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 form in lieu of hard copy and is hereby incorporated by reference. The text file name containing the sequence listing is 700128_421WO_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): TIFF0007721142000001.tif45128In formula, R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , and n is as defined herein.

[0009] Another aspect provides a compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000002.tif45128In formula, R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , and n is as defined herein.

[0010] Another aspect provides a compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000003.tif43128In formula, R 25 , R 26a , R 26b , R27 , R 28 , and p is as defined herein.

[0011] A further aspect of the present disclosure provides a pharmaceutical composition comprising a compound of structure (I), (II) or (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), (II) or (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: TIFF0007721142000004.tif45128 During the ceremony, R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i , and R 2j are each independently hydrogen, halo, or C(=O)OR 5 , OC(=O)R 5 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 5 R6 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , N.R. 5 C(=O)NR 6 , S(O) t , S.R. 5 , nitro, N(R 5 )C(O)OR 6 , C(=NR 5 )NR 6 R 7 , N(R 5 )C(=NR 6 )NR 7 R 8 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , N(R 5 )S(O) 2 R 6 , S(O) 2 NR 5 R 6 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i , and R 2j At least one of the is not hydrogen; R3 is NR 3a R 3b and; R 3a and R 3b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH 2 ) n C(=O)OR 6 , or (CH 2 ) n P(=O)(OR 6 ) 2 or R 3a and R 3b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; or R 3a and R 4 together with the nitrogen and carbon to which they are respectively attached to form an optionally substituted 4- to 7-membered heterocyclyl, and R 3b is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH 2 ) n C(=O)OR 6 , or (CH 2 ) n P(=O)(OR 6 ) 2 and; R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl when n is 2, 3, 4, 5, or 6; or R 4 is a substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted heterocyclyl when n is 0 or 1; or R 4 and R 3a taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl; R 5 、R 6 、R 7 , and R 8 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; X is a direct bond, -CR 2e R 2f - or -CR 2e R 2f -CR 2g R2h - and; Y is a direct bond or -CR 2i R 2j - and; n is an integer from 0 to 6; and t is an integer of 0 to 3. [The present invention 1002] R 1 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 claims 1001 to 1003, wherein is substituted or unsubstituted phenyl. [The present invention 1005] R 1 The compound of any one of 1001 to 1004 of the present invention, wherein is substituted phenyl. [The present invention 1006] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and R 1e and 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 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)R9 , 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) 2R 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 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 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 , 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 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 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 )NR10 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 But 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: TIFF0007721142000005.tif173148 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: TIFF0007721142000006.tif85156 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: TIFF0007721142000007.tif58128 1007. A compound of the present invention 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, 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 to 1020, wherein is substituted or unsubstituted pyridinyl, pyrrolopyridinyl, 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, 1H-pyrrolo[3,2-c]pyridin-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, 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) 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 C6~10 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 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 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 , 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 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 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: TIFF0007721142000008.tif104148TIFF0007721142000009.tif228148TIFF0007721142000010.tif213143TIFF0007721142000011.tif81129 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 independently C 1~6 Alkyl, amino, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , OC(O)NR 9 R 10 1025. The compound of claim 1025, wherein the compound is a halogen atom or halo. [The present invention 1027] R 1a or R 1b 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 Each one is C 1~6 Alkyl, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , or OC(O)NR 9 R 10 The compound of the present invention 1025, [The present invention 1030] R 1a or R 1b is methyl or ethyl. [The present invention 1031] R 1 But the following structure: TIFF0007721142000012.tif124156 The compound of any one of 1001 or 1019 to 1020 of the present invention, having one of the following: [The present invention 1032] R 1 But the following structure: TIFF0007721142000013.tif94143 The compound of any one of 1001 or 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, 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 R11 , 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 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, C1~6 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 , 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 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 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] R1 is a substituted or unsubstituted 4- to 10-membered heterocyclyl. [The present 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 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 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 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 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 R15 , 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 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 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] The following structure: TIFF0007721142000014.tif152128TIFF0007721142000015.tif154128 The compound of any one of 1001 to 1044 of the present invention, having one of the following: [The present invention 1046] R 2a 、R 2b 、R 2c , and R 2d At least one of the groups is alkoxy, alkoxyalkyl, cyano, halo, C(=O)OR 5 , OC(=O)R 5 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 5 ) heterocyclyl, where R 5 and R 6 is independently hydrogen or C in each occurrence. 1 ~C 6 The compound of any one of 1001 to 1045 of the present invention, which is alkyl. [This invention 1047] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of is methoxy. [This invention 1048] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of the groups is methoxymethyl. [This invention 1049] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of the groups is cyano. [The present invention 1050] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of the groups is -C(=O)OH. [This invention 1051] R 2a 、R 2b 、R 2c , and R 2d At least one of the following is -C(=O)OCH 3 or -OC(=O)CH 3 The compound of any one of claims 1001 to 1046 of the present invention, [This invention 1052] R 2a 、R 2b 、R 2c , and R 2d At least one of the following is -C(=O)N(R') 2 or —NR′(C═O)alkyl, where R′ is independently at each occurrence C 1 ~C 6 The compound of any one of 1001 to 1046 of the present invention, which is alkyl. [This invention 1053] 1052. A compound of the present invention wherein each occurrence of R' is methyl. [This invention 1054] R 2a 、R 2b 、R 2c , and R 2d At least one of the groups is —C(═O)NR″ heterocyclyl, where R″ is hydrogen or C 1 ~C 6 The compound of any one of 1001 to 1046 of the present invention, which is alkyl. [This invention 1055] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of is substituted or unsubstituted phenyl. [The present invention 1056] R 2a 、R 2b 、R2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of is substituted or unsubstituted heterocyclyl. [This invention 1057] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1001 to 1046, wherein at least one of is substituted or unsubstituted heteroaryl. [This invention 1058] R 2a 、R 2b 、R 2c , and R 2d at least one of which has the following structure: TIFF0007721142000016.tif67153 The compound of any one of 1001 to 1057 of the present invention, having one of the following: [This invention 1059] R 2a 、R 2b 、R 2c , and R 2d at least one of which has the following structure: TIFF0007721142000017.tif108142 The compound of any one of 1001 to 1057 of the present invention, having one of the following: [The present invention 1060] R 3 But the following structure: TIFF0007721142000018.tif71141 The compound of any one of 1001 to 1059 of the present invention, having one of the following: [This invention 1061] R 3 Ga-NH 2 The compound of any one of claims 1001 to 1060 of the present invention, [The present invention 1062] The compound of any one of claims 1001 to 1061, wherein n is 0. [The present invention 1063] The compound of any one of claims 1001 to 1061, wherein n is 1. [This invention 1064] The compound of any one of claims 1001 to 1061, wherein n is 2. [This invention 1065] The compound of any one of claims 1001 to 1061, wherein n is 3, 4, 5, or 6. [The present invention 1066] n is 2 and R 4 The compound of any one of claims 1001 to 1061, wherein is substituted or unsubstituted aryl. [This invention 1067] R 4 But the following structure: TIFF0007721142000019.tif157145TIFF0007721142000020.tif199146TIFF0007721142000021.tif63147 1066. A compound of the present invention having one of the following: [The present invention 1068] R 4 But the following structure: TIFF0007721142000022.tif75146 1066. A compound of the present invention having one of the following: [The present invention 1069] n is 2 and R 4 The compound of any one of claims 1001 to 1061, wherein is substituted or unsubstituted heteroaryl. [The present invention 1070] R 4 But the following structure: TIFF0007721142000023.tif221150TIFF0007721142000024.tif163148 1069 compounds of the present invention, having one of the following: [This invention 1071] R 4 But the following structure: TIFF0007721142000025.tif220145TIFF0007721142000026.tif230149TIFF0007721142000027.tif73143 1069 compounds of the present invention, having one of the following: [This invention 1072] R 4 But the following structure: TIFF0007721142000028.tif28136 1001 compounds of the present invention, having one of the following: [This invention 1073] n is 0 and R 4 But the following structure: TIFF0007721142000029.tif106136 The compound of any one of 1001 to 1061 of the present invention, having one of the following: [This invention 1074] R 4 But the following structure: TIFF0007721142000030.tif21128 The compound of the present invention 1073, having one of the following: [This invention 1075] A compound having the following structure (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000031.tif45128 During the ceremony, X is a direct bond, -[C(R 2e )R 2f ]-, or -[C(R 2e )R 2f ]-[C(R 2g )R 2h ]- and; Y is a direct bond or -[C(R 2i )R 2j ]- and; R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i , and R 2j are each independently hydrogen, halo, OR 5 , C(=O)OR 5 , OC(=O)R 5 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 5 R 6 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , N.R. 5 C(=O)NR 6 , S(O) t , S.R. 5 , nitro, N(R 5 )C(O)OR 6 , C(=NR 5 )NR 6 R 7 , N(R 5 )C(=NR 6 )NR 7 R 8 , S(O)R 5 , S(O)NR 5 R 6 , S(O) 2 R 5 , N(R 5 )S(O) 2 R 6 , S(O) 2 NR 5 R 6 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g、R 2h 、R 2i , or R 2j At least one occurrence of is not hydrogen; R 3 is NR 3a R 3b and; R 3a and R 3b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, -CH 2 C(C=O)OH, -CH 2 C(═O)O alkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or cycloalkyl; or R 3a and R 3b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or 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 when n is 2, 3, 4, 5, or 6; or R 4 is, when n is 0 or 1, a substituted or unsubstituted monocyclic heteroaryl or a substituted or unsubstituted heterocyclyl; R 5 、R 6 、R 7 , and R 8 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; n is an integer from 0 to 6; and t is an integer between 0 and 