0251] IV. Treatment 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.

[0252] 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), (II), or (III) according to any of the preceding embodiments.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.).

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] In some embodiments, the method comprises 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), (II), or (III)) 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.

[0289] 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.

[0290] 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.

[0291] 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), (II), or (III)) 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.

[0292] 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), (II), or (III)) 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.

[0293] In some embodiments, the subject requires anticoagulant therapy, and the MASP-2 inhibitory compound (e.g., a compound of structure (I), (II), or (III)) is used as a substitute for standard anticoagulant therapy (e.g., warfarin). In some embodiments, the subject has a condition in 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.

[0294] 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.

[0295] 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).

[0296] 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.

[0297] 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.

[0298] V. Composition, Dosage, and Administration The compounds described herein (e.g., compounds of structure (I), (II), or (III)) 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 that accompany the administration of the compound in a particular individual.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] The compounds described herein (e.g., compounds of structure (I), (II) or (III)) can be administered to a subject in need of treatment using methods known in the art, such as by oral administration or injection. Injection may be, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular. As described herein, parenteral formulations 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 containing a predetermined amount of active compound calculated to produce the desired therapeutic effect.

[0303] 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), (II), or (III)) 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.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] Dosage forms for topical or transdermal administration of the compounds disclosed in the foregoing embodiments (e.g., compounds of structure (I), (II), or (III)) 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.

[0310] 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.

[0311] 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.

[0312] In general, the compounds (e.g., compounds of structure (I), (II), or (III)) are administered alone or in combination with one or more other therapeutic agents in a therapeutically effective amount via any of the usual and acceptable modes 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.

[0313] 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.

[0314] In certain embodiments, a therapeutic amount or dose of a compound (e.g., a compound of structure (I), (II), or (III)) 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.

[0315] 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.

[0316] However, it will be understood that the total daily usage of the compounds (e.g., compounds of structure (I), (II), or (III)) 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 time of administration, route of administration, and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors well known in the medical field.

[0317] 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.

[0318] 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)). [Example]

[0319] The following examples are offered by way of illustration only, and not by way of limitation. Those of ordinary skill in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially similar results.

[0320] basic method 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 noncritical parameters that can be changed or modified to yield essentially similar results.

[0321] Unless otherwise stated, chromatography refers to flash chromatography performed on silica gel.

[0322] Amine column refers to flash chromatography performed on a Redisep Rf Gold high performance amine column.

[0323] An alternative method for HPLC purification is to use a UV / MS detector (254 nm and 280 nm) and an XBridge Prep (19 × 50 mm) C 18The analysis was performed on a Waters preparative reverse-phase HPLC system coupled with a 10 μM OBD column. The eluent was a mixture of water and acetonitrile (containing 0.1% trifluoroacetic acid). The flow rate was typically 50 mL / min, with a linear gradient of 15–40%, 25–50%, or 5–30% water in acetonitrile over 8 min. Injection volumes ranged from 0.2 to 1 mL, with a maximum of 20 mg per load.

[0324] 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

[0325] Example 1 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-15) TIFF0007721143000165.tif34128 Process 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) 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 stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and 10% KHSO solution. The organic layer was separated, washed with H2O and saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by chromatography (10% EtOAc-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).

[0326] TIFF0007721143000166.tif35149 Process 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). The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give benzyl ((2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetate (201 mg, 100% yield).

[0327] TIFF0007721143000167.tif42149 Process 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. After adding diethyl (2-bromoethyl)phosphonate (0.2 mL), the reaction mixture was stirred at 50 °C for 2 hours, during which time the reaction was monitored by LCMS. The crude reaction mixture was quenched with water, extracted with EtOAc (2 x 20 mL), and the crude product was dissolved in MeOH solution. To the solution was added 10% Pd / C, and the reaction mixture was stirred under an H2 atmosphere for 1 hour. The crude reaction mixture was filtered over Celite®, washed with MeOH, 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.

[0328] TIFF0007721143000168.tif47149 Process 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 the solution was stirred for 1 h, followed by the addition of 1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (32 mg, 0.22 mmol). The resulting mixture was sonicated and stirred at room temperature overnight. After filtration through a Celite® bed, the solution was evaporated to dryness and the crude material was purified by flash chromatography using an amine column eluted with EtOAc to give 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.

