Masp-2 inhibitors and methods of use

Abstract

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

Description

MASP-2 INHIBITORS AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of U.S. Provisional Application Serial Numbers 62677472, filed May 29, 2018, U.S. Provisional Application Serial Numbers 62677538, filed May 29, 2018, U.S. Provisional Application Serial Numbers 62677495, filed May 29, 2018, and U.S. Provisional Application Serial Numbers 62677514, filed May 29, 2018. Each of the foregoing related applications is incorporated herein by reference in its entirety.STATEMENT REGARDING SEQUENCE LISTINGThe sequence listing associated with this application is provided in text format in lieu of a paper copy and is hereby incorporated by reference into the specification. The name of the text file containing the sequence listing is MP_l_028l_PCT_SequenceListing_20l90528. The text file is 7 KB, was created on May 28, 2019, and is being submitted via EFS-Web with the filing of the specification.FIELDThe present disclosure is directed generally to compositions and methods that are useful in the field of medicine. More specifically, the disclosure provides small molecule synthetic inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including small molecule inhibitors that are selective for MASP-2 over thrombin,compositions thereof, and methods for the manufacture and use thereof.BACKGROUNDThe complement system plays a role in the inflammatory response and becomes activated because of tissue damage or microbial infection. Complement activation must be tightly regulated to ensure selective targeting of invading microorganisms and avoid self- inflicted damage (Ricklin et al., Nat. Immunol. 11 :785-797, 2010). Currently, it is widely accepted 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 usually triggered by a complex composed of host antibodies bound to a foreign particle (i.e., an antigen) and generally requires prior exposure to an antigen for the generation of a specific antibody response. Since activation of the classical pathway depends on a prior adaptive immune response by the host, the classical pathway is part of the acquired immune system. InSUBSTITUTE SHEET (RULE 26)lcontrast, both the lectin and alternative pathways are independent of adaptive immunity and are part of the innate immune system.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 principal 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, which is a critical component of the acquired immune response to infection. As described in U.S. Patent No. 9,011,860 (assigned to Omeros corporation), which is hereby incorporated by reference, discloses a fully human monoclonal antibody targeting human MASP-2 has been generated which binds to human MASP-2 with high affinity and blocks the lectin pathway complement activity and is therefore useful to treat various lectin complement pathway-associated diseases and disorders.MASP-2-dependent complement activation has been implicated as contributing to the pathogenesis of numerous acute and chronic disease states. Therefore, a need exists for small molecule compounds which are suitable for administration for treatment of subject suffering from MASP-2 complement pathway-associated diseases and disorders.An important protein for mammalian immunity is the mannan-binding lectin- associated serine protease-2 (MASP-2), which has been shown to be required for the function of the lectin pathway, one of the principal 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). Inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. Inhibiting human MASP-2 to block the lectin pathway complement activity is useful to treat various lectin complement pathway-associated diseases and disorders.Therapeutic compounds and methods of identifying small molecule inhibitors of MASP-2 are needed as they are important to treat various lectin complement pathway- associated diseases and disorders, including diseases that are not suitably or efficiently treated with large molecule biologic inhibitors.SUMMARYThe present disclosure provides, inter alia, compounds of Formulae (1-1) and (1-2):SUBSTITUTE SHEET (RULE 26)or a salt thereof; wherein the variables are as defined below.The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (1-1) or (1-2), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.The compounds of Formula (1-1) or (1-2) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (1-1) or (1-2), or a salt thereof.The present disclosure provides, inter alia, compounds of Formulae (IIA) and (IIB):or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (IIA) or (IIB), are also described.SUBSTITUTE SHEET (RULE 26)The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.The compounds of Formula (IIA) or (IIB) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IIA) or (IIB), or a salt thereof.The present disclosure provides, inter alia, compounds of Formula (III):or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (III), are also described.The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.The compounds of Formula (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. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient atherapeutically effective amount of a compound of Formula (III), or a salt thereof.The present disclosure provides, inter alia, compounds of Formulae (IV):or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (IV), are also described.The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.SUBSTITUTE SHEET (RULE 26)The compounds of Formula (IV) are useful as MASP-2 inhibitors. The compounds of Formula (IV) are useful in therapy. The compounds of Formula (IV) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IV), or a salt thereof.The present disclosure provides, inter alia, compounds of Formulae (VA) or (VB):or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (VA) or (VB) are also described.The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.The compounds of Formula (VA) and (VB) are useful as MASP-2 inhibitors. The compounds of Formula (VA) and (VB) are useful in therapy. The compounds of Formula (VA) and (VB) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VA) or (VB), or a salt thereof.The present disclosure provides, inter alia, compounds of Formulae (VIA) or (VIB):SUBSTITUTE SHEET (RULE 26)or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (VIA) or (VIB) are also described.The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VIA) or (VIB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.The compounds of Formula (VIA) and (VIB) are useful as MASP-2 inhibitors. The compounds of Formula (VIA) and (VIB) are useful in therapy. The compounds of Formula (VIA) and (VIB) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIA) or (VIB), or a salt thereof.The present disclosure provides, inter alia, compounds of Formulae (VIIA) or(VIIB):or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (VIIA) or (VIIB) are also described.The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VIIA) or (VIIB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.SUBSTITUTE SHEET (RULE 26)The compounds of Formula (VIIA) and (VIIB) are useful as MASP-2 inhibitors. The compounds of Formula (VIIA) and (VIIB) are useful in therapy. The compounds of Formula (VIIA) and (VIIB) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIIA) or (VIIB), or a salt thereof.The present disclosure provides, inter alia, small molecule compounds having MASP- 2 inhibitory activity, especially for therapeutic use. The small molecule compound with MASP-2 inhibitory activity interacts with the MASP-2 serine protease domain in an enzyme- inhibitor complex with a plurality of intermolecular interactions. In certain aspects, the small molecule is described with complete specificity and description by the number and type(s) of intermolecular interactions within a MASP-2 binding site, using an empirically derived rule set. The inhibitors follow one or more of the interaction rules.In certain aspects, the present disclosure provides a small molecule compound with MASP-2 inhibitory activity, for therapeutic use, wherein the compound has one or more such as 1, 2, 3, 4, or 5 of the following interactions (a) to (e):a) the compound binds via H-bonds with one or more of PRO 606, ASP 627,SER 628, ARG 630, SER 633, SER 654, GLY 656, SER 657, CYS 660 and GLN 665 in MASP-2;b) the compound binds via ionic or electrostatic interactions or hydrogen bonding to one or more of ASP 627 and ARG 630 in MASP-2;c) the compound interacts via a water molecule in MASP-2 to one or more ofTYR 602, TYR 607, ASP 627, SER 628, SER 657, ASN 659, GLU 662, TRP 655, GLY656, CYS660, GLN 665, TYR 666, VAL 668, and ARG 630 in MASP-2;d) the compound interacts via p-p interactions with one or more of PHE 529,TYR 607, and TRP 