3, however, a) R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i , and R 2j If one of the groups is OH, then R 1 has the following structure: TIFF0007721142000032.tif17128 without; b) R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g , and R 2h is —OH, then n is an integer from 2 to 6; and c) R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i , and R 2j When one of R is unsubstituted phenyl, 3a MoR 3b also has the following structure: TIFF0007721142000033.tif13128 does not have. [This invention 1076] R 1 1075. The compound of the present invention, wherein is substituted or unsubstituted aryl. [This invention 1077] R 1 substituted or unsubstituted C 6 ~C 10 The compound of the present invention 1075 or 1076, which is aryl. [This invention 1078] R 1 The compound of any one of claims 1075 to 1077, wherein is substituted or unsubstituted phenyl. [This invention 1079] R 1 The compound of any one of 1075 to 1078 of the present invention, wherein is substituted phenyl. [The present invention 1080] R 1 But R 1a 、R 1b 、R 1c 、R 1d , and R 1e and 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 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(=NOR9 )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 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, C1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Any of the compounds 1075 to 1079 of the present invention. [This invention 1081] 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 14R 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 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1080 of the present invention. [This invention 1082] 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 1075 to 1081, which is a phenyl substituted with at least one substituent selected from the group consisting of: [This invention 1083] 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 1075 to 1082 of the present invention, which is substituted with at least one substituent selected from the group consisting of: [This invention 1084] R 1 But there is at least one C(=NR 9 )NR 10 R 11 1083 compounds of the present invention, substituted with [This invention 1085] R 1 But there is at least one -C(=NH)NH 2 The compound of claim 1083 or 1084, wherein the compound is substituted with [The present invention 1086] R 1 But the following structure: TIFF0007721142000034.tif177148 Any of the compounds of 1081 to 1085 of the present invention, having one of the following: [This invention 1087] R 1 But the following structure: TIFF0007721142000035.tif81156 Any of the compounds of 1075 to 1086 of the present invention, having one of the following: [This invention 1088] R 1 But the following structure: TIFF0007721142000036.tif58128 The compound of the present invention 1081, having one of the following: [This invention 1089] R 9 But C 1~6 Alkyl or C 1~6 1088 compounds of the present invention which are haloalkyl. [The present invention 1090] R 9 The compound of the present invention 1089, wherein is methyl. [This invention 1091] R 9 The compound of the present invention 1089, wherein is trifluoromethyl. [This invention 1092] R 1 The compound of any one of 1075 to 1078, wherein is unsubstituted phenyl. [This invention 1093] R 1 1075. The compound of the present invention, wherein is substituted or unsubstituted heteroaryl. [This invention 1094] R 1 is a substituted or unsubstituted 5- to 10-membered heteroaryl. [This invention 1095] R 1 The compound of any one of claims 1075 and 1093 to 1094, wherein is substituted or unsubstituted pyridinyl, pyrrolopyridinyl, or benzimidazolyl. [This invention 1096] R 1 The compound of any one of claims 1075 and 1093 to 1095, wherein is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-c]pyridin-2-yl, or 1H-benzo[d]imidazol-6-yl. [This invention 1097] R 1 But R 1a 、R 1b 、R1c 、R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-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 10R 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 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; The compound of the present invention is any one of compounds 1075 and 1093 to 1096. [This invention 1098] 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 R16 , 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 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1097 of the present invention. [This invention 1099] R 1 But the following structure: TIFF0007721142000037.tif155148TIFF0007721142000038.tif226148TIFF0007721142000039.tif212143TIFF0007721142000040.tif33128 The compound of any one of 1075 or 1093 to 1097 of the present invention, having one of the following: [The present invention 1100] R 1a or R 1b But independently C 1~6 Alkyl, amino, C(O)R 9 , C(O)NR9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , or OC(O)NR 9 R 10 1099. The compound of claim 1099, wherein the compound is a methyl group, or halo. [The present invention 1101] R 1a or R 1b is methyl or ethyl. [The present invention 1102] R 1a or R 1b 110. The compound of claim 1100, wherein is F, Cl, or Br. [The present invention 1103] R attached to nitrogen 1a or R 1b Each one is C 1~6 Alkyl, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , or OC(O)NR 9 R 10 The compound of the present invention 1099. [The present invention 1104] R 1a or R 1b is methyl or ethyl. [This invention 1105] R 1 But the following structure: TIFF0007721142000041.tif126156 The compound of any one of 1075 and 1093 to 1094 of the present invention, having one of the following: [The present invention 1106] R 1 But the following structure: TIFF0007721142000042.tif93147 The compound of any one of 1075 and 1093 to 1094 of the present invention, having one of the following: [This invention 1107] R 1 1075. A compound of the present invention wherein is substituted or unsubstituted cycloalkyl. [This invention 1108] R 1 substituted or unsubstituted C 3 ~C 6 The compound of the present invention 1075 or 1107, which is cycloalkyl. [This invention 1109] R 1 But substitution C 3 ~C 6 Compounds of any one of 1075 and 1107 to 1108 of the present invention, which are cycloalkyl. [The present invention 1110] 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 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1109 of the present invention. [The present invention 1111] 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 R1e , 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 、R15 , 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; The compound of the present invention 1110. [The present invention 1112] R 1 But unsubstituted C 3 ~C 6 1108. A compound of the present invention which is cycloalkyl. [The present invention 1113] R 1 1075. A compound of the present invention, wherein is substituted or unsubstituted heterocyclyl. [This invention 1114] R 1 The compound of the present invention 1075 or 1113, wherein is substituted or unsubstituted 4- to 10-membered heterocyclyl. [This invention 1115] R 1 The compound of any one of claims 1075 and 1073 to 1084, wherein is substituted 4- to 10-membered heterocyclyl. [The present invention 1116] 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 R10 , 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 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1115 of the present invention. [This invention 1117] 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 、R1b 、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) 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 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 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; Compound 1116 of the present invention. [This invention 1118] R 1 is an unsubstituted 4- to 10-membered heterocyclyl. [This invention 1119] The following structure: TIFF0007721142000043.tif210127TIFF0007721142000044.tif97128 The compound of any one of 1075 to 1118 of the present invention, which has one of the following: [The present invention 1120] R 2a 、R 2b 、R 2c , and R 2d At least one of the following is alkoxy, alkoxyalkyl, cyano, or C(=O)OR 5 , OC(=O)R 5 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 5 ) heterocyclyl, where R 5 and R 6 is independently hydrogen or C in each occurrence. 1 ~C 6 The compound of any one of claims 1075 to 1119 of the present invention, wherein the compound is alkyl. [This invention 1121] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1075 to 1120, wherein at least one of is methoxy. [This invention 1122] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1075 to 1120, wherein at least one of the groups is methoxymethyl. [This invention 1123] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1075 to 1120, wherein at least one of the groups is cyano. [This invention 1124] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of claims 1075 to 1120, wherein at least one of the groups is -C(=O)OH. [Invention 1125] R 2a 、R 2b 、R 2c , and R 2d At least one of the following is -C(=O)OCH 3 or -OC(=O)CH 3 The compound of any one of 1075 to 1120 of the present invention, [Invention 1126] R 2a 、R 2b 、R 2c , and R 2d At least one of the following is -C(=O)N(R') 2 or —NR′(C═O)alkyl, where R′ is independently at each occurrence C 1 ~C 6 The compound of any one of 1075 to 1120 of the present invention, which is alkyl. [This invention 1127] 1126. A compound of the invention wherein each occurrence of R' is methyl. [This invention 1128] R 2a 、R 2b 、R 2c , and R 2d At least one of the groups is —C(═O)NR″ heterocyclyl, where R″ is hydrogen or C 1 ~C 6 The compound of any one of 1075 to 1120 of the present invention, which is alkyl. [This invention 1129] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of 1075 to 1120, wherein at least one of is substituted or unsubstituted phenyl. [The present invention 1130] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of 1075 to 1120, wherein at least one of is substituted or unsubstituted heterocyclyl. [This invention 1131] R 2a 、R 2b 、R 2c , and R 2d The compound of any one of 1075 to 1120, wherein at least one of is substituted or unsubstituted heteroaryl. [This invention 1132] R 2a 、R 2b 、R 2c , and R 2d at least one of which has the following structure: TIFF0007721142000045.tif68156 The compound of any one of 1075 to 1131 of the present invention, having one of the following: [This invention 1133] R 2a 、R2b 、R 2c , and R 2d at least one of which has the following structure: TIFF0007721142000046.tif124148 The compound of any one of 1075 to 1132 of the present invention, which has one of the following: [This invention 1134] R 3 But the following structure: TIFF0007721142000047.tif71144 The compound of any one of claims 1075 to 1133 of the present invention, which has one of the following: [This invention 1135] R 3 Ga-NH 2 The compound of any one of claims 1075 to 1134 of the present invention, [This invention 1136] The compound of any one of 1075 to 1135 of the present invention, wherein n is 0. [This invention 1137] The compound of any one of 1075 to 1135 of the present invention, wherein n is 1. [This invention 1138] The compound of any one of 1075 to 1135 of the present invention, wherein n is 2. [This invention 1139] The compound of any one of claims 1075 to 1135, wherein n is 3, 4, 5, or 6. [This invention 1140] n is 2 and R 4 is a substituted or unsubstituted aryl. [This invention 1141] R 4 But the following structure: TIFF0007721142000048.tif156146TIFF0007721142000049.tif199146TIFF0007721142000050.tif63128 1140. A compound of the present invention having one of the following: [This invention 1142] R 4 But the following structure: TIFF0007721142000051.tif73145 1140. A compound of the present invention having one of the following: [This invention 1143] n is 2 and R 4 is a substituted or unsubstituted heteroaryl. [This invention 1144] R 4 But the following structure: TIFF0007721142000052.tif227147TIFF0007721142000053.tif164146 1143 compounds of the present invention, having one of the following: [Invention 1145] R 4 But the following structure: TIFF0007721142000054.tif214148TIFF0007721142000055.tif214148TIFF0007721142000056.tif119148 1143 compounds of the present invention, having one of the following: [Invention 1146] R 4 But the following structure: TIFF0007721142000057.tif28138 1139 compounds of the present invention, having one of the following: [This invention 1147] n is 0 and R 4 But the following structure: TIFF0007721142000058.tif104148 The compound of any one of 1075 to 1135 of the present invention, which has one of the following: [This invention 1148] R 4 But the following structure: TIFF0007721142000059.tif22128 1147. The compound of the present invention, having one of the following: [This invention 1149] A compound having the structure in Table 1 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. [This invention 1150] A compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000060.tif36128 