[0329] TIFF0007721143000169.tif45145 Process 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). The reaction mixture was stirred at 40° C. for 3 h, during which time the reaction was monitored by TLC. Upon completion, the reaction mixture was slowly quenched with MeOH (2 mL) at 0° C. The solvent was evaporated under reduced pressure and the crude material was purified by preparative 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.

[0330] Example 2 Preparation of benzyl (imino(4-(((S)-2-((2R,4S)-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate ditrifluoroacetate (compound I-32)

[0331] TIFF0007721143000170.tif20147 Process 1 To a stirred solution of (tert-butoxycarbonyl)-L-alanine (1.23 g, 6.52 mmol) in DCM (125 mL) was added DCC (1.48 g, 7.17 mmol) and NHS (825 mg, 7.17 mmol). The suspension was stirred at room temperature for 1 h and then added to a suspension of benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride (2.5 g, 7.82 mmol) in saturated aqueous NaHCO (125 mL). After stirring the reaction mixture at room temperature for 1 h, the aqueous layer was separated and extracted with DCM (2 x 60 mL). The organic layers were combined, dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a 0-100% hexane / EtOAc gradient to give benzyl (S)-((4-((2-((tert-butoxycarbonyl)amino)propanamido)methyl)phenyl)(imino)methyl)carbamate (2.0 g, 56% yield).

[0332] TIFF0007721143000171.tif22132 Process 2 To benzyl (S)-((4-((2-((tert-butoxycarbonyl)amino)propanamido)methyl)phenyl)(imino)methyl)carbamate (1.0 g, 2.15 mmol) was added 6 M HCl in IPA (11 mL). The solution was stirred at room temperature for 2 hours, after which the reaction was judged complete by TLC. The solution was concentrated under reduced pressure to give benzyl (S)-((4-((2-((tert-butoxycarbonyl)amino)propanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride (540 mg, 64%) as a white solid.

[0333] TIFF0007721143000172.tif31147 Process 3 To a stirred solution of benzyl (S)-((4-((2-((tert-butoxycarbonyl)amino)propanamido)methyl)phenyl)(imino)methyl)carbamate (1.27 g, 3.24 mmol), (2R,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-2-carboxylic acid (900 mg, 2.95 mmol) in DMF (10 mL) was added EDC (622 mg, 3.29 mmol), HOBt (570 mg, 3.24 mmol), and DIEA (700 μL). The reaction was stirred at room temperature overnight. The solution was diluted with EtOAc (100 mL) and washed with water (4×60 mL) and saturated aqueous NH4Cl (80 mL). After drying over MgSO4, the solution was filtered, concentrated in vacuo, and the crude material was purified by flash chromatography using a 0-100% heptane / EtOAc gradient to give tert-butyl (2R,4S)-2-(((S)-1-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (905 mg, 48% yield).

[0334] TIFF0007721143000173.tif31147 Process 4 To a 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 (22 mg, 0.035 mmol) in DCM (3 mL) was added TFA (500 μL). The mixture was stirred at room temperature for 90 minutes, and then the solution was concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using a 15% to 40% gradient to give benzyl (imino(4-(((S)-2-((2R,4S)-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate ditrifluoroacetate (10 mg, 44%) as a white solid.

[0335] Example 3 Preparation 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 (compound I-12) TIFF0007721143000174.tif37150 To a stirred solution of benzyl (imino(4-(((S)-2-((2R,4S)-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate (100 mg, 0.14 mmol) in DCM (2 mL) and NEt3 (0.8 mL) under Ar atmosphere was added the bromoester (0.2 mL). After stirring at room temperature for 24 h, the reaction mixture was concentrated and purified using an amine column eluted with EtOAc to give ethyl acetate. 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) was obtained as a white solid.

[0336] Example 4 Preparation of ethyl 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (Compound I-13) 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) and 10% Pd / C was stirred under an atmosphere of H for 2 hours. Upon reaction completion, the mixture was filtered through Celite® and washed with MeOH. The organic residue was concentrated under reduced pressure to afford ethyl 3-((2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-1-yl)propanoate (43 mg, 100% yield) as a white solid.