655 in MASP-2; ande) the compound interacts via van der Waals contacts to one or more of ALA 468, ALA 469, HIS 483, ASP 526, ALA 527, GLY 528, PHE 529, LEU 575, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, GLY 631, ASP 632, SER 633, GLY 634, GLY 635, VAL 653, SER 654, TRP 655, GLY656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, and TYR 669 in MASP-2,In some embodiments, the compound is not an endogenous MASP-2 ligand.In some embodiments, the compound is a synthetic small molecule MASP-2 inhibitor.SUBSTITUTE SHEET (RULE 26)In some embodiments, the compound selectively inhibits MASP-2 as compared to thrombin.Various embodiments of the compounds defined by interaction rules are described. The disclosure provides a composition comprising such a compound, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. The compounds are useful as MASP-2 inhibitors. The compounds are useful in therapy. The compounds 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of defined by interaction rules set forth herein.The present disclosure provides, inter alia, compounds of Formula (VIII):or a salt thereof; wherein the elements of the Formula may have values as described below. Various embodiments of the compounds of Formula (VIII) are also described. The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient. The compounds of Formula (VIII) are useful as MASP-2 inhibitors. The compounds of Formula (VIII) are useful in therapy. The compounds of Formula (VIII) 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIII), or a salt thereof.The present disclosure provides, inter alia, a pharmacophore model for describing small molecule compounds including synthetic compounds that inhibit MASP-2 and compounds defined with specificity by reference to such a pharmacophore model.In some embodiments, the compounds that are active as inhibitors of MASP-2 may include one or combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,SUBSTITUTE SHEET (RULE 26)21, or 22 of the pharmacophore elements, preferably combinations of 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 of the pharmacophore elements listed in Table 1. In some embodiments, the compounds may have pharmacophore elements corresponding to those listed in Table 1, wherein the (x, y, z) coordinates of the pharmacophore elements are within four standard deviations, preferably within three standard deviations, more preferably within two standard deviations and most preferably within one standard deviation as listed in Table 1.In some embodiments, a compound is provided that comprises a combination of pharmacophore elements comprising:(a) an Sl pharmacophore group comprising CA1 and Nl pharmacophore elements or CA1 and C5 pharmacophore elements; and / or(b) an S2 pharmacophore group comprising H4 and 02 pharmacophore elements; and / or(c) an S3 pharmacophore group comprising a C2 pharmacophore element and an N2 or H3 pharmacophore element;wherein:C2 and C5 are hydrophobic groups;CA1 is an aromatic ring;H3 and H4 are hydrogen bond donors;Nl and N2 are positive ionizable groups; and02 is a hydrogen bond acceptor;wherein C2, C5, CA1, H3, H4, Nl, N2, and 02 have coordinates in the ranges given in Table 3, 4 or 5 below.In some embodiments, a compound is provided that comprises a combination of pharmacophore elements comprising:(a) an Sl pharmacophore group comprising CA1 and Nl pharmacophore elements or CA1 and C5 pharmacophore elements;(b) an S2 pharmacophore group comprising H4 and 02 pharmacophore elements; and(c) an S3 pharmacophore group comprising a C2 pharmacophore element and an N2 or H3 pharmacophore element.Various embodiments of the small molecule compounds defined by thepharmacophore model are described. The disclosure provides a composition comprising such a compound, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. The compounds are useful as MASP-2 inhibitors. The compounds are useful in therapy. The compounds are useful in the treatment of MASP-2-5UB5TITUTE SHEET (RULE 26)associated diseases and disorders, and in the manufacture of medicaments for treating MASP- 2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of defined by the pharmacophore model.The present disclosure also provides small molecule compounds with MASP-2 inhibitory activity, wherein the compound interacts with a binding site of MASP-2, wherein the compounds are defined by reference to "binding rules" or "rule sets" derived using virtual docking models of crystallographically-derived MASP-2 enzyme co-crystal structures and binding sites within the MASP-2 enzyme. In certain aspects, the amino acids and their respective atoms of the MASP-2 binding site that are accessible to small molecule MASP-2 inhibitors are described. By using a variety of compounds and their intermolecular interactions, it is possible to design a set of "binding rules" or "rule set" by which MASP-2 inhibitors are specifically described.In certain aspects, an small molecule MASP-2 inhibitor is described by a rule set. The compound with MASP-2 inhibitory activity interacts with a binding site of MASP-2 such as an enzyme-inhibitor complex, with a plurality of intermolecular interactions. In certain aspects, the molecule is described with complete specificity and a complete description by the number and type(s) of in silico intermolecular interactions between atoms of the MASP-2 amino acid residues of the binding site and atoms of the inhibitor molecule. These rules are empirically derived using virtual docking models of crystallographically-derived MASP-2 enzyme co-crystal structures and binding sites within the MASP-2 enzyme. In certain instances, a plurality of MASP-2 enzyme-inhibitor models can be used such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or even more protein models to generate a set of rules.In some embodiments, the present disclosure provides a compound with MASP-2 inhibitory activity, wherein the compound interacts with a binding site, the interactions being one or more of (a) to (e):a) the compound interacts via H-bonds with one or more amino acid residues in the binding site of MASP-2 (SEQ ID NO: 1);b) the compound interacts via ionic or electrostatic interactions or hydrogen bonding in the binding site of SEQ ID NO: 1;c) the compound interacts via a water molecule in a binding site of SEQ ID NO: 1; d) the compound interacts via p-p interactions with one or more amino acid residues in the binding site of SEQ ID NO: 1; and / orSUBSTITUTE SHEET (RULE 26)e) the compound interacts via van der Waals contacts to one or more amino acid residues in the binding site of SEQ ID NO: 1, wherein the compound is not an endogenous ligand or substrate.In certain aspects, the compound has 1, 2, 3, 4, or 5 of the interactions (a)-(e).In another embodiment, the present disclosure provides a method for identifying a small molecule capable of inhibiting MASP-2, comprising:a) screening small molecule libraries using in silico docking for candidate small molecules that are selectively identified for their ability to target and bind to MASP-2 at a binding site of a MASP-2 model; andb) testing / evaluating the candidate agents identified in step (a) through one or more in vitro assays for their ability to target and bind to a MASP-2 binding site, to thereby identify the small molecule capable of inhibiting MASP-2.In certain aspects, the candidate small molecules comprise unique chemical scaffolds as identified in step (b) and are optimized for their ability to inhibit MASP-2.These and other aspects, objects and embodiments will become more apparent when read with the detailed description and figures which follow.BRIEF DESCRIPTION OF THE FIGURESFIG. 