During the ceremony, X is a direct bond, -CR2e R 2f - or -CR 2e R 2f -CR 2g R 2h - and; Y is a direct bond or -CR 2i R 2j - and; Z is O or S; R 17 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 18a 、R 18b 、R 18c 、R 18d 、R 18e 、R 18f 、R 18g 、R 18h 、R 18i , and R 18j are each independently hydrogen, halo, or -OR 21 , C(=O)OR 21 , OC(=O)R 21 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 21 R 22 , C(=O)NR 21 R 22 , N(R 21 )C(=O)R 22 , N.R. 21 C(=O)NR 22 , S(O) t , S.R. 21 , nitro, 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 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 18a 、R 18b 、R 18c 、R 18d 、R 18e 、R 18f 、R 18g 、R 18h 、R 18i , and R 18j at least one of which is not hydrogen; R 19 is NR 19a R 19b and; R 19a and R 19b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH 2 ) n C(=O)OR 5 , or (CH 2 ) n P(=O)(OR 5 ) 2 or R 19a and R 19b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; R 20 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 21 、R 22 、R 23 , and R 24 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; m is an integer from 0 to 6; and t is an integer of 0 to 3. [This invention 1151] R 17 But the following structure: TIFF0007721142000061.tif105145 1150. A compound of the present invention having one of the following: [This invention 1152] R 17 1150. A compound of the present invention wherein is unsubstituted phenyl. [This invention 1153] R 17 But the following structure: TIFF0007721142000062.tif213148TIFF0007721142000063.tif208148TIFF0007721142000064.tif87149 1150. A compound of the present invention having one of the following: [This invention 1154] R 17 But the following structure: TIFF0007721142000065.tif93147 1150. A compound of the present invention having one of the following: [This invention 1155] R 18a or R 18b At least one of the groups is alkoxy, alkoxyalkyl, cyano, C(=O)OR 21 , OC(=O)R 21 , C(=O)NR21 R 22 , N(R 21 )C(=O)R 22 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 21 ) heterocyclyl, where R 21 and R 22 is independently hydrogen or C in each occurrence. 1 ~C 6 The compound of any one of 1150 to 1154 of the present invention, which is alkyl. [Invention 1156] R 18a or R 18b at least one of which has the following structure: TIFF0007721142000066.tif54140 The compound of any one of 1150 to 1154 of the present invention, having one of the following: [This invention 1157] R 19 But the following structure: TIFF0007721142000067.tif74148 The compound of any one of 1150 to 1156 of the present invention, having one of the following: [This invention 1158] R 20 But the following structure: TIFF0007721142000068.tif219146TIFF0007721142000069.tif200144 The compound of any one of 1150 to 1157 of the present invention, which has one of the following: [This invention 1159] R 20 But the following structure: TIFF0007721142000070.tif223149TIFF0007721142000071.tif162149 The compound of any one of 1150 to 1157 of the present invention, which has one of the following: [The present invention 1160] R 20 But the following structure: TIFF0007721142000072.tif221148TIFF0007721142000073.tif232148TIFF0007721142000074.tif88145 The compound of any one of 1150 to 1157 of the present invention, which has one of the following: [This invention 1161] A compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000075.tif43128 During the ceremony, X is a direct bond or -CR 26c R 26d - and; R 25 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 26a 、R 26b 、R 26c , and R 26d are each independently hydrogen, halo, or -OR 29 , C(=O)OR 29 , OC(=O)R 29 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 29 R 30 , C(=O)NR 29 R 30 , N(R 29 )C(=O)R 30 , N.R. 29 C(=O)NR 30 , S(O) t , S.R. 29 , nitro, N(R 29 )C(O)OR 30 , C(=NR 29 )NR 30 R 31 , N(R 29 )C(=NR 30 )NR 31R 32 , S(O)R 29 , S(O)NR 29 R 30 , S(O) 2 R 30 , N(R 29 )S(O) 2 R 30 , S(O) 2 NR 29 R 30 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 26a 、R 26b 、R 26c , and R 26d at least one of which is not hydrogen; R 27 is NR 27a R 27b and; R 27a and R 27b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH 2 ) n C(=O)OR 29 , or (CH 2 ) n P(=O)(OR 29 ) 2 or R 27a and R 27b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; R 28 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 29 、R 30 、R 31 , and R 32 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; p is an integer from 0 to 6; and t is an integer of 0 to 3. [This invention 1162] R 25 But the following structure: TIFF0007721142000076.tif112145 1161. A compound of the present invention having one of the following: [This invention 1163] R 25 1161. A compound of the present invention, wherein is unsubstituted phenyl. [Invention 1164] R 25 But the following structure: TIFF0007721142000077.tif120146TIFF0007721142000078.tif213148TIFF0007721142000079.tif175149 1161. A compound of the present invention having one of the following: [This invention 1165] R 25 But the following structure: TIFF0007721142000080.tif94147 1161. A compound of the present invention having one of the following: [Invention 1166] R 26a and R 26b At least one of the groups is alkoxy, alkoxyalkyl, cyano, C(=O)OR 29 , OC(=O)R 29 , C(=O)NR 29 R 30 , N(R 29 )C(=O)R 30 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 29 ) heterocyclyl, where R 29 and R 30 is independently hydrogen or C in each occurrence. 1 ~C 6 The compound of any one of 1161 to 1165 of the present invention, which is alkyl. [This invention 1167] R 26a and R26b at least one of which has the following structure: TIFF0007721142000081.tif54140 The compound of any one of claims 1161 to 1165, having one of the following: [Invention 1168] R 27 But the following structure: TIFF0007721142000082.tif74148 The compound of any one of claims 1161 to 1167, having one of the following: [This invention 1169] R 28 But the following structure: TIFF0007721142000083.tif50146TIFF0007721142000084.tif204146TIFF0007721142000085.tif165142 The compound of any one of 1161 to 1168 of the present invention, having one of the following: [This invention 1170] R 28 But the following structure: TIFF0007721142000086.tif223149TIFF0007721142000087.tif162149 The compound of any one of 1161 to 1168 of the present invention, having one of the following: [This invention 1171] R 28 But the following structure: TIFF0007721142000088.tif214148TIFF0007721142000089.tif214148TIFF0007721142000090.tif119148 The compound of any one of 1161 to 1168 of the present invention, having one of the following: [This invention 1172] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1171 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. [This invention 1173] A method for treating a MASP-2-related disease or disorder in a subject in need thereof, comprising the step of administering to the subject an effective amount of any of the compounds of the present inventions 1001 to 1171 or the pharmaceutical composition of the present invention 1172. [This invention 1174] The method of claim 1173, wherein the compound is administered in an amount sufficient to inhibit MASP-2-dependent complement activation in a subject. [This invention 1175] The method of claim 1173, wherein the subject has been diagnosed with a condition in need of treatment for a lectin complement-associated disease or disorder. [Invention 1176] The method of the present invention 1173, wherein the disease or disorder is thrombotic microangiopathy (TMA), renal disease, inflammatory response due to tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, cardiovascular disease or disorder, inflammatory gastrointestinal disorder, pulmonary disorder, eye 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. [This invention 1177] The method of claim 1173, wherein the disease or disorder is thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), factor H-independent atypical hemolytic uremic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplant, TMA associated with hematopoietic stem cell transplantation, or a combination thereof. [This invention 1178] The method of claim 1173, wherein the disease or disorder is graft-versus-host disease. [This invention 1179] The method of claim 1173, wherein the disease or disorder is diffuse alveolar hemorrhage (DAH). [This invention 1180] The method of claim 1173, wherein the disease or disorder is veno-occlusive disease (VOD). [This invention 1181] The method of claim 1173, wherein the disease or disorder is a renal disease. [This invention 1182] The method of claim 1173, wherein the renal disease is mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangial capillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, microimmune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, or a combination thereof. [This invention 1183] The method of claim 1173, wherein the disease or disorder is renal fibrosis, proteinuria, or a combination thereof. [This invention 1184] The method of claim 1173, wherein the disease or disorder is an inflammatory response resulting from tissue or solid organ transplantation. [This invention 1185] The method of claim 1173, wherein the disease or disorder is ischemia-reperfusion injury (I / R). [Invention 1186] The method of claim 1173, 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. [This invention 1187] The method of claim 1173, wherein the disease or disorder is a cardiovascular disease or disorder. [This invention 1188] The method of claim 1173, wherein the disease or disorder is an inflammatory gastrointestinal disorder. [This invention 1189] The method of claim 1173, wherein the disease or disorder is a pulmonary disorder. [This invention 1190] The method of claim 1173, wherein the disease or disorder is an in vitro exposure-induced inflammatory response. [This invention 1191] The method of claim 1190, further comprising treating a subject undergoing an extracorporeal circulation procedure. [This invention 1192] The method of claim 1173, wherein the disease or disorder is inflammatory arthritis, non-inflammatory arthritis, a musculoskeletal disorder, or a combination thereof. [This invention 1193] The method of claim 1173, wherein the disease or disorder is a skin disorder. [This invention 1194] The method of claim 1173, wherein the disease or disorder is a peripheral nervous system (PNS) disorder or injury, a central nervous system (CNS) disorder or injury, or a combination thereof. [This invention 1195] The method of claim 1173, wherein the disease or disorder is sepsis or a condition resulting from sepsis. [This invention 1196] The method of claim 1173, wherein the disease or disorder is a genitourinary disorder. [This invention 1197] The method of claim 1173, wherein the disease or disorder is an inflammatory response in a subject being treated with a chemotherapeutic agent, radiation therapy, or a combination thereof. [This invention 1198] The method of claim 1173, wherein the disease or disorder is an angiogenesis-dependent cancer. [This invention 1199] The method of claim 1173, wherein the disease or disorder is an angiogenesis-dependent benign tumor. [The present invention 1200] The method of claim 1173, wherein the disease or disorder is an endocrine disorder. [The present invention 1201] The method of claim 1173, wherein the disease or disorder is an ocular disease or disorder. [This invention 1202] The method of claim 1173, wherein the disease or disorder is an ocular neovascular disease or condition. [This invention 1203] The method of claim 1173, wherein the disease or disorder is disseminated intravascular coagulation (DIC), a complement-mediated coagulopathy, or a combination thereof. [The present invention 1204] The method of claim 1173, wherein the disease or disorder is acute radiation syndrome, dense deposit disease, Degos disease, fulminant antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia; paroxysmal nocturnal hemoglobinuria ("PNH"), cold agglutinin disease, or a combination thereof. [This invention 1205] The method of claim 1173, wherein the disease or disorder is atypical hemolytic uremic syndrome (aHUS). [The present invention 1206] 1173. The method of claim 1173, wherein the disease or disorder is hematopoietic stem cell transplantation-associated TMA. [This invention 1207] The method of claim 1173, wherein the disease or disorder is immunoglobulin A nephropathy (IgAN). [This invention 1208] The method of claim 1173, 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 is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[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)R 102, -N(R 102 )S(O) p R 102 (where p is 1 to 2), -S(O) p OR 102 (where p is 1 to 2), -S(O) t R 102 (where t is 0 to 2), and -S(O) p N(R 100 )2 (where p is 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl. In some embodiments, alkyl is C1-C 12 alkyl, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl.