[0337] Example 5 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-14) TIFF0007721143000176.tif41147 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) in THF (2 mL) at room temperature was added a solution of LiOH (15 mg) in 2 mL of water. After stirring at room temperature for 18 hours, the reaction mixture was acidified with TFA and purified by reverse-phase 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.

[0338] Example 6 Preparation of (2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-1,1-dimethyl-4-phenylpiperidin-1-ium 2,2,2-trifluoroacetate trifluoroacetate (Compound I-10) To a stirred solution of benzyl (imino(4-(((S)-2-((2R,4S)-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)methyl)carbamate trifluoroacetate (50 mg, 0.068 mmol) in DCM (2 mL) and NEt (0.1 mL) under an Ar atmosphere was added methyl iodide (0.048 mL, 0.8 mmol). After stirring at room temperature for 18 h, the reaction mixture was concentrated and purified through an amine column eluted with EtOAc. The residue was dissolved in MeOH, and the resulting solution was added 10% Pd / C and stirred under an H atmosphere for 30 min. The crude reaction was filtered over Celite, washed with MeOH, and the washings were concentrated in vacuo and purified by reverse phase HPLC to afford (2R,4S)-2-(((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-1,1-dimethyl-4-phenylpiperidin-1-ium 2,2,2-trifluoroacetate trifluoroacetate (15 mg, 33% yield over two steps) as a white solid.

[0339] Example 7 Preparation of (2R,4S)-N-((S)-1-(((5-((Z)-N'-hydroxycarbamimidoyl)thiophen-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide hydrochloride (compound I-24) TIFF0007721143000178.tif37151 Process 1 A solution of ((2R,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-2-carbonyl)-L-alanine (100 mg, 0.27 mmol) and DCC (60 mg, 0.29 mmol) in DCM (6 mL) was stirred at room temperature for 1 h. The resulting slurry was then added to a suspension of 5-(aminomethyl)thiophene-2-carbonitrile hydrochloride (60 mg, 0.33 mmol) in saturated aqueous NaHCO3 (6 mL), and the mixture was stirred at room temperature for 1 h. The mixture was partitioned, and the aqueous portion was extracted with DCM (3 x 40 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash chromatography (SiO, 12 g) using a gradient of 0–100% heptane / ethyl acetate to afford tert-butyl (2R,4S)-2-(((S)-1-(((5-cyanothiophen-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (130 mg, 97%) as an off-white solid.

[0340] TIFF0007721143000179.tif36149 Process 2 To a suspension of tert-butyl (2R,4S)-2-(((S)-1-(((5-cyanothiophen-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.2 mmol) and hydroxylamine hydrochloride (56 mg, 0.8 mmol) in methanol (2 mL) was added DIEA (139 μL, 0.8 mmol). The mixture was heated to 69° C. and stirred at this temperature overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with water (5 mL), and the solid was collected by filtration. The solid was washed with water (2×5 mL) and dried under vacuum to give tert-butyl (2R,4S)-2-(((S)-1-(((5-((Z)-N′-hydroxycarbamimidoyl)thiophen-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (100 mg, 94%) as an off-white solid.

[0341] TIFF0007721143000180.tif44146 Process 3 To tert-butyl (2R,4S)-2-(((S)-1-(((5-((Z)-N'-hydroxycarbamimidoyl)thiophen-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (30 mg, 0.057 mmol), hydrochloric acid (6 M in IPA, 3 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give (2R,4S)-N-((S)-1-(((5-((Z)-N'-hydroxycarbamimidoyl)thiophen-2-yl)methyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide hydrochloride (18 mg, 68%) as an off-white solid.

[0342] Example 8 Preparation of (2R,4S)-N-((S)-1-((4-((Z)-N'-hydroxycarbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (compound I-30) TIFF0007721143000181.tif28147 Process 1 A solution of ((2R,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-2-carbonyl)-L-alanine and DCM (6 mL) was stirred at room temperature for 1 h. The resulting slurry was then added to a suspension of 5-(aminomethyl)phenyl-carbonitrile hydrochloride (60 mg, 0.33 mmol) in saturated aqueous NaHCO3 (6 mL), and the mixture was stirred at room temperature for 1 h. The mixture was partitioned, and the aqueous portion was extracted with DCM (3 x 40 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash chromatography (SiO2, 12 g) using a gradient of 0-100% heptane / EtOAc to give the desired product.