1 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1129) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 2 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1034) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A ) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 3 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1024) with those of MASP-2 amino acids as computed by LigPlot+SUBSTITUTE SHEET (RULE 26)software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 4 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1059) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 5 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1088) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 6 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1036) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 7 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1081) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.SUBSTITUTE SHEET (RULE 26)FIG. 8 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1063) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 9 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1065) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 10 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1030) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 11 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1037) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 12 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1118) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contactSUBSTITUTE SHEET (RULE 26)distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 13 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1090) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 14 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1007) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 15 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1021) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters(3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 16 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1097) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A)employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 17 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound (1089) with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters betweenSUBSTITUTE SHEET (RULE 26)hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A)employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 18 is a plot illustrating a schematic of one embodiment of the atoms of an inhibitory compound melagatran with those of MASP-2 amino acids as computed by LigPlot+ software settings for hydrogen-bond calculation parameters (3.35 A for maximum distance between hydrogen bond donor and acceptor; and non-bonded contact parameters between hydrophobic to any contacts, such as van der Waals interactions with maximum contact distance of 3.90 A) employing models derived from the corresponding crystallographic MASP-2-compound co-structures.FIG. 19 is a plot showing the binding of compound (14) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 20 is a plot showing the binding of compound (54) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 21 is a plot showing the binding of compound (1042) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 22 is a plot showing the binding of compound (2018) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 23 is a plot showing the binding of compound (1149) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 24 is a plot showing the binding of compound (1031) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 25 is a plot showing the binding of compound (1153) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 26 is a plot showing the binding of compound (1025) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 27 is a plot showing the binding of compound (1012) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 28 is a plot showing the binding of compound (1078) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 29 is a plot showing the binding of compound (1145) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 30 is a plot showing the binding of compound (1050) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.SUBSTITUTE SHEET (RULE 26)FIG. 31 is a plot showing the binding of compound (1253) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 32 is a plot showing the binding of compound (1257) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 33 is a plot showing the binding of compound (1297) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 34 is a plot showing the binding of compound (1304) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 35 is a plot showing the binding of compound (1306) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 36 is a plot showing the binding of compound (1307) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 37 is a plot showing the binding of compound (1328) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 38 is a plot showing the binding of compound (1334) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 39 is a plot showing the binding of compound (1335) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 40 is a plot showing the binding of compound (1338) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 41 is a plot showing the binding of compound (1345) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 42 is a plot showing the binding of compound (1351) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 43 is a plot showing the binding of compound (1353) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 44 is a plot showing the binding of compound (1360) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 45 is a plot showing the binding of compound (1367) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 46 is a plot showing the binding of compound (1368) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 47 is a plot showing the binding of compound (1371) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.SUBSTITUTE SHEET (RULE 26)FIG. 48 is a plot showing the binding of compound (1372) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 49 is a plot showing the binding of compound (1373) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 50 is a plot showing the binding of compound (1492) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 51 is a plot showing the binding of compound (1399) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 52 is a plot showing the binding of compound (1406) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 53 is a plot showing the binding of compound (1411) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 54 is a plot showing the binding of compound (1433) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 55 is a plot showing the binding of compound (1435) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 56 is a plot showing the binding of compound (1441) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 57 is a plot showing the binding of compound (1450) to MASP-2 showing hydrogen bonds as computed by LigPlot+ software.FIG. 58 is a plot depicting melagatran bound to thrombin.FIG. 59 is a plot showing melagatran bound to thrombin overlaid with a MASP-2 selective compound (1065) bound to MASP-2.FIG. 60 is a plot showing compound (1065) bound to the SP domain of MASP-2.FIG. 61 is a plot showing compound (1334) bound to thrombin.FIG. 62 is a plot showing compound (1334) bound to the SP domain of MASP-2.FIG. 63 is a plot showing compound (1334) bound to MASP-2 overlaid with compound (1334) bound to thrombin.FIG. 64 is a plot illustrating the S3-S4 binding pockets of MASP-2.FIG. 65 is a plot illustrating the S3-S4 binding pockets of thrombin.FIG. 66 is a plot showing a representation of the MASP-2 binding sub-pockets.FIG. 67 is a depiction of the distances between pharmacophore elements describing the Sl and S2 regions. The S2 region comprises H4, 01, 02 and CA6. The Sl region area consists of H2, 04, CA1, C3, C5, C7, and Nl. Distances mentioned in the text are shown.SUBSTITUTE SHEET (RULE 26)FIG. 68 is a plot depicting the angles between pharmacophore elements describing the Sl and S2 region.FIG. 69 is a plot depicting the definitions of torsion angles used in the text.FIG. 70 is a plot depicting the definitions of torsion angles used in the text.FIG. 71 is a plot depicting the definitions of torsion angles used in the text.FIG. 72 is a plot depicting the distances between pharmacophore elements describing the S2, S4 and RM region.FIG. 73 is a plot depicting the definitions of angles used in the text.FIG. 74 is a plot depicting the definitions of torsion angles used in the text.FIG, 75 is a plot depicting the definitions of torsion angles used in the text.FIG. 76 is a flow chart illustrating one embodiment of a process of this disclosure.DESCRIPTIONI. DefinitionsUnless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.In the Summary above, the present Description, and the claims below, reference is made to particular features and aspects of the invention, including method steps. The disclosure of the invention in this specification includes all possible combinations of such particular features within the embodiments of the invention disclosed, at least to the extent that such combinations are non-contradictory. For example, if the description presents aspects A, B, and C of an embodiment, it is understood that this also discloses particularembodiments including both aspects A and B, both aspects B and C, and both aspects A and C, as well as an embodiment with aspects A, B, and C. a. General DefinitionsThe terms "a," "an," or "the" not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example,SUBSTITUTE SHEET (RULE 26)reference to "a cell" includes a plurality of such cells and reference to "the agent" includes reference to one or more agents known to those skilled in the art.