[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 or alkenyl 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(R100 )C(O)R 102 , -N(R 102 )S(O) p R 102 (where p is 1 to 2), -S(O) p OR 102 (where p is 1 to 2), -S(O) t R 102 (where t is 0 to 2), and -S(O) p N(R 100 )2 (where p is 1 to 2), where each R 100 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; each R 102 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[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 1, 2, 3, 4, 5, 6, or more hydroxy groups. Examples can include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl. In some embodiments, a hydroxyalkyl group is a C1-C 12 hydroxyalkyl, C1-C8 hydroxyalkyl, C1-C6 hydroxyalkyl, or C1-C4 hydroxyalkyl.

[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, a carboxyalkyl contains one carboxy group. In some embodiments, a carboxyalkyl is a C1-C 12 carboxyalkyl, C1-C8 carboxyalkyl, C1-C6 carboxyalkyl, or C1-C4 carboxyalkyl.

[0060] "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 , -R 101 -C(O)N(R 100 )2, -R 101 -N(R 100 )C(O)OR 102 , -R 101 -N(R100 )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: TIFF0007721142000091.tif24128

[0061] "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-C1~4 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.

[0062] "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).

[0063] "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).

[0064] "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.

[0065] "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.

[0066] "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.

[0067] "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.

[0068] "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.

[0069] "Sulfide" refers to the group =S.

[0070] "Amino" refers to the group -NH2.

[0071] "Carbamyl" refers to the group -C(O)NH2.

[0072] "Carboxy" refers to the group --C(O)OH.

[0073] "Carbonyl" refers to the group C(=O), which may also be written as C(O).

[0074] "Cyano" or "nitrile" refers to the group -C≡N, which may also be written as -CN.

[0075] "Nitro" refers to the -NO2 group.

[0076] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0077] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0078] "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.

[0079] 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.

[0080] "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.

[0081] "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.

[0082] "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: TIFF0007721142000092.tif23128

[0083] "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.

[0084] "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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] "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.

[0091] "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.

[0092] 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.

[0093] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0094] "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.

[0095] "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.

[0096] 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.

[0097] 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.

[0098] 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:

[0099] 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).

[0100] 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.

[0101] "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).

[0102] "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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] The following abbreviations may be used herein and, unless otherwise specified, have the meanings indicated below: ACN or MeCN (acetonitrile); chrom. (chromatography); CHCl (dichloromethane); DIAD (diisopropyl azodicarboxylate); L (liter); m- (meta); Ms (methanesulfonyl); NCS (N-chlorosuccinimide); NIS (N-iodosuccinimide); Phth (phthalimide); TPP (triphenylphosphine); and Tr (trityl). Other abbreviations may also be used and have meanings understood by those skilled in the art.

[0110] II. Compounds In certain aspects, the present disclosure provides a compound of structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000093.tif45128In formula, X is a direct bond, -CR 2e R 2f - or -CR 2e R 2f -CR 2g R 2h - and; Y is a direct bond or -CR 2i R 2j - and; R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j are each independently hydrogen, halo, C(=O)OR 5 , OC(=O)R 5 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 5 R 6 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , N.R. 5 C(=O)NR 6 , S(O) t , S.R. 5 , nitro, N(R 5 )C(O)OR 6 , C(=NR 5 )NR 6 R 7 , N(R 5 )C(=NR 6 )NR 7 R 8 , S(O)R 5 , S(O)NR 5 R 6 , S(O)2R 5 , N(R5 )S(O)2R 6 , S(O)NR 5 R 6 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j At least one of the is not hydrogen; R 3 is NR 3a R 3b and; R 3a and R 3b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or cycloalkyl; or R 3a and R 3b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; or R 3a and R 4 together with the nitrogen and carbon to which they are respectively attached to form an optionally substituted 4- to 7-membered heterocyclyl, and R 3b is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH2) n C(=O)OR 6 , or (CH2) n P(=O)(OR 6 )2; R 4is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl when n is 2, 3, 4, 5, or 6; or R 4 is a substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted heterocyclyl when n is 0 or 1; or R 4 and R 3a taken together with the carbon and nitrogen to which they are respectively attached form an optionally substituted 4- to 7-membered heterocyclyl; R 5 , R 6 , R 7 , and R 8 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; n is an integer from 0 to 6; and t is an integer of 1 to 3.

[0111] 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 specific embodiments, R 1 is a substituted phenyl.

[0112] In some embodiments, R 1 is R 1a , R 1b , R 1c , R 1d , and R 1e and 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 1~6 Alkyl, C 2~6 Alkenyl, C2~6 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 3~10cycloalkyl, 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.

[0113] In some more specific 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. 13C(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.

[0114] In certain 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 more specific embodiments, R is phenyl substituted with at least one substituent selected from the group consisting of 1 is C(=NR 9 )NR 10 R11 , 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 embodiments, R is substituted with at least one substituent selected from the group consisting of 1 must contain at least one C(=NR 9 )NR 10 R 11 In some specific embodiments, R 1 is substituted with at least one -C(=NH)NH2.

[0115] In certain more specific aspects, R 1 has the following structure: I have one of the following: TIFF0007721142000094.tif174147.

[0116] In even more specific embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000095.tif83156.

[0117] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000096.tif58128.

[0118] 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 embodiments, R 9 is trifluoromethyl. In more embodiments, R 1 is unsubstituted phenyl.

[0119] In certain other embodiments, R 1 is substituted or unsubstituted heteroaryl. In more specific embodiments, R 1 is a substituted or unsubstituted 5-10 membered heteroaryl. In some more specific embodiments, R 1 is substituted or unsubstituted pyridinyl, pyrrolopyridinyl, or benzimidazolyl. 1 is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-c]pyridin-2-yl, or 1H-benzo[d]imidazol-6-yl. 1 is R 1a , R 1b , R 1c , R 1d , and R 1e pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-c]pyridin-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(R9 )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.

[0120] In some embodiments, R1a , 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 16are 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.

[0121] In certain specific embodiments, R 1 has the following structure: It has one of the following: TIFF0007721142000097.tif104148TIFF0007721142000098.tif228148TIFF0007721142000099.tif213143TIFF0007721142000100.tif81129

[0122] In some specific embodiments, R 1a or R 1b independently, C 1~6 Alkyl, amino, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , OC(O)NR 9 R 10 or halo. In some embodiments, R 1a or R 1b is methyl or ethyl. In some specific embodiments, R 1a or R 1b is F, Cl, or Br. In certain embodiments, the R bonded to the nitrogen 1a or R 1b Each is C 1~6 Alkyl, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR10 R 11 , N(R 9 )C(O)OR 10 , or OC(O)NR 9 R 10 In a more specific embodiment, R 1a or R 1b is methyl or ethyl.

[0123] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000101.tif130156.

[0124] In certain embodiments, R 1 has the following structure: It has one of the following: TIFF0007721142000102.tif145144TIFF0007721142000103.tif217148TIFF0007721142000104.tif73156.

[0125] In certain embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000105.tif92143.

[0126] In some embodiments, R 1 is substituted or unsubstituted cycloalkyl. In certain embodiments, R 1 is a substituted or unsubstituted C3-C6 cycloalkyl. In some more specific embodiments, R 1 is a substituted C3-C6 cycloalkyl.

[0127] In some 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 , R1d , and R 1e are each independently 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)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 C6~10 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.

[0128] In certain of the foregoing 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. 13C(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.

[0129] In some embodiments, R 1 is unsubstituted C3-C6 cycloalkyl. In certain embodiments, R 1 is substituted or unsubstituted heterocyclyl. In certain specific embodiments, R 1 is a substituted or unsubstituted 4-10 membered heterocyclyl. In some embodiments, R 1 is a substituted 4-10 membered heterocyclyl.

[0130] 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 R10 , 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.

[0131] In some of the foregoing 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)R13 , 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.

[0132] In some embodiments, R 1 is an unsubstituted 4-10 membered heterocyclyl.

[0133] In some embodiments, the compound has the following structure: It has one of the following: TIFF0007721142000106.tif208126TIFF0007721142000107.tif98128

[0134] In some embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of is selected from alkoxy, alkoxyalkyl, cyano, C(=O)OR 5 , OC(=O)R 5 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 5 ) heterocyclyl, where R 5 and R 6 is independently at each occurrence hydrogen or C1-C6 alkyl. In some embodiments, R 2a and R 2b are both halo (e.g., fluoro).