[0343] TIFF0007721143000182.tif36147 Process 2 To a suspension of tert-butyl (2R,4S)-2-(((S)-1-((4-cyanobenzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate and hydroxylamine hydrochloride in methanol was added DIEA. The mixture was heated to 69°C and stirred at this temperature overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated in water (5 mL) and the solid was collected by filtration. The solid was washed with water (2 x 5 mL) and dried under reduced pressure to give tert-butyl (2R,4S)-2-(((S)-1-((4-((Z)-N'-hydroxycarbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate.

[0344] TIFF0007721143000183.tif37148 Process 3 A solution of tert-butyl (2R,4S)-2-(((S)-1-((4-((Z)-N'-hydroxycarbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate in 6 M HCl / IPA (1 mL) was stirred at room temperature for 1.5 hours. The reaction was concentrated, and the residue was purified by preparative HPLC to give the desired compound.

[0345] Example 9 Preparation of (2R,4S)-N-((2S)-1-((4-((Z)-N'-((((2-ethylhexyl)oxy)carbonyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (Compound I-1) TIFF0007721143000184.tif46148 Process 1 To a stirred solution of tert-butyl (2R,4S)-2-(((S)-1-((4-((Z)-N'-hydroxycarbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (see Example 8, Step 2) (28 mg, 0.053 mmol) in DCM (2.5 mL) was added DIEA (0.2 mL) followed by 2-ethylhexyl chloroformate (0.1 mL), and the resulting solution was stirred at room temperature for 15 minutes. After the reaction was determined to be complete by LCMS, the reaction was quenched with MeOH and the solution was concentrated to dryness. The residue was purified by chromatography (100% EtOAc eluting from the column) to give tert-butyl (2R,4S)-2-(((2S)-1-((4-((Z)-N'-((((2-ethylhexyl)oxy)carbonyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (20 mg, 56% yield) as a white solid.

[0346] TIFF0007721143000185.tif44146 Process 2 To a stirred solution of tert-butyl (2R,4S)-2-(((2S)-1-((4-((Z)-N'-((((2-ethylhexyl)oxy)carbonyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (20 mg, 0.029 mmol) in DCM (2 mL) was added TFA (0.4 mL). The resulting solution was stirred at room temperature until complete as determined by LCMS. The crude solution was concentrated and purified by reverse phase HPLC to give (2R,4S)—N-((2S)-1-((4-((Z)-N′-((((2-ethylhexyl)oxy)carbonyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide bistrifluoroacetate (11 mg, 55% yield) as a white solid.

[0347] The following compounds were synthesized in a similar manner as described in Step 1 of Example 9 using the appropriate chloroformate, followed by deprotection as described for Step 2 of Example 9. TIFF0007721143000186.tif94150

[0348] Example 14 Preparation of (2R,4S)-N-((S)-1-((4-((Z)-N'-((L-valyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide dihydrochloride (compound I-7) TIFF0007721143000187.tif39151 Process 1 The synthesis of tert-butyl (2R,4S)-2-(((S)-1-((4-((Z)-N'-(((tert-butoxycarbonyl)-L-valyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate was obtained by following Step 4 of the procedure described in Example 1.

[0349] TIFF0007721143000188.tif39152 Process 2 A procedure similar to that used in Step 3 of Example 8 was used, except the desired compound was obtained without further purification by preparative HPLC to afford (2R,4S)—N-((S)-1-((4-((Z)-N′-((L-valyl)oxy)carbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide dihydrochloride (5 mg, 58% yield) as a white solid.

[0350] Example 15 Preparation of (2R,4S)-N-((S)-1-oxo-1-((4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (compound I-5) To a stirred solution of tert-butyl (2R,4S)-2-(((S)-1-((4-((Z)-N'-hydroxycarbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (Step 2 of Example 8) (30 mg, 0.057) in dioxane (1 mL) was added CDI (46 mg, 0.29 mmol). The reaction mixture was stirred at 100°C for 30 minutes, at which point it was determined to be complete by LCMS. The residue was passed through a silica plug using EtOAc as the eluent. After concentration under reduced pressure, the isolated material was treated using Step 4 of the conditions described in Example 2 to give the desired product (2R,4S)—N-((S)-1-oxo-1-((4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (10 mg, 31% yield over two steps).