[0001] The terms "about" and "approximately" refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Typical, exemplary degrees of error are within 20 percent (%); preferably, within 10%; and more preferably, within 5% of a given value or range of values. Any reference to "about X" specifically indicates 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 written support for a claim limitation of, e.g., "0.98X." Alternatively, in biological systems, the terms "about" and "approximately" may mean values that are within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" or "approximately" can be inferred when not expressly stated. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5% to about 20%. " When "about" is applied to the first value of a set of values, it applies to all values in that set. Thus, "about 7,9, or 11 mg / kg" is equivalent to "about 7, about 9, or about 11 mg / kg."The term "MASP-2" refers to mannan-binding lectin-associated serine protease-2. Human MASP-2 protein with UniProt accession code 000187 (SEQ ID NO: l). The Serine Protease Domain ('B-chain' = Mannan-binding lectin serine protease 2 B chain, based on UniProtKB - 000187 (MASP-2_HUMAN)) includes residues 445 to 686 (or consists of residues 445 to 686).The term "MASP-2-dependent complement activation" refers to MASP-2-dependent activation of the lectin pathway, which occurs under physiological conditions (i.e.. in the presence of Ca++) leading to the formation of the lectin pathway C3 convertase C4b2a and upon accumulation of the C3 cleavage product C3b subsequently to the C5 convertase C4b2a(C3b)n.The term "MASP-2-dependent complement-associated disease or disorder" refers to a disease or disorder that is associated with MASP-2-dependent complement activation.The term "MASP-2-associated disease or disorder" refers to a disease or disorder that is associated with activation or activity of MASP-2, including MASP-2-dependent complement-associated disease or disorders, and wherein inhibition of MASP-2 is or is expected to be therapeutically beneficial.SUBSTITUTE SHEET (RULE 26)The term "lectin pathway" refers to complement activation that occurs via the specific binding of serum and non-serum carbohydrate-binding proteins including mannan-binding lectin (MBL), CL- 11 and the ficolins (H-ficolin, M-ficolin, or L-ficolin).The term "classical pathway" refers to complement activation that is triggered by an antibody bound to a foreign particle and requires binding of the recognition molecule Clq.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).In the broadest sense, the naturally occurring amino acids can be divided into groups based upon the chemical characteristic of the side chain of the respective amino acids. By "hydrophobic" amino acid is meant either His, Leu, Met, Phe, Trp, Tyr, Val, Ala, Cys or Pro. By "hydrophilic" amino acid is meant either Gly, Asn, Gln, Ser, Thr, Asp, Glu, Lys, Arg or His. This grouping of amino acids can be further sub-classed as follows: by "uncharged hydrophilic" amino acid is meant either Ser, Thr, Asn or Gln. By "acidic" amino acid is meant either Glu or Asp. By "basic" amino acid is meant either Lys, Arg or His.The term "conservative amino acid substitution" is illustrated by a substitution among 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.The term "a subject" includes all mammals, including without limitation, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs and rodents.The terms "small molecule" and "small organic molecule" refers to a small carbon- containing molecule that has a molecular weight of about 2500 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 2000 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 1500 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 1000 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 750 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 500 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 50 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 75 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 100 daltons or greater. In some embodiments, a small molecule has a molecular weightSUBSTITUTE SHEET (RULE 26)of about 150 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 250 daltons or greater. In some emboiments, small molecules may have a molecular weight in the range from about 50 daltons to about 500 daltons, from about 50 daltons to about 750 daltons, from about 50 daltons to about 1000 daltons, from about 50 daltons to about 1500 daltons, from about 50 daltons to about 2000 daltons, or from about 50 daltons to about 2500 daltons. When the term "compound" is used herein, the term is explicitly intended to include small molecule compounds as defined herein (including any of the embodiments thereof).The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.The terms "disorder," "disease," and "condition" are used interchangeably for a condition in a subject. A disorder is a disturbance or derangement that affects the normal function of the body of a subject. A disease is a pathological condition of an organ, a body part, or a system resulting from various causes, such as infection, genetic defect, or environmental stress that is characterized by an identifiable group of symptoms.The term "effective amount" or "effective dose" means an amount sufficient to achieve the desired result and accordingly will depend on the ingredient and its desired result. Nonetheless, once the desired effect is identified, determining the effective amount is within the skill of a person skilled in the art.The term "subcutaneous administration" refers to administration of a formulation under all layers of the skin of a subject.The term "histidine" specifically includes L-histidine unless otherwise specified.The term "isotonic" refers to a formulation that has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to about 350 mOsmol / L. Isotonicity can be measured using a vapor pressure or freezing point depression osmometer, for example.The term "hypertonic" refers to a formulation with an osmotic pressure above that of human (i.e., greater than 350 mOsm / L).The term "hydrogen-bonding" is a partially electrostatic attraction between a hydrogen (H) which is bound to a more electronegative atom such as nitrogen (N) or oxygen (O) and another adjacent atom bearing a lone pair of electrons. For example, when it is statedSUBSTITUTE SHEET (RULE 26)that the nitrogen acts as a "hydrogen bond donor" it means that a hydrogen (H) bound to a nitrogen (N) is donated by the nitrogen as it electrostatically attracted to or accepted by an adjacent atom bearing a lone pair of electrons such as an oxygen. Similarly, when it is stated that an oxygen acts as a "hydrogen bond acceptor," it means that a hydrogen (H) bound to a more electronegative atom such as nitrogen (N) is electrostatically attracted to or "accepted by" an adjacent atom such as oxygen bearing a lone pair of electrons. Sometimes the hydrogen bonded atoms are called out without explicitly stating the origin and presence of an intermediate hydrogen atom. The term "hydrogen bonding" is used wherever LigPlot+ software predicts a hydrogen bonding interaction using its algorithm and applied parameters of 3.35 A for maximum distance between hydrogen bond donor and acceptor. Not all hydrogen bonds may actually be in place simultaneously; this is evident for atoms that are shown to form 4 putative hydrogen bonds, where however, at any given time only 3 hydrogen bonds are chemically possible. In general, although crystal structures such as the co-crystal structural information herein does not directly show or detect hydrogen bonding, the software used to describe the co-crystal does predict such H-bonding exists. Therefore, throughout the disclosure when a H-bond is present and described, it may be said to be "predicted" by software to be present.The term ionic bonding includes a type of chemical bond that involves the electrostatic attraction between oppositely charged ions, and is the primary interaction occurring in ionic compounds.The term "van der Waals" interaction includes weak, short-range electrostatic attractive forces between uncharged molecules, arising from the interaction of permanent or transient electric dipole moments. As determined by LigPlot+ software employing models derived from the corresponding crystallographic MASP-2 compound co-structures, such interactions include all contacts that are computed using non-bonded contact parameters between hydrophobic to any contacts for interactions with a maximum contact distance of 3.90 A.The term "p-p interaction or p-p stacking" interaction includes attractive, noncovalent interactions between aromatic rings that are oriented either roughly parallel or roughly perpendicular (such as in "edge-face" interactions) to each other, since they contain p bonds.Typically, the active site of serine proteases such as MASP-2 is shaped as a cleft where the polypeptide substrate or inhibitor binds. Schechter and Berger labeled amino acid residues from the N to C terminus of the polypeptide substrate as follows: Pi,..., P3, P2, Pl,SUBSTITUTE SHEET (RULE 26)RG, P2', P3',..., Pj) and their respective binding sub-sites Si,..., S3, S2, Sl, S 1 ', S2', S3',.··, Sj. The cleavage is catalyzed between Pl and RG (Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27 (1967)).The term "binding site" is an area on the protein wherein a small molecule can interact with such as a region on the surface of MASP-2, which region does not or only partially overlaps with the active site, but nevertheless render the MASP-2 molecule less active or inactive.The term "or" refers to an alternative and should in general be construed non- exclusively. For example, a claim to "a composition comprising A or B" would typically present an aspect with a composition comprising both A and B. "Or" should, however, be construed to exclude those aspects presented that cannot be combined without contradiction ( e.g ., a composition pH that is between 9 and 10 or between 7 and 8).The group "A or B" is equivalent to the group "selected from the group consisting of A and B."The linking term "comprising" or "comprise" is not closed. For example, "a composition comprising A" must include at least the component A, but it may also include one or more other components (e.g., B; B and C; B, C, and D; and the like). The term "comprising" therefore should in general be construed as not excluding additional ingredients. For example, a claim to "a composition comprising A" would covercompositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; and the like.The term "hypertonic" refers to a formulation with an osmotic pressure above that of human (i.e., greater than 350 mOsm / KglHhO).The term "agent" refers to a compound or mixture of compounds that, when added to a composition, tend to produce a particular effect on the composition's properties. For example, a composition comprising a thickening agent is likely to be more viscous than an otherwise identical comparative composition that lacks the thickening agent.