[0135] In some more specific embodiments, X is CH, Y is a direct bond, and R 2c and R 2d are all hydrogen, and R 2a and R 2b In more specific embodiments, R 3b is hydrogen and R 3a and R 4 are taken together with the nitrogen and carbon to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl (e.g., piperidinyl or pyrrolyl). In some more specific embodiments, the compound of structure (I) has the structure: TIFF0007721142000108.tif29128In formula, R 33 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 33 has the following structure: I have TIFF0007721142000109.tif27128.

[0136] In certain embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of R is methoxy. 2a , R 2b , R 2c , and R 2d In certain embodiments, at least one of R 2a , R 2b , R 2c , and R 2d In some more specific embodiments, at least one of R 2a , R 2b , R 2c , and R 2d In certain more specific embodiments, at least one of R 2a , R 2b , R 2c , and R 2d At least one of R is —C(═O)OCH or —OC(═O)CH. In some embodiments, R 2a , R 2b , R 2c , and R 2d At least one of R is -C(=O)N(R')2 or -NR'(C=O)alkyl, where R' is, independently at each occurrence, C1-C6 alkyl. In more specific embodiments, each occurrence of R' is methyl. In some embodiments, R 2a , R 2b , R 2c , and R 2d At least one of is -C(=O)NR'' heterocyclyl, where R'' is hydrogen or C1-C6 alkyl (eg, methyl, ethyl, or isopropyl).

[0137] In some specific embodiments, R 2a , R 2b , R2c , and R 2d In some embodiments, at least one of R 2a , R 2b , R 2c , and R 2d In some embodiments, at least one of R is substituted or unsubstituted heterocyclyl. 2a , R 2b , R 2c , and R 2d At least one of R is a substituted or unsubstituted heteroaryl (e.g., tetrazolyl, triazolyl, oxadiazolyl, imidazolidinyl, pyrazolyl, etc.). 2a is heteroaryl or heterocyclyl. In some more specific embodiments, R 2c is heteroaryl or heterocyclyl. In some embodiments, R 2a is heterocyclyl. In some more specific embodiments, R 2c is heterocyclyl. In certain specific embodiments, R 2a is heteroaryl. In certain more specific embodiments, R 2c is heteroaryl.

[0138] In some embodiments, R 2a , R 2b , R 2c , and R 2d at least one of which has the following structure: I have one of the following: TIFF0007721142000110.tif67152.

[0139] In a more specific embodiment, R 2a , R 2b , R 2c , and R 2d at least one of which has the following structure: I have one of the following: TIFF0007721142000111.tif108142.

[0140] In some more specific embodiments, R3 has the following structure: I have one of the following: TIFF0007721142000112.tif71142.

[0141] In certain embodiments, R 3 is -NH2.

[0142] In some embodiments, n is 0. In certain embodiments, n is 1. In yet other embodiments, n is 2. In some embodiments, n is 3, 4, 5, or 6.

[0143] In some embodiments, n is 2 and R 4 is substituted or unsubstituted aryl. In some more specific embodiments, R 4 is substituted aryl. In certain more specific embodiments, R 4 is substituted with a substituent selected from the group consisting of alkyl, halo (e.g., fluoro, chloro, bromo), haloalkyl, hydroxyl, amino, nitro, and combinations thereof. 4 is unsubstituted aryl. In certain embodiments, R 4 has the following structure: It has one of the following: TIFF0007721142000113.tif78144 TIFF0007721142000114.tif211146 TIFF0007721142000115.tif129147.

[0144] In some more specific embodiments, R 4 has the following structure: I have one of the following: TIFF0007721142000116.tif76146.

[0145] In certain specific embodiments, n is 2 and R 4 is substituted or unsubstituted heteroaryl. In some more specific embodiments, R 4 has the following structure: It has one of the following: TIFF0007721142000117.tif105148TIFF0007721142000118.tif216148TIFF0007721142000119.tif63132.

[0146] In some embodiments, R 4 has the following structure: It has one of the following: TIFF0007721142000120.tif137144 TIFF0007721142000121.tif213149 TIFF0007721142000122.tif179143.

[0147] In some embodiments, R 4 has the following structure: I have one of the following: TIFF0007721142000123.tif28135.

[0148] In certain related embodiments, n is 0 and R 4 has the following structure: I have one of the following: TIFF0007721142000124.tif105136.

[0149] In some specific embodiments, R 4 has the following structure: I have one of the following: TIFF0007721142000125.tif21128.

[0150] One embodiment provides a compound having the following structure (II): TIFF0007721142000126.tif45128In formula, X is a direct bond, -[C(R 2e )R 2f ]-, or -[C(R 2e )R 2f ]-[C(R 2g )R 2h ]-; Y is a direct bond or -[C(R 2i )R 2j]- and; R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j are each independently hydrogen, halo, OR 5 , C(=O)OR 5 , OC(=O)R 5 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 5 R 6 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , N.R. 5 C(=O)NR 6 , S(O) t , S.R. 5 , nitro, N(R 5 )C(O)OR 6 , C(=NR 5 )NR 6 R 7 , N(R 5 )C(=NR 6 )NR 7 R 8 , S(O)R 5 , S(O)NR 5 R 6 , S(O)2R 5 , N(R 5 )S(O)2R 6 , S(O)NR 5 R 6 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 2a , R 2b , R 2c , R 2d , R 2e, R 2f , R 2g , R 2h , R 2i , and R 2j at least one of which is not hydrogen; R 3 is NR 3a R 3b and; R 3a and R 3b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, —CHC(C═O)OH, —CHC(═O)Oalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or cycloalkyl; or R 3a and R 3b taken together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; R 4 is, when n is 2, 3, 4, 5, or 6, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; or R 4 is, when n is 0 or 1, a substituted or unsubstituted monocyclic heteroaryl or a substituted or unsubstituted heterocyclyl; R 5 , R 6 , R 7 , and R 8 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; n is an integer from 0 to 6; and t is an integer from 1 to 3, provided that: a) R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R2i , and R 2j If one of the groups is OH, then R 1 has the following structure: Without TIFF0007721142000127.tif17128; b) R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , and R 2h is —OH, then n is an integer from 2 to 6; and c) R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j When one of R is unsubstituted phenyl, 3a and R 3b are all of the following structure: Does not have TIFF0007721142000128.tif12128.

[0151] In some embodiments, R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In some more embodiments, none of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In some embodiments, none of R 2a , R 2b , R2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In certain embodiments, none of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In some embodiments, none of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In some embodiments, none of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In some embodiments, none of R is halo (e.g., fluoro). 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j In some embodiments, none of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R2i , or R 2j In certain specific embodiments, none of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , or R 2j Each of the following structures: Does not have TIFF0007721142000129.tif29128.

[0152] In yet another embodiment, R 3a and R 3a In some more embodiments, none of R 3a and R 3a is not arylalkylcarbonyl. 3a and R 3a In some embodiments, none of R 3a and R 3a In some embodiments, none of R is heteroarylsulfo or alkylsulfo (e.g., —S(O)CH). 3a and R 3a None of the is arylalkoxycarbonyl (eg, Fmoc).

[0153] 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 embodiments, R 1 is substituted or unsubstituted phenyl. In certain embodiments, R 1 is substituted phenyl. In some more specific 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 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 C6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein R 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.

[0154] In some more specific 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)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)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.

[0155] In certain more specific aspects, 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 some 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 embodiments, R is substituted with at least one substituent selected from the group consisting of 1 must contain at least one C(=NR 9 )NR 10 R 11 In a more specific embodiment, R 1 is substituted with at least one -C(=NH)NH. In even more specific embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000130.tif183148.

[0156] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000131.tif107146.

[0157] In certain specific embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000132.tif58128.

[0158] In some of the foregoing embodiments, R 9 is C 1~6 Alkyl or C 1~6 In a more specific embodiment, R 9is methyl. In certain embodiments, R 9 is trifluoromethyl. In some embodiments, R 1 is unsubstituted phenyl.

[0159] In some embodiments, R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments, R 1 is substituted or unsubstituted pyridinyl, pyrrolopyridinyl, or benzimidazolyl. In some more specific embodiments, R 1 is substituted or unsubstituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[3,2-c]pyridin-2-yl, or 1H-benzo[d]imidazol-6-yl.

[0160] In some 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, 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 1~6Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0161] In a more specific embodiment, 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 R14 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.

[0162] In some specific embodiments, R 1 has the following structure: It has one of the following: TIFF0007721142000133.tif102145TIFF0007721142000134.tif230148TIFF0007721142000135.tif209147TIFF0007721142000136.tif58131.

[0163] In some specific embodiments, R 1a or R 1b independently, C 1~6 Alkyl, amino, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , or OC(O)NR 9 R 10 or halo. In more specific embodiments, R 1a or R 1b is methyl or ethyl. In another specific embodiment, R 1a or R 1b is F, Cl, or Br.

[0164] In some embodiments, the R attached to the nitrogen 1a or R 1b Each is C 1~6 Alkyl, C(O)R 9 , C(O)NR 9 R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , or OC(O)NR 9 R 10 In certain embodiments, R 1a or R 1b is methyl or ethyl.

[0165] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000137.tif127156.

[0166] In some specific embodiments, R 1 has the following structure: It has one of the following: TIFF0007721142000138.tif172146TIFF0007721142000139.tif218148TIFF0007721142000140.tif47156.

[0167] In some embodiments, R 1 has the following structure: I have one of the following: TIFF0007721142000141.tif92143.

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

[0169] In some more specific embodiments, R1 is R 1a , R 1b , R 1c , R 1d , and R 1e wherein R is a 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(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.

[0170] In some more specific 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)NR13 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.

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

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

[0174] In a more specific embodiment, 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 3~10cycloalkyl, 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.