[0351] Example 16 Preparation of (2R,4S)-N-((S)-1-oxo-1-((4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (Compound I-11) TIFF0007721143000190.tif38144 Using the procedure described for the synthesis of Example 15, but substituting thio-CDI for CDI, the synthesis of (2R,4S)—N-((S)-1-oxo-1-((4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate was obtained (6 mg, 18% yield over two steps).

[0352] Example 17 Preparation of (2R,4S)-N-((S)-1-oxo-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (compound I-30) TIFF0007721143000191.tif36148 To a solution of tert-butyl (2R,4S)-2-(((S)-1-((4-((Z)-N'-hydroxycarbamimidoyl)benzyl)amino)-1-oxopropan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (50 mg, 0.095) in anhydrous THF (5 mL) cooled to ice bath temperature was added trifluoroacetic anhydride (40 μL, 0.28 mmol). The reaction mixture was allowed to warm to room temperature over 2 h, at which point it was judged complete by TLC. The reaction mixture was further diluted with DCM, washed with cold saturated NaHCO3 solution, dried over Na2SO4, and then concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO) using a 0-100% heptane / EtOAc gradient to afford tert-butyl (2R,4S)-2-(((S)-1-oxo-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (34 mg, 60% yield). The isolated intermediate was deprotected using Step 4 of the conditions described in Example 2 to afford the title compound (19 mg, 55%).

[0353] Example 18 Preparation of (2R,4S)-1-ethyl-N-((S)-1-oxo-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (compound I-8) TIFF0007721143000192.tif37149 To a stirred solution of (2R,4S)—N—((S)-1-oxo-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (60 mg, 0.097 mmol) from Example 17 in DCM (2 mL) and NEt3 (0.3 mL) was added ethyl bromide (0.3 mL) under an Ar atmosphere. After stirring at room temperature for 18 hours, the reaction mixture was concentrated and purified using reverse-phase HPLC to give (2R,4S)-1-ethyl-N-((S)-1-oxo-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)-4-phenylpiperidine-2-carboxamide trifluoroacetate (16 mg, 26% yield) as a white solid.

[0354] Example 19 Preparation of ethyl (2R,4S)-2-(((S)-1-oxo-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)propan-2-yl)carbamoyl)-4-phenylpiperidine-1-carboxylate (compound I-25) TIFF0007721143000193.tif34148 Using the procedure described for the synthesis of Example 18, but substituting ethyl chloroformate for ethyl bromide as a reactant, the desired product (11.1 mg, 69%) was obtained.

[0355] The following compounds were synthesized in a similar manner as described in Example 18 using the appropriate chloroformate. TIFF0007721143000194.tif70150

[0356] Example 24 Preparation of (2R,4S)-N-((S)-1-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)-1-oxopropan-2-yl)-1-ethyl-4-phenylpiperidine-2-carboxamide trifluoroacetate (compound I-9) TIFF0007721143000195.tif36148 Using the procedure described for the synthesis of Example 17, but substituting 2,2-difluoroacetic anhydride for trifluoroacetic anhydride as a reactant, the desired compound was obtained (15 mg, 44% yield).

[0357] Example 25 Preparation of benzyl ((4-(((S)-2-((2R,4S)-1-ethyl-4-phenylpiperidine-2-carboxamido)propanamido)methyl)phenyl)(imino)methyl)carbamate (compound I-20) TIFF0007721143000196.tif34148 Using the procedure described for the synthesis of Example 3, but substituting ethyl bromide for the bromoester as a reactant, the desired compound was obtained (62 mg, 98% yield).

[0358] Example 26 Preparation of (2R,4S)-N-((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-1-ethyl-4-phenylpiperidine-2-carboxamide (Compound I-21) A solution of (2R,4S)—N—((S)-1-((4-carbamimidoylbenzyl)amino)-1-oxopropan-2-yl)-1-ethyl-4-phenylpiperidine-2-carboxamide (31 mg, 0.05 mmol) and 10% Pd / C (15 mg, 50 wt%) in anhydrous MeOH (550 μL, 0.1 M) was stirred under an atmosphere of H for approximately 30 minutes, at which point it was determined to be complete by LCMS. The reaction mixture was filtered through Celite®, washed with MeOH, and the filtrate was concentrated under reduced pressure to afford di-tert-butyl (2R,4R)-4-(4-fluorophenyl)-6-oxopiperidine-1,2-dicarboxylate (12.2 mg, 51% yield) as a white solid powder after lyophilization.