[0002] A "subject" includes all mammals, including without limitation, humans, non human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs and rodents.A "synthetic" compound means a compound that is not naturally occurring and that has been synthesized by humans. Reference to a compound herein may be understood to include reference to synthetic compounds, unless the context indicates otherwise.The terms "treat," "treating," or "treatment" includes administering or applying a composition (e.g., a composition described herein) in an amount, manner (e.g., schedule ofSUBSTITUTE SHEET (RULE 26)administration), and mode (e.g., route of administration) that is effective to improve a disorder or a symptom thereof, or to prevent, to retard, or to slow the progression of a disorder or a symptom thereof. Such improvements can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable."Treating" and "treatment" also include prophylactic treatment. In certainembodiments, treatment methods comprise administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may comprise a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the subject, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In one aspect, chronic administration may be required. For example, the compositions are administered to the subject in an amount, and for a duration, sufficient to treat the subject.The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C. b. Chemical DefinitionsAt various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the terms "Ci-6 alkyl" and "C1-C6 alkyl" are specifically intended to individually disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and Ce alkyl.At various places in the present specification, variables defining divalent linking groups are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R")n- includesSUBSTITUTE SHEET (RULE 26)both -NR(CR'R")n- and -(CR'R")nNR- and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta- substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. The phrase "optionally substituted" means substituted or unsubstituted. The term "substituted" means that a hydrogen atom is formally removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.The terms "Cn-m" and "Cn-Cm" where n and m are integers indicates a group that contains from n to m carbon atoms. Examples include Ci-4, Ci-6, and the like. The term is intended to expressly disclose every member in the range, i.e., Cn, Cn+i, Cn+2 ... Cm-2, Cm-1, Cm. For example, Ci-6 is intended to disclose Ci, C2, C3, C4, C5, and Ce. "Cn-m" means the same as "Cn-Cm".The term "alkyl" employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. The terms "Cn-m alkyl" and "Cn-Cm alkyl" refer to an alkyl group having n to m carbon atoms. For example, C1-C12 indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. If not otherwise indicated, an alkyl group about 1 to about 20 carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, «-propyl, isopropyl, «-butyl, fe / T-butyl, isobutyl, .sec-butyl: higher homologs such as 2-methyl- 1 -butyl, l,l-dimethylpropyl, «-pentyl, 3-pentyl, «-hexyl, 1,2,2- trimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and the like. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms in the chain. A "substituted alkyl" group is an alkyl group that is substituted with one or more substituents.SUBSTITUTE SHEET (RULE 26)The term "alkenyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The terms "Cn-m alkenyl" and "Cn-Cm alkenyl" refer to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n- propenyl, isopropenyl, / l-butenyl. ve -butenyl and the like.The term "alkynyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term "Cn-m alkynyl" and "Cn-Cmalkynyl" refer to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-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.The term "alkylene", employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bonds replaced by points of attachment of the alkylene group to the remainder of the compound. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethan-l,2-diyl, propan-l,3-diyl, propan- 1 ,2-diyl, butan-l,4-diyl, butan-l,3-diyl, butan-l,2-diyl, 2-methyl- propan-l,3-diyl and the like. In some embodiments, "Cn-m alkylene" can refer to chain of from n to m methylene (CH2) groups, -(CH2)n-m-, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, etc.The term "alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "Cn-m alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., 12-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.The term "alkoxy alkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by an alkoxy group. The term "Cn-m alkoxy-CP-q alkyl" refers to a CP- q alkyl group substituted by a Cn-m alkoxy group. In some embodiments, the hydroxyalkyl group has one alkoxy group. In some embodiments, the alkoxyalkyl group has one or twoSUBSTITUTE SHEET (RULE 26)alkoxy groups, each on a different carbon atom. Examples may include, but are not limited to, methoxymethyl, ethoxymethyl, 3-ethoxy ethyl, and l-methoxy ethyl.The term "amino" refers to a group of formula -NH2.The term "carbamyl" refers to a group of formula -C(0)NH2.The term "carbonyl", employed alone or in combination with other terms, refers to a - C(=0)- group, which also may be written as C(O).The term "cyano" or "nitrile" refers to a group of formula -CºN, which also may be written as -CN.The terms "halo" or "halogen", used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom 10 selected from F, Cl, or Br. In some embodiments, halo is F.The term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term " Cn-m haloalkyl" refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+l } halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCh, CHCh, C2CI5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.The term "haloalkoxy", employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "Cn-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.The term "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a hydroxy. The term " Cn-m hydroxyalkyl" refers to a Cn-malkyl group having n to m carbon atoms and from at least one hydroxy group. In some embodiments, the hydroxyalkyl group has one alcohol group. In certain aspects, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, and 1 -hydroxy ethyl.The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an / V-oxide group.SUBSTITUTE SHEET (RULE 26)The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when atached to carbon.The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. The term "n-m membered" wherein n and m are integers describes a range where the number of ring forming atoms is from n to m. For example, piperidinyl is an example of a 6-memberedheterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and l,2,3,4-tetrahydro-naphthalene is an example of a lO-membered cycloalkyl group.The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e.. having (4n + 2) delocalized p (pi) electrons where n is an integer).The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetracenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms, from 6 to about 18 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In some embodiments, the aryl group is phenyl.The term "arylalkyl" or "aralkyl" or "alkylaryl" employed alone or in combination with other terms, refers to a group of formula -alkylene-aryl, and refers to an alkyl group as defined herein wherein at least one hydrogen has been replaced by an aryl group as defined herein. In some embodiments, arylalkyl is C6-10 aryl-Ci-3 alkyl. In some embodiments, arylalkyl is C6-10 aryl-Ci-4 alkyl. In some embodiments, arylalkyl is C6-10 aryl-Ci-3 alkyl. In some embodiments, arylalkyl is phenyl-Ci-3 alkyl. Examples include, but are not limited to, benzyl, l-phenylethyl, 4-methylbenzyl, and l,l,-dimethyl-l-phenylmethyl. In some embodiments, arylalkyl is benzyl.The term "heteroaryl" or "heteroaromatic," employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. An "n-membered heteroaryl" or "n-membered heteroaromatic", wherein n is an integer, refers to a heteroaryl having n ring-forming atoms. An "n-m membered heteroaryl" or "n-m membered heteroaromatic", wherein n and m are integers, refers to a heteroaryl having from n to m ring forming atoms. The number of carbon atoms in the ring is fewer than the number of ringSUBSTITUTE SHEET (RULE 26)forming atoms by the number of heteroatoms. Thus, in some embodiments, an n-membered heteroaryl may have n-l, n-2, n-3 or n-4 ring carbon atoms and an n-m membered heteroaryl may have from n-l, n-2, n-3 or n-4 ring carbon atoms to m-l, m-2, m-3 or m-4 ring carbon atoms. In some embodiments, an n-m membered heteroaryl may have from 1 to m-l ring carbon atoms. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, quinoline, isoquinoline, naphthyridine (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6- naphthyridine), indole, azaindole, benzothiophene, benzofuran, benzisoxazole,benzimidazole, imidazo| 1.2-6 |thiazole. purine, furazane, triazole, tetrazole, l,2,4-thiadiazole, quinazoline, phthalazine, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, or the like.A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g.. 1, 2 or 3) ring atoms are independently selected from N, O and S.Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, l,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, l,2,3-oxadiazolyl, 1 ,2,4-triazolyl, l,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1,3,4- triazolyl, l,3,4-thiadiazolyl and l,3,4-oxadiazolyl.A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.The term "heteroarylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heteroaryl. The term "n-membered heteroarylalkyl" wherein n is an integer refers to a heteroarylalkyl group in which the heteroaryl is n-membered. The term "n-m membered-Cp-q-alkyl" wherein n, m, p and q are integers refers to heteroarylalkyl group in which the heteroaryl is n to m membered and the alkyl has from p to q carbon atoms.SUBSTITUTE SHEET (RULE 26)In some embodiments, heteroarylalkyl is 5-10 membered heteroaryl-Ci-3 alkyl or C1-9 heteroaryl-Ci-3 alkyl, wherein the heteroaryl portion is monocyclic or bi cyclic and has 1, 2, 3, 4 or 5 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heteroarylalkyl is C 1-9 heteroaryl-Ci-4 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. Examples include pyridylmethyl, such as 2-pyridylmethyl, 3 -pyridylmethyl, or 4-pyridylmethyl.The term "cycloalkyl", employed alone or in combination with other terms, refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. The term includes cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic ( e.g ., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e.. having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, bicyclo[l. l. l]pentanyl, bicyclo[2.l.l]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.The term " cycloalky lalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-cycloalkyl. The term Cn-m cycloalkyl-Cp-q alkyl wherein n, m, p and q are integers, refers to a cycloalkyl group having from n to m carbon atoms attached to an alkyl group having from p to q carbon atoms. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic orSUBSTITUTE SHEET (RULE 26)bicyclic. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentanemethyl, and cyclohexylmethyl.The term "heterocycloalkyl", employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. An "n-membered heterocycloalkyl" wherein n is an integer, refers to a heteroaryl having n ring-forming atoms. An "n-m membered heterocycloalkyl" wherein n and m are integers, refers to aheterocycloalkyl having from n to m ring-forming atoms. The number of carbon atoms in the ring is fewer than the number of ring forming atoms by the number of heteroatoms. Thus, in some embodiments, an n-membered heterocycloalkyl may have n-l, n-2, n-3 or n-4 ring carbon atoms and an n-m membered heterocycloalkyl may have from n-l, n-2, n-3 or n-4 ring carbon atoms to m-l, m-2, m-3 or m-4 ring carbon atoms. In some embodiments, an n-m membered heterocycloalkyl may have from 1 to m-l ring carbon atoms. In someembodiments, a heterocycloalkyl has 4-12 ring members, 4-10 ring members, 4-7 ring members or 4-6 ring members. Included in heterocycloalkyl groups are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic ( e.g ., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfide group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(0)2, A-oxide etc.) or a nitrogen atom can be quatemized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e.. having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidine, azepane, dihydrobenzofuran, dihydrofuran, dihydropyran, morpholine, 3-oxa-9- azaspiro[5.5]undecane, l-oxa-8-azaspiro[4.5]decane, piperidine, piperazine, pyran, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, l,2,3,4-tetrahydroquinoline, tropane, and thiomorpholine.SUBSTITUTE SHEET (RULE 26)As used herein, the term "heterocycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heterocycloalkyl. The term "n- membered heterocycloalkylalkyl" wherein n is an integer refers to a hereoarylalkylalkyl group in which the heterocycloalkyl is n-membered. The term "n-m membered-Cp-q-alkyl wherein n, m, p and q are integers refers to heterocycloalkylalkyl group in which the heterocycloalkyl is n to m membered and the alkyl has from p to q carbon atoms. In some embodiments, heterocycloalkylalkyl is 4-10 membered heterocycloalkyl-Ci-3 alkyl or C1-9 heterocycloalkyl-Ci-3 alkyl, wherein the heterocycloalkyl portion is monocyclic or bi cyclic and has 1, 2, 3, 4 or 5 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is C2-9 heterocycloalkyl-Ci-4 alkyl or C2-9 heterocycloalkyl-Ci-3 alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.At certain places, the definitions or embodiments may refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3 -position.When any two groups or two instances of the same substituent group are"independently selected" from a list of alternatives, the groups may be the same or different. For example, if Raand Rbare independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two Ragroups and two Rbgroups could have all groups be alkyl group (e.g., four different alkyl groups). Alternatively, the first Racould be alkyl, the second Racould be fluoro, the first Rbcould be hydroxyalkyl, and the second Rbcould be amino (or any other substituents taken from the group). Alternatively, both Raand the first Rbcould be fluoro, while the second Rbcould be alkyl (i.e.. some pairs of substituent groups may be the same, while other pairs may be different). Unless otherwise indicated, if two or more groups having the same definition are present, but the definition provides for alternatives, it should be understood that each occurrence of the same group is independently selected from the possible alternatives. For example, if two or more Ragroups are present in a compound, and the definition of Raprovides that Racan be A, B or C, then it should be understood that each Ragroup present in the compound is independently chosen from A, B and C, so that the Ragroups present in the compound can be the same or different.SUBSTITUTE SHEET (RULE 26)The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds described herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, l,2-diaminocyclohexane and the like.Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.In some embodiments, the compounds of the invention have the (^-configuration. In other embodiments, the compounds have the (^-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently ( R ) or (S), unless otherwise indicated.Compounds described herein may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or moreSUBSTITUTE SHEET (RULE 26)positions of a heterocyclic system, e.g., 1H- and 5 / / -i midazole. 1H-, 2H- and 4H- 1, 2,4- triazole, 1H- and 2H- isoindole and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. The disclosure is intended to encompass all such tautomers of the compounds described.Compounds described herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.The term, "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.Compounds described herein may include acidic and / or basic groups and be capable of forming salts. It should be understood that the present disclosure is intended to include all salts of compounds that are capable of forming salts, whether or not the possible existence of salts is expressly described, including both acid and base salts of a compound. Furthermore, when a compound is described that is a salt, it is understood that the disclosure of the compound is intended to include all forms of the compound, including the free base or free acid, as well as alternative salt forms thereof. The term "salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The terms "a salt thereof," "salt thereof," or "salts thereof' can be applied to any preceding member of an associated Markush group. For example, a group consisting of A, B, C, and salts thereof would include within its scope embodiments that were a salt of A, embodiments that were a salt of B, and embodiments that were a salt of C.Salts of the compounds disclosed herein include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are foundSUBSTITUTE SHEET (RULE 26)in Remington's Pharmaceutical Sciences, 17thEd., (Mack Publishing Company, Easton,1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66( 1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA, which is incorporated herein by reference.Compounds, and salts thereof, including pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein, and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid-state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference to compounds and salts thereof should be understood as encompassing any solid-state form of the compound.In some embodiments, the compounds described herein or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the invention. Substantial separation can include compositions 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% by weight of the compounds of the invention, or salt thereof. c. AbbreviationsThe following abbreviations may be used herein and, unless otherwise noted, have the meanings indicated below: m (micro); °C (degrees Celsius); Ac (acetyl); ACN (acetonitrile); anhyd (anhydrous); aq (aqueous); atm (atmosphere(s)); Bn (benzyl); Boc (tert- butoxy carbonyl); Bu (butyl); calcd (calculated); Cbz (benzyloxycarbonyl); chrom.(chromatography); CPME (cyclopentyl methyl ether); CH2CI2 (dichloromethane); coned (concentrated); cone (concentration); DCC (N A'-dicyclohexylcarbodiimide); DIAD(Diisopropyl azodicarboxylate); DIEA (A.A-di isopropyl ethyl amine): DMAP (4-(A,A- dimethylamino)pyridine); DMF (dimethylformamide); DMSO (dimethylsulfoxide); EDC (A- (3-dimethylaminopropyl)-A-ethylcarbodiimide hydrochloride); equiv (equivalent); ES (electrospray); Et (ethyl); Et20 (diethyl ether); g (gram(s)); h (hour(s)); HATU ( N -SUBSTITUTE SHEET (RULE 26)[(Dimethy lamino)- \H- 1 ,2,3 -triazolo- [4,5 -b\ py ridin- 1 -y lmethy lene] -A-methy lmethanaminium hexafluorophosphate A-oxide); HBTU (0-(Benzotriazol-l-yl)-AAA',A'-tetramethyl-O-(lA- benzotriazol-l-yl)uronium hexafluorophosphate,); HPLC (high-performance liquid chromatography); HOBt (l-hydroxybenzotriazole hydrate); L (liter(s)); m (milli); in- meta ; M (molar); MeCN (acetonitrile); min (minute(s)); mL (milliliter); mol (mole; molecular (as in mol wt)); Ms (methanesulfonyl); MS (mass spectrometry); MW (molecular weight); NBS (A- bromosuccinimide); NCS (A-chlorosuccinimide); NIS (A-iodosuccinimide): NHS (A- hydroxysuccinimide); NMM (4-methylmorpholine); NMR (nuclear magnetic resonance); o- (ortho); obsd (observed); p- (para); Ph (phenyl); Phth (Phthalimide); ppt (precipitate); Pr (propyl); psi (pounds per square inch); temp (temperature); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TPP (triphenylphosphine); and Tr (trityl). Other abbreviations may also be used and have the meanings that would be understood by the person having skill in the art.II. CompoundsA. Compounds of Formula 1-1In certain aspects, the present disclosure provides a compound of Formula (1-1):or a salt thereof, wherein:Cy1Ais unsubstituted or substituted Ce-io aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy1Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy1Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCylA, halogen, Ci-6 haloalkyl, C0C(0)NRclC(=NRell)NRcllRdn, C(=NORall)NRcllRdn, C(=N0C(0)Rbll)NRcllRdn,C(=NRell)NRcllC(0)0Ral1, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;each RCylAis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl,SUBSTITUTE SHEET (RULE 26)wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming Rt l Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming Rt l Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen,S(0)2NRcllRdnand oxo, and wherein each Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC l Ais independentlyunsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, ORa11, SRa11, C(0)Rbn,C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, 0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;R11is H or Ci-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the Ci-6 alkyl forming R11is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn,C(0)ORa11, OC(0)Rbn, 0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo, and wherein the C6-10 aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R11is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn, 0C(0)NRcllRdn,S(0)2NRcllRdnand oxo;R12is H or Ci-6 alkyl; orR11and R12, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;A11is CR13R15or N;each R13is independently Cy1B, (CR13AR13B)n3Cy1B, (Ci-6 alkylene)Cy1B, (C2-6 alkenylene)Cy1B, (C2-6 alkynylene)Cy1Bor OCy1B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R13is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa11,SUBSTITUTE SHEET (RULE 26)SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)0Ral1, 0C(0)Rbn, 0C(0)NRcllRdn, NRcllRdn,S(0)2NRcllRdnand oxo;each R14is independently selected from H and Ci-6 alkyl;R15is selected from H, R13, Ci-6 alkyl and OH;a pair of R14groups attached to adjacent carbon atoms, or a pairing of R14and R15groups attached to adjacent carbon atoms, may, independently of other occurrences of R14, together be replaced a bond connecting the adjacent carbon atoms to which the pair of R14groups or pairing of R14and R15groups is attached, such that the adjacent carbon atoms are connected by a double bond; ora pair of R14groups attached to the same carbon atom, or a pairing of R13and R15groups attached to the same carbon atom, may, independently of other occurrences of R14, and together with the carbon atom to which the pair of R14groups or pairing of R13and R15groups is attached together form a spiro-fused C3-10 