[0175] In some embodiments, R 1 is an unsubstituted 4- to 10-membered heterocyclyl.

[0176] In certain embodiments, the compound has the following structure: It has one of the following: TIFF0007721142000142.tif208126TIFF0007721142000143.tif98128

[0177] In some embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of is selected from alkoxy, alkoxyalkyl, cyano, C(=O)OR 5 , OC(=O)R 5 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 5 ) heterocyclyl, where R 5 and R 6 is independently at each occurrence hydrogen or C1-C6 alkyl. In certain embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of R is methoxy. 2a , R 2b , R 2c , or R 2d At least one occurrence of R is methoxymethyl. 2a , R 2b , R 2c , or R 2d At least one occurrence of R is cyano. 2a , R 2b , R 2c, or R 2d At least one occurrence of R is —C(═O)OH. 2a , R 2b , R 2c , or R 2d At least one occurrence of R is —C(═O)OCH or —OC(═O)CH. In some more specific embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of is -C(=O)N(R')2 or -NR'(C=O)alkyl, where R' at each occurrence is independently C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl). In some of the foregoing embodiments, each occurrence of R' is methyl. In certain embodiments, R 2a , R 2b , R 2c , or R 2d At least one of is -C(=O)NR'' heterocyclyl, where R'' is hydrogen or C1-C6 alkyl (eg, methyl, ethyl, or isopropyl).

[0178] In some embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of R is substituted or unsubstituted phenyl. 2a , R 2b , R 2c , or R 2d At least one occurrence of R is substituted or unsubstituted heterocyclyl. 2a , R 2b , R 2c , or R 2d At least one occurrence of is substituted or unsubstituted heteroaryl.

[0179] In some embodiments, R 2a , R 2b , R 2c , or R 2dAt least one occurrence of has the following structure: I have one of the following: TIFF0007721142000144.tif67152.

[0180] In some embodiments, R 2a , R 2b , R 2c , or R 2d At least one occurrence of has the following structure: I have one of the following: TIFF0007721142000145.tif108142.

[0181] In some embodiments, R 3 has the following structure: I have one of the following: TIFF0007721142000146.tif76146.

[0182] In some embodiments, R 3 is -NH2. In certain embodiments, n is 0. In some other embodiments, n is 1. In certain other embodiments, n is 2. In still other embodiments, n is 3, 4, 5, or 6.

[0183] In some more specific embodiments, n is 2 and R 4 is substituted or unsubstituted aryl. In certain more specific embodiments, R 4 has the following structure: It has one of the following: TIFF0007721142000147.tif218146TIFF0007721142000148.tif173143.

[0184] In certain embodiments, R 4 has the following structure: I have one of the following: TIFF0007721142000149.tif76146.

[0185] In some embodiments, n is 2 and R 4 is substituted or unsubstituted heteroaryl. In some more specific embodiments, R 4 has the following structure: It has one of the following: TIFF0007721142000150.tif111146 TIFF0007721142000151.tif216150 TIFF0007721142000152.tif63132.

[0186] In some embodiments, R 4 has the following structure: It has one of the following: TIFF0007721142000153.tif137144 TIFF0007721142000154.tif213149 TIFF0007721142000155.tif179143.

[0187] In certain specific embodiments, R 4 has the following structure: I have one of the following: TIFF0007721142000156.tif28137.

[0188] In some embodiments, n is 0 and R 4 has the following structure: I have one of the following: TIFF0007721142000157.tif105136.

[0189] In some specific embodiments, R 4 has the following structure: I have one of the following: TIFF0007721142000158.tif21128.

[0190] Another aspect provides a compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000159.tif36128In formula, X is a direct bond, -CR 2e R 2f - or -CR 2e R 2f -CR 2g R 2h - and; Y is a direct bond or -CR 2i R 2j- and; Z is O or S; R 17 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 18a , R 18b , R 18c , R 18d , R 18e , R 18f , R 18g , R 18h , R 18i , and R 18j are each independently hydrogen, halo, or -OR 21 , C(=O)OR 21 , OC(=O)R 21 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 21 R 22 , C(=O)NR 21 R 22 , N(R 21 )C(=O)R 22 , N.R. 21 C(=O)NR 22 , S(O) t , S.R. 21 , nitro, 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 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 18a , R 18b , R 18c , R18d , R 18e , R 18f , R 18g , R 18h , R 18i , and R 18j at least one of which is not hydrogen; R 19 is NR 19 aR 19 b; R 19a and R 19b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH2) n C(=O)OR 5 , or (CH2) n P(=O)(OR 5 )2; or R 19a and R 19b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; R 20 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 21 , R 22 , R 23 , and R 24 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; m is an integer from 0 to 6; and t is an integer of 1 to 3.

[0191] In some embodiments, R 17 has the following structure: I have one of the following: TIFF0007721142000160.tif105145.

[0192] In some embodiments, R 17 has the following structure: I have one of the following: TIFF0007721142000161.tif127156.

[0193] In certain embodiments, R 17 is unsubstituted phenyl. In some more specific embodiments, R 17 has the following structure: It has one of the following: TIFF0007721142000162.tif172146TIFF0007721142000163.tif218148TIFF0007721142000164.tif47156.

[0194] In some more specific embodiments, R 17 has the following structure: I have one of the following: TIFF0007721142000165.tif93147.

[0195] In some embodiments, R 18a and R 18b At least one of the groups is alkoxy, alkoxyalkyl, cyano, C(=O)OR 21 , OC(=O)R 21 , C(=O)NR 21 R 22 , N(R 21 )C(=O)R 22 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 21 ) heterocyclyl, where R 21 and R 22 is independently at each occurrence hydrogen or C1-C6 alkyl. In certain more specific embodiments, R 18a and R 18b at least one of which has the following structure: I have one of the following: TIFF0007721142000166.tif54140.

[0196] In some embodiments, R 19 has the following structure: I have one of the following: TIFF0007721142000167.tif74148.

[0197] In some embodiments, R 20 has the following structure: It has one of the following: TIFF0007721142000168.tif78146TIFF0007721142000169.tif211146TIFF0007721142000170.tif129142.

[0198] In some embodiments, R 20 has the following structure: It has one of the following: TIFF0007721142000171.tif83148TIFF0007721142000172.tif204149TIFF0007721142000173.tif98140.

[0199] In some embodiments, R 20 has the following structure: It has one of the following: TIFF0007721142000174.tif113147TIFF0007721142000175.tif213148TIFF0007721142000176.tif187148TIFF0007721142000177.tif33139

[0200] Another aspect provides a compound having the following structure (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF0007721142000178.tif43128In formula, X is a direct bond or -CR 26c R 26d - and; R 25 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 26a , R 26b , R 26c , and R 26dare each independently hydrogen, halo, or -OR 29 , C(=O)OR 29 , OC(=O)R 29 , hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cyano, aminylalkyl, carboxyalkyl, NR 29 R 30 , C(=O)NR 29 R 30 , N(R 29 )C(=O)R 30 , N.R. 29 C(=O)NR 30 , S(O) t , S.R. 29 , nitro, N(R 29 )C(O)OR 30 , C(=NR 29 )NR 30 R 31 , N(R 29 )C(=NR 30 )NR 31 R 32 , S(O)R 29 , S(O)NR 29 R 30 , S(O)2R 30 , N(R 29 )S(O)2R 30 , S(O)NR 29 R 30 , aryl, heteroaryl, heterocyclyl, cycloalkyl, and oxo, with the proviso that R 26a , R 26b , R 26c , and R 26d At least one of the is not hydrogen; R 27 is NR 27a R 27b and; R 27a and R 27b are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, (CH2) n C(=O)OR 29 , or (CH2) nP(=O)(OR 29 )2; or R 27a and R 27b together with the nitrogen to which they are attached form an optionally substituted 4- to 7-membered heteroaryl or an optionally substituted 4- to 7-membered heterocyclyl; R 28 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; R 29 , R 30 , R 31 , and R 32 is independently at each occurrence hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, carboxyalkyl, heterocyclyl, heteroaryl, or cycloalkyl; p is an integer from 0 to 6; and t is an integer of 1 to 3.

[0201] In some embodiments, R 25 has the following structure: I have one of the following: TIFF0007721142000179.tif105145.

[0202] In some embodiments, R 25 is unsubstituted phenyl.

[0203] In some more specific embodiments, R 25 has the following structure: It has one of the following: TIFF0007721142000180.tif222146TIFF0007721142000181.tif215156.

[0204] In some embodiments, R 25 has the following structure: I have one of the following: TIFF0007721142000182.tif124156.

[0205] In some embodiments, R 25has the following structure: I have one of the following: TIFF0007721142000183.tif95147.

[0206] In certain embodiments, R 26a and R 26b At least one of the groups is alkoxy, alkoxyalkyl, cyano, C(=O)OR 29 , OC(=O)R 29 , C(=O)NR 29 R 30 , N(R 29 )C(=O)R 30 , aryl, heteroaryl, heterocyclyl, or C(═O)N(R 29 ) heterocyclyl, where R 29 and R 30 is independently at each occurrence hydrogen or C1-C6 alkyl. In more specific embodiments, R 26a or R 26b At least one occurrence of has the following structure: I have one of the following: TIFF0007721142000184.tif54140.

[0207] In certain embodiments, R 27 has the following structure: I have one of the following: TIFF0007721142000185.tif74148.

[0208] In some embodiments, R 28 has the following structure: It has one of the following: TIFF0007721142000186.tif219146TIFF0007721142000187.tif200144.

[0209] In some embodiments, R 28 has the following structure: It has one of the following: TIFF0007721142000188.tif223149TIFF0007721142000189.tif162149.

[0210] In certain embodiments, R 28 has the following structure: It has one of the following: TIFF0007721142000190.tif47147TIFF0007721142000191.tif220148TIFF0007721142000192.tif222148TIFF0007721142000193.tif53143

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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).

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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).

[0222] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.).

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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).

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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)).

[0294] 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.