[0359] Example 27 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)-1-ethylpiperidine-2-carboxamide (Compound I-22) TIFF0007721143000198.tif35128 Process 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 DCM (140 mL, 0.25 M) at 0 °C, DMAP (6.3 g, 52 mmol) was added, followed by EDC (10 g, 52 mmol). The reaction temperature was maintained at 0 °C for 1 h and then allowed to warm to room temperature. Upon completion as determined by TLC, the reaction mixture was washed with 1 N KHSO 4 , dried over sodium sulfate, concentrated, and thoroughly dried under reduced pressure. The crude mixture was then dissolved in anhydrous toluene (350 mL, 0.1 M) and heated to reflux. Upon reaction completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford di-tert-butyl (R)-4,6-dioxopiperidine-1,2-dicarboxylate as a pale yellow solid (10.34 g, 95% yield).

[0360] TIFF0007721143000199.tif35128 Process 2 To a solution of di-tert-butyl (R)-4,6-dioxopiperidine-1,2-dicarboxylate (10.34 g, 33 mmol) in anhydrous DCM (110 mL) was added N-phenyl-bis(trifluoromethanesulfonimide) (14 g, 40 mmol) followed by DIEA (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 a 5–20% EtOAc / heptane gradient 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% yield).

[0361] TIFF0007721143000200.tif50128 Process 3 To a solution of di-tert-butyl (R)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1,2(2H)-dicarboxylate (300 mg, 0.67 mmol), (3-(1H-pyrazol-1-yl)phenyl)boronic acid (270 mg, 1 mmol), and bis(triphenylphosphine)palladium(II) chloride (24 mg, 0.03 mmol) in THF (17 mL) was added potassium carbonate solution (2 N aqueous, 10 mL). The solution was sparged with argon for 10 minutes and then heated to 40° C. Upon completion, the reaction mixture was cooled to room temperature, diluted with EtOAc, and partitioned. The organic solvent was dried over sodium sulfate, concentrated, and purified on a silica column using a 20-100% EtOAc / heptane gradient to give di-tert-butyl (R)-4-(3-(1H-pyrazol-1-yl)phenyl)-6-oxo-3,6-dihydropyridine-1,2(2H)-dicarboxylate as a white solid, which was carried forward without further purification.

[0362] TIFF0007721143000201.tif50128 Process 4 A solution of di-tert-butyl (R)-4-(3-(1H-pyrazol-1-yl)phenyl)-6-oxo-3,6-dihydropyridine-1,2(2H)-dicarboxylate (0.67 mmol) and 10% Pd / C (60 mg, 20 wt%) in EtOAc (3.5 mL) and MeOH (1 mL) was stirred under an atmosphere of H at 40° C. overnight.

[0363] The reaction mixture was filtered through a Celite® bed, washed thoroughly with MeOH, and then concentrated under reduced pressure to give di-tert-butyl (2R,4R)-4-(3-(1H-pyrazol-1-yl)phenyl)-6-oxopiperidine-1,2-dicarboxylate (245 mg, 82% yield) as a white solid.

[0364] TIFF0007721143000202.tif50128 Process 5 To a solution of di-tert-butyl (2R,4R)-4-(4-fluorophenyl)-6-oxopiperidine-1,2-dicarboxylate (245 mg, 0.55 mmol) in anhydrous THF (3.4 mL) was added dropwise borane-dimethyl sulfide in THF (2 M, 1.4 mL, 2.8 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature overnight and then cooled to 0 °C. The reaction mixture was quenched by the addition of MeOH (1 mL). After stirring for 10 min, the reaction mixture was concentrated and the crude material was purified on a silica column using a 0-40% EtOAc / heptane gradient to give di-tert-butyl (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)piperidine-1,2-dicarboxylate (196 mg, 83% yield over two steps) as a white solid.