[0295] Unless otherwise noted, chromatography refers to flash chromatography performed on silica gel. Amine column refers to flash chromatography performed on a Redisep Rf Gold high performance amine column.

[0296] HPLC purification was performed using a UV / MS detector (254 nm and 280 nm) and an XBridge Prep (19 × 50 mm) C 18 The 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 0.05% trifluoroacetic acid). The flow rate was typically 50 mL / min with a linear gradient of 5 to 95% water in acetonitrile over 8 min. Injection volumes ranged from 0.2 to 1 mL, with a maximum of 20 mg per load.

[0297] 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 (mol wt, etc.) 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 [Example]

[0298] Example 1 Preparation of (3R,5S)-1-((R)-2-amino-4-phenylbutanoyl)-5-((4-carbamimidoylbenzyl)carbamoyl)pyrrolidine-3-carboxylate methyl ditrifluoroacetate (Compound I-1) TIFF0007721142000194.tif23149 Step 1:To a solution of 1-(tert-butyl)2-methyl (2S,4R)-4-cyanopyrrolidine-1,2-dicarboxylate (90 mg, 0.38 mmol, 1 eq.) and N-hydroxysuccinamide (48 mg, 0.42 mmol, 1.1 eq.) in dichloromethane (3.8 mL, 0.1 M) was added DCC (93 mg, 0.38 mmol, 1.1 eq.). After stirring for 1 hour, benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride (120 mg, 0.38 mmol, 1 eq.) suspended in saturated sodium bicarbonate (3.8 mL, 0.1 M) was added to the solution. The mixture was stirred for an additional hour, after which the layers were separated and the organics were concentrated through a 0.45 micron filter. The resulting residue was purified on a silica column with EtOAc / heptane to give tert-butyl (2S,4R)-2-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)-4-cyanopyrrolidine-1-carboxylate (180 mg, 95%) as an off-white film.

[0299] TIFF0007721142000195.tif26133 Step 2: To a solution of tert-butyl (2S,4R)-2-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)-4-cyanopyrrolidine-1-carboxylate (180 mg, 0.36 mmol, 1 eq.) in methanol (1.8 mL, 0.2 M) was added HCl in dioxane (4 M, 1.8 mL, 0.2 M) and the reaction mixture was stirred until the reaction was complete as monitored by LCMS. The reaction mixture was then concentrated in vacuo to give methyl (3R,5S)-5-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)pyrrolidine-3-carboxylate hydrochloride as a clear film, which was carried forward without further purification.

[0300] TIFF0007721142000196.tif25154 Step 3:To a solution of (3R,5S)-methyl 5-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)pyrrolidine-3-carboxylate hydrochloride (0.36 mmol, 1 eq.) and D-homophenylalanine (121 mg, 0.43 mmol, 1.2 eq.) in anhydrous N,N-dimethylformamide (7.2 mL, 0.05 M) was added DIEA (250 μL, 1.2 mmol, 4 eq.), followed by hydroxybenzotriazole (60 mg, 0.43 mmol, 1.2 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (83 mg, 0.43 mmol, 1.2 eq.). After stirring overnight, the reaction mixture was diluted with ethyl acetate and then extracted with saturated ammonium chloride, followed by saturated sodium bicarbonate, then water (twice), and then brine. The organic layer was then concentrated and purified on a silica column with EtOAc / heptane to give methyl (3R,5S)-5-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)-1-((R)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoyl)pyrrolidine-3-carboxylate (34 mg, 13%).

[0301] TIFF0007721142000197.tif31149 Step 4:To a solution of methyl (3R,5S)-5-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)-1-((R)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoyl)pyrrolidine-3-carboxylate (30 mg, 0.04 mmol, 1 eq.) in dichloromethane (100 μL, 0.2 M) was added trifluoroacetic acid (40 μL, 0.45 mmol, 20 eq.). After stirring for 3 h, the reaction was complete as monitored by LCMS, and the reaction mixture was concentrated to dryness and dissolved in anhydrous methanol (200 μL, 0.1 M). To this was added 10% palladium on carbon (5 mg, 15 wt%), and the reaction mixture was sparged with argon for 10 min, followed by hydrogen for 10 min. The reaction mixture was left under a balloon of hydrogen for approximately 30 min until the reaction was complete as monitored by LCMS. The reaction mixture was then sparged with argon for 10 minutes and filtered through Celite. The filtrate was then concentrated in vacuo to give methyl (3R,5S)-1-((R)-2-amino-4-phenylbutanoyl)-5-((4-carbamimidoylbenzyl)carbamoyl)pyrrolidine-3-carboxylate ditrifluoroacetate (27.1 mg, 98% over two steps) as a solid white powder after lyophilization.

[0302] Example 2 Preparation of (2S,4S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-(methoxymethyl)pyrrolidine-2-carboxamide dihydrochloride (Compound I-2) TIFF0007721142000198.tif33128 (2S,4S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-(methoxymethyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedure of Example 1, except that in step 4, the Boc group was deprotected with HCl in anhydrous methanol-modified isopropanol as the solvent.

[0303] Example 3 Preparation of (2S,4R)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride (compound I-3) TIFF0007721142000199.tif33128 (2S,4R)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedure in Example 2.

[0304] Example 4 Preparation of ((R)-1-((2S,4R)-2-((4-carbamimidoylbenzyl)carbamoyl)-4-phenylpyrrolidin-1-yl)-1-oxo-4-phenylbutan-2-yl)glycine (Compound I-4) TIFF0007721142000200.tif33142 Step 1: To a solution of ((4-(((2S,4R)-1-((R)-2-amino-4-phenylbutanoyl)-4-phenylpyrrolidine-2-carboxamido)methyl)phenyl)(imino)methyl)carbamate benzyl hydrochloride (114 mg, 0.17 mmol, 1 eq.) in anhydrous acetonitrile (1.1 mL, 0.16 M) was added DIEA (120 μL, 1.5 M) followed by benzyl bromoacetate (35 μL, 0.22 mmol, 1.3 eq.). The reaction mixture was stirred for 16 h, at which point additional benzyl bromoacetate (35 μL, 0.22 mmol, 1.3 eq.) was added and the reaction was stirred for an additional 24 h. The reaction mixture was then diluted with ethyl acetate and washed four times with water and then once with brine. The organic layer was concentrated and purified on an amine column with EtOAc / heptane to give ((R)-1-((2S,4R)-2-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)-4-phenylpyrrolidin-1-yl)-1-oxo-4-phenylbutan-2-yl)benzyl glycinate (43 mg, 32%).

[0305] TIFF0007721142000201.tif33149 Step 2:To a solution of ((R)-1-((2S,4R)-2-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)-4-phenylpyrrolidin-1-yl)-1-oxo-4-phenylbutan-2-yl)benzyl glycinate (43 mg, 0.056 mmol, 1 eq.) in anhydrous methanol (560 μL, 0.1 M) was added 10% palladium on carbon (20 mg, 50 wt%) and the reaction mixture was sparged with argon for 10 minutes followed by hydrogen for 10 minutes. The reaction mixture was left under a balloon of hydrogen for approximately 2 hours until completion as monitored by LCMS. The reaction mixture was then sparged with argon for 10 minutes and filtered through Celite. The filtrate was then concentrated in vacuo to give ((R)-1-((2S,4R)-2-((4-carbamimidoylbenzyl)carbamoyl)-4-phenylpyrrolidin-1-yl)-1-oxo-4-phenylbutan-2-yl)glycine (22.4 mg, 74%) as a solid white powder after lyophilization.

[0306] Example 5 Preparation of (2S,4S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride (Compound I-11) TIFF0007721142000202.tif31128 (2S,4S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedure in Example 2.

[0307] Example 6 Preparation of (2S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride (compounds I-26 and I-27) TIFF0007721142000203.tif19128 Step 1:To di-tert-butyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (500 mg, 1.7 mmol, 1 eq.) and triethylamine (840 μL, 6 mmol, 3 eq.) in dichloromethane (8 mL, 0.25 M) was added DMAP (24 mg, 0.2 mmol, 0.1 eq.) followed by tosyl chloride (460 mg, 2.4 mmol, 1.2 eq.). After stirring for 16 h, the mixture was further diluted with dichloromethane and washed twice with 1N HCl, twice with 1N NaOH, and then with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified on a silica column using EtOAc / heptane to give di-tert-butyl (2S,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate (690 mg, 90%) as a white solid.

[0308] TIFF0007721142000204.tif24128 Step 2: A mixture of di-tert-butyl (2S,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate (100 mg, 0.23 mmol, 1 eq.), 1H-pyrazole (30 mg, 0.46 mmol, 2 eq.), and cesium carbonate (98 mg, 0.3 mmol, 1.5 eq.) in N,N-dimethylformamide (1 mL, 0.2 M) was sealed and heated to 60 °C. After stirring for 16 h, the mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was further washed with water followed by brine, then dried over sodium sulfate and concentrated. The resulting residue was purified on a silica column using EtOAc / heptane to give di-tert-butyl (2S)-4-(1H-pyrazol-1-yl)pyrrolidine-1,2-dicarboxylate (41.1 mg, 53%) as a white solid.

[0309] TIFF0007721142000205.tif30128 Step 3:To a solution of di-tert-butyl (2S)-4-(1H-pyrazol-1-yl)pyrrolidine-1,2-dicarboxylate (41 mg, 0.12 mmol, 1 eq.) in methanol (2.4 mL, 0.05 M) was added hydrochloric acid in dioxane (4 N solution, 300 μL, 0.4 mmol, 20 eq.). After stirring for 16 h, the reaction was incomplete, so additional hydrochloric acid in dioxane (4 N solution, 300 μL, 0.4 mmol, 20 eq.) was added and the reaction mixture was heated to 40° C. After 3 days, the reaction mixture was concentrated in vacuo and carried on to the next step without further purification.

[0310] TIFF0007721142000206.tif33128 Step 4: To a solution of (2S)-methyl 4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxylate hydrochloride (0.12 mmol, 1 eq.) and D-homophenylalanine (40 mg, 0.14 mmol, 1.2 eq.) in anhydrous N,N-dimethylformamide (1.2 mL, 0.05 M) was added DIEA (84 μL, 0.48 mmol, 4 eq.), followed by hydroxybenzotriazole (20 mg, 0.14 mmol, 1.2 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (28 mg, 0.14 mmol, 1.2 eq.). After stirring overnight, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed with saturated ammonium chloride, saturated sodium bicarbonate, water, and then brine. The organic layer was concentrated and the resulting residue was purified on a silica column with EtOAc / heptane to give methyl (2S)-1-((R)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoyl)-4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxylate (34 mg, 58%).

[0311] TIFF0007721142000207.tif29149 Step 5:Methyl (2S)-1-((R)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoyl)-4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxylate was saponified with THF, HO, and LiOH by stirring at room temperature; the reaction mixture was concentrated to remove THF, and 10% KHSO solution was added to the aqueous solution. The resulting ppt was collected via vacuum filtration and washed with hexane. To the product of the saponification, (2S)-1-((R)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoyl)-4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxylic acid (0.07 mmol), ((4-(aminomethyl)phenyl)(imino)methyl)benzyl carbamate hydrochloride (29 mg, 0.09 mmol), was added DIEA (50 μL, 0.28 mmol) and DMF (540 μL). After cooling the reaction mixture to 0° C., HBTU (35 mg, 0.12 mmol) was added in one portion, and the reaction was allowed to stir at room temperature until complete. The mixture was concentrated and purified by silica column with EtOAc / heptane to give two crude products, one of which was dissolved in ethyl acetate and washed with 0.1 N HCl to give the isomer of benzyl ((4-(((2S)-1-((R)-2-amino-4-phenylbutanoyl)-4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxamido)methyl)phenyl)(imino)methyl)carbamate (8.5 mg, 13%). The other crude material was purified by a second column with MeOH / dichloromethane to give the other isomer of benzyl ((4-(((2S)-1-((R)-2-amino-4-phenylbutanoyl)-4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxamido)methyl)phenyl)(imino)methyl)carbamate (9.8 mg, 15%).

[0312] TIFF0007721142000208.tif35147 Step 6:Each isomer of benzyl ((4-(((2S)-1-((R)-2-amino-4-phenylbutanoyl)-4-(1H-pyrazol-1-yl)pyrrolidine-2-carboxamido)methyl)phenyl)(imino)methyl)carbamate was deprotected using Step 4 of Example 1, except the Boc group was deprotected with HCl in anhydrous methanol-modified isopropanol as the solvent, to provide the title compound.

[0313] Example 7 Preparation of (2S,4S)-N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-1-((R)-2-amino-4-phenylbutanoyl)-4-(methoxymethyl)pyrrolidine-2-carboxamide ditrifluoroacetate (compound I-24) TIFF0007721142000209.tif29128 Step 1: tert-Butyl (2S,4S)-2-(((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)carbamoyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate was prepared using the conditions in Example 6, Step 5.

[0314] TIFF0007721142000210.tif28128 Step 2: (2S,4S)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-((R)-2-amino-4-phenylbutanoyl)-4-(methoxymethyl)pyrrolidine-2-carboxamide ditrifluoroacetate was prepared using the conditions of steps 2-4 of Example 1, except that the Boc group was deprotected using TFA / dichloromethane and hydrogenation was not performed in step 4.

[0315] Example 8 Preparation of (2S,4S)-N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-1-((R)-2-amino-4-phenylbutanoyl)-4-cyanopyrrolidine-2-carboxamide ditrifluoroacetate (compound I-25) TIFF0007721142000211.tif30128 (2S,4S)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-((R)-2-amino-4-phenylbutanoyl)-4-cyanopyrrolidine-2-carboxamide ditrifluoroacetate was synthesized according to the procedure of Example 1, except that hydrogenation deprotection was not required and the Boc group was deprotected using TFA / dichloromethane.

[0316] Example 9 Preparation of (2S,4S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-cyanopyrrolidine-2-carboxamide ditrifluoroacetate (Compound I-6) TIFF0007721142000212.tif30128 (2S,4S)-1-((R)-2-amino-4-phenylbutanoyl)-N-(4-carbamimidoylbenzyl)-4-cyanopyrrolidine-2-carboxamide ditrifluoroacetate was synthesized according to the procedure of Example 1, except that the Boc group was deprotected using TFA / dichloromethane.

[0317] The example compounds described above, as well as additional compounds that can be prepared according to methods similar to those described for the compounds above and other methods known to those of skill in the art, are listed in Table 1. In some embodiments, the compound is a compound in Table 1.

[0318] Table 1: Exemplary compounds TIFF0007721142000213.tif180152TIFF0007721142000214.tif199152TIFF0007721142000215.tif217152TIFF0007721142 000216.tif210152TIFF0007721142000217.tif214152TIFF0007721142000218.tif203152TIFF0007721142000219.tif74152

[0319] Example 10 Enzyme assay for MASP-2 The MASP-2 assay utilizes a fluorogenic substrate based on the cleavage site of its natural substrate, C2. The assay is performed at room temperature in an assay buffer containing 20 mM HEPES, pH 7.4, 140 mM NaCl, and 0.1% Tween 20. Assay parameters are adjusted so that the assay is proportional to time, enzyme, and substrate concentration. Under these optimized assay conditions, IC values are low, except in the case of some "tight-binding" inhibitors. 50 The value is equivalent to the Ki value. "Tight-binding" or possible "slow-binding" inhibitors are treated by the method described in Copeland RA (2013) Evaluation of Enzyme Inhibitors in Drug Discovery. 2nd Ed., John Wiley and Sons, Inc., Chapters 5-7.

[0320] The MASP-2 assay protocol is as follows: Test compounds are serially diluted in DMSO and 100 nL of each dilution is transferred to an assay plate. 10 μL of assay buffer is added, followed by 15 μL of the enzyme MASP-2 (CCP1-CCP2-SP) in assay buffer. 15 μL of substrate in assay buffer is then added and mixed to initiate the reaction. After 20 minutes at room temperature, 15 μL of stop solution (0.1 M acetic acid) is added, mixed, and the plate is read on a SpectraMax i3x microplate reader and exported as an Excel file. Each assay plate included a "no inhibitor" (DMSO only) control, a "no enzyme" control, and a reference inhibitor control. % activity value = 100 * (Mean test compound fluorescence - Mean "no enzyme" fluorescence) / (Mean "DMSO only" fluorescence - Mean "no enzyme" fluorescence). IC 50 and Ki values are highly reproducible, well within ±2-fold.

[0321] The results of biological assays for the compounds listed in Table 1 are listed in Table 2 below.

[0322] Table 2: MASP-2 inhibition by exemplary compounds TIFF0007721142000220.tif61150MASP-2 Inhibition Ki Value: *K > 10 μM i **K between 2.5 and 10 μM i ***K between 0.5 and 2.5 μM i ****K less than 0.5 μM i -- Not tested

[0323] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are within the spirit and scope of this application and the scope of the appended claims. Each reference, including, but not limited to, all patents, patent applications, and publications cited in this application is incorporated herein by reference in its entirety for all purposes.

[0324] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 943,629, filed December 4, 2019, which is incorporated herein by reference in its entirety.

Claims

1. A compound having the following structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: During the ceremony, R 1 is substituted or unsubstituted aryl, or unsubstituted heteroaryl; R 2a , R 2b , R 2c , and R 2d are each independently hydrogen, C(=O)OR 5 , OC(=O)R 5 , unsubstituted alkoxy, alkoxyalkyl, cyano, C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , aryl, heteroaryl, and heterocyclyl, with the proviso that R 2a , R 2b , R 2c , and R 2d at least one of is not hydrogen; R 3 is NR 3a R 3b and R 3a and R 3b are each independently hydrogen or (CH 2 ) n C(=O)OR 6 and R 4 is substituted or unsubstituted aryl; R 5 and R 6 is independently at each occurrence hydrogen or alkyl; X is a direct bond, -CR 2e R 2f - or -CR 2e R 2f -CR 2g R 2h -, where each of R 2e , R 2f , R 2g , and R 2h is hydrogen; Y is a direct bond or -CR 2i R 2j -, where each of R 2i and R 2j is hydrogen; n is 2, 3, 4, 5, or 6; R 1 The substituted aryl of the formula has the following structure: It has one of the following.

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

3. R 1 but, 2. The compound of claim 1, wherein:

4. R 1 2. The compound of claim 1, wherein is unsubstituted heteroaryl.

5. R 1 2. The compound of claim 1, wherein is unsubstituted pyridinyl, pyrrolopyridinyl, or benzimidazolyl.

6. R 1 but has the following structure:

2. The compound of claim 1, wherein

7. R 1 but has the following structure:

2. The compound of claim 1, wherein

8. The following structure:

2. The compound of claim 1, wherein

9. R 2a , R 2b , R 2c , and R 2d At least one of the groups is unsubstituted alkoxy, alkoxyalkyl, cyano, C(═O)OR 5 , OC(=O)R 5 , C(=O)NR 5 R 6 , N(R 5 )C(=O)R 6 , aryl, heteroaryl, or heterocyclyl, where R 5 and R 6 is independently hydrogen or C in each occurrence. 1 ~C 6 2. The compound of claim 1, wherein the compound is alkyl.

10. R 2a , R 2b , R 2c , and R 2d at least one of which has the following structure:

2. The compound of claim 1, wherein

11. R 3 but has the following structure:

2. The compound of claim 1, wherein

12. 2. The compound of claim 1, wherein n is 2.

13. n is 2 and R 4 2. The compound of claim 1, wherein is substituted or unsubstituted aryl.

14. R 4 but has the following structure:

14. The compound of claim 13, having one of:

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

16. 10. A pharmaceutical composition comprising the compound of claim 1 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 claim 1 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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