[0365] TIFF0007721143000203.tif41128 Process 6 To di-tert-butyl (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)piperidine-1,2-dicarboxylate (196 mg, 0.46 mmol) was added 4 M HCl in dioxane (2.3 mL). The reaction mixture was stirred until the reaction was complete as determined by LCMS. Upon completion, the reaction mixture was concentrated, and the crude material was dissolved in a solution consisting of THF (920 μL) and 1 N aqueous sodium hydroxide (1.8 mL). Boc anhydride (105 mg, 0.48 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was acidified with 1 M potassium hydrogen sulfate, extracted three times with EtOAc, and the organic layer was concentrated under reduced pressure to afford (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (168 mg, 98% yield over two steps) as a white solid.

[0366] TIFF0007721143000204.tif31128 Process 7 Using steps 1 and 4 of the procedure described in Example 2, tert-butyl (S)-(1-((5-chloro-2-(1H-tetrazol-1-yl)benzyl)amino)-1-oxopropan-2-yl)carbamate trifluoroacetate was synthesized (3.54 g, 76% yield over two steps).

[0367] TIFF0007721143000205.tif39148 Process 8 To a solution of (2R,4S)-4-(3-(1H-pyrazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)...

Claims

1. A compound having the following structure (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: During the ceremony, R 1 is a substituted aryl or a substituted or unsubstituted heteroaryl, wherein the heteroaryl is selected from the group consisting of: R 2 is -CH3; R 3 is hydrogen; or R 2 and R 3 taken together with the carbon and nitrogen to which they are respectively attached form an unsubstituted or substituted 4-membered heterocyclyl; R 4 has the following structure: having one of: R 5a is hydrogen, alkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) n C(=O)OR 6 , or C(=O)OR 6 and R 5b is an electron pair or alkyl; R 6 is hydrogen, alkyl, haloalkyl, or arylalkyl; R 8 is alkyl, haloalkyl, aminylalkyl, or substituted or unsubstituted arylalkyl; n is 1, 2, or 3; however, R 2 and R 3 unless they, taken together with the carbon and nitrogen to which they are respectively attached, form an unsubstituted or substituted 4-membered heterocyclyl. (A) R 5a is an alkyl, cycloalkyl, phosphonoalkyl, (CH 2 ) n C(=O)OR 6 , or C(=O)OR 6 or R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 and is substituted with one or more substituents selected from the group consisting of: (B) R 5a is alkyl or (CH 2 ) n C(=O)OR 6 If R 1 has the following structure: does not have.

2. R 1 2. The compound of claim 1, wherein is substituted phenyl.

3. R 1 has the following structure:

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

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

5. R 1 is a substituted heteroaryl, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , and C(=NOH)NH 2 2. The compound of claim 1, substituted with one or more substituents selected from the group consisting of:

6. R 1 C(=NH)NHC(=O)OR 8 is substituted with R 8 6. The compound of claim 5, wherein is substituted or unsubstituted arylalkyl.

7. R 1 However, C(=NOC(=O)R 8 )NH 2 is substituted with R 8 6. The compound of claim 5, wherein is aminylalkyl.

8. R 1 But C(=NOC(=O)OR 8 )NH 2 is substituted with R 8 6. The compound of claim 5, wherein is alkyl, haloalkyl, or substituted or unsubstituted arylalkyl.

9. R 1 has the following structure:

6. The compound of claim 5, having one of:

10. R 2 and R 3 10. The compound of claim 1, wherein: is taken together with the carbon and nitrogen to which they are respectively attached to form an unsubstituted or substituted 4-membered heterocyclyl.

11. R 5a is alkyl, C(=O)OR 6 , phosphonoalkyl, or (CH 2 ) n C(=O)OR 6 2. The compound of claim 1, wherein:

12. R 5a has the following structure:

12. The compound of claim 11, having one of:

13. R 5b 2. The compound of claim 1, wherein is an electron pair.

14. R 5b 2. The compound of claim 1, wherein is alkyl.

15. The following structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

16. 16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

17. A pharmaceutical composition for treating a MASP-2-associated disease or disorder in a subject in need thereof, comprising an effective amount of a compound described in any one of claims 1 to 15 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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