cycloalkyl or 4-10 memberedheterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein the spiro-fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn,C(0)ORa11, OC(0)Rbn, 0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo; orpairs of R14groups attached to adjacent carbon atoms, or a pairing of R14and R15groups attached to adjacent carbon atoms, may, independently of other occurrences of R14, together with the adjacent carbon atoms to which the pair of R14groups or pairing of R14and R15groups is attached, form a fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein the fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, C0C(0)NRclSUBSTITUTE SHEET (RULE 26)C(=NRell)NRcllRdll, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo; ora grouping of four R14groups attached to two adjacent carbon atoms, or a grouping of two R14, one R13and one R15groups attached to two adjacent carbon atoms, may, independently of other occurrences of R14, together with the two adjacent carbon atoms to which the grouping of four R14groups or grouping of two R14, one R13and one R15groups are attached, form a fused C6-10 aryl or 5-10 membered heteroaryl, C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, and wherein the fused C6-io aryl or 5-10 membered heteroaryl, C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, haloalkyl, CN, ORa11, SRa11, C(0)Rb n, C(0)NRc l lRd n,C(0)ORa11, OC(0)Rbn, OC(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;nl is 1 or 2;n2 is 0, 1 or 2;provided that the sum of nl and n2 is 1, 2 or 3;provided that if nl is 1 or n2 is 0, then A11is CR13R15;n3 is 0, 1 or 2;each R13Ais independently H or C1-6 alkyl;each R13Bis independently H or C1-6 alkyl; oror R13Aand R13Battached to the same carbon atom, independently of any other R13Aand R13Bgroups, together may form -(CH2)2-5-, thereby forming a 3-6 membered cycloalkyl ring;Cy1Bis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy1Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; andwherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy1Bare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCylB, halogen, Ci-6SUBSTITUTE SHEET (RULE 26)haloalkyl, CN, ORa11, S^11, C(0)Rbn, C(0)NRcllRdn, C(0)0Ral1, 0C(0)Rbn,NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;wherein each RC 1 Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC 1 Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 1 Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C0C(0)NRcllRdnC(=NRell)NRcllRdll, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 1 Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa11, SRa11,S(0)2NRcllRdnand oxo;R16is H, Cyic, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R16is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cyic, halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, OC(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rb11, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo, provided that no more than one of the substituents of R16is Cyic;Cyicis unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cyicconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; andSUBSTITUTE SHEET (RULE 26)wherein the substituted Ce-io aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cyicare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCylc, halogen, Ci-6 haloalkyl, CN, ORa11, S®311, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn,0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, C(=NORall)NRcllRdn, C(=NOC(0)Rbll)NRcllRdn,C(=NRell)NRcllC(0)ORa11, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;wherein each RC 1 cis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC l tconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCylcis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn,NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCylcis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn, OC(0)NRcllRdn, NRcllRdn,NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn,NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn,S(0)2NRcllRdnand oxo;Raii, Rbn, Rcl1and Rdnare each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- C1-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ral1, Rbn, Rcl1and Rdnare each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa12, SRa12, C(0)Rbl2, C(0)NRcl2Rdl2, C(0)ORa12, OC(0)Rb12,SUBSTITUTE SHEET (RULE 26)0C(0)NRcl2Rdl2, NRcl2Rd12, NRcl2C(0)Rbl2, NRcl2C(0)NRcl2Rdl2, NRcl2C(0)0Ral2, C(=NRel2)NRcl2Rd12, NRcl2C(=NRel2)NRcl2Rd12, S(0)Rbl2, S(0)NRcl2Rdl2, S(0)2Rbl2, NRcl2S(0)2Rbl2, S(0)2NRcl2Rdl2and oxo;or Rcl 1and Rdnatached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, ORa12, SRa12, C(0)Rbl2, C(0)NRcl2Rdl2, C(0)0Ral2, 0C(0)Rbl2, 0C(0)NRcl2Rdl2, NRcl2Rd12, NRcl2C(0)Rbl2, NRcl2C(0)NRcl2Rdl2,NRcl2C(0)0Ral2, C(=NRel2)NRcl2Rd12, NRcl2C(=NRel2)NRcl2Rd12, S(0)Rbl2, S(0)NRcl2Rdl2, S(0)2Rbl2, NRcl2S(0)2Rbl2, S(0)2NRcl2Rdl2and oxo;Ral 2. Rbl2, Rcl2and Rdl2are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ral2, Rbl2, Rcl2and Rdl2are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rcl2and Rdl2atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRel 1and Re12are each, independently, H, CN or N02.In some embodiments, the compound is of Formula (1-2):SUBSTITUTE SHEET (RULE 26)In some embodiments, Cy1Ais unsubstituted or substituted aryl.In some embodiments, Cy1Ais unsubstituted or substituted phenyl.In some embodiments, Cy1Ais substituted phenyl.In some embodiments, Cy1Ais substituted with at least one ORa11or at least one C(=NRell)NRcllRdn, C(=NORall)NRcllRdn, C(=N0C(0)Rbll)NRcllRdn, orC(=NRell)NRcllC(0)0Ral1.In some embodiments, Cy1Ais substituted with at least one ORa11and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy1Ais substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy1Ais substituted with at least one C(=NRell)NRcllRdn, C(=NORall)NRcllRdn, C(=N0C(0)Rbll)NRcllRdn, C(=NRell)NRcllC(0)0Ral1, preferably in the 4-position.In some embodiments, Cy1Ais substituted with at least one C(=NRell)NRcllRdn, preferably in the 4-position.In some embodiments, Cy1Ais substituted with at least one C(=NH)NH2, preferably in the 4-position.In some embodiments, Cy1Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)In some embodiments, in the formula defining Cy1A, each Rtv 1 Lis independently Ci-6 alkyl, such as methyl, or halogen, such as Cl or Br, or amino.In some embodiments, Cy1Ais of any one of the following formulae:In some embodiments, in the formula defining Cy1A, Ral1is Ci-6 alkyl, such as methyl, Rbnis Ci-6 alkyl, such as methyl, Rbnis Ci-6 haloalkyl, such as trifluoromethyl, and Rcl1is alkyl such as methyl.In some embodiments, Cy1Ais unsubstituted or substituted heteroaryl.In some embodiments, Cy1Ais unsubstituted or substituted pyridin-3-yl, 1H- pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.In some embodiments, Cy1Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)In some embodiments, each RC 1 Lin the formula defining Cy1Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.In some embodiments, each Rt 1 Lattached to nitrogen in the formula defining Cy1Ais Ci-6 alkyl, such as methyl or ethyl.In some embodiments, R11is Ci-6 alkyl.In some embodiments, R11is methyl.In some embodiments, R11is H.In some embodiments, R12is H.In some embodiments, R12is Ci-6 alkyl, such as methyl or ethyl, preferably methyl. In some embodiments, R11and R12, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.In some embodiments, nl is 1.In some embodiments, nl is 2.In some embodiments, n2 is 0.In some embodiments, n2 is 1.In some embodiments, n2 is 2.In some embodiments, the compound is according to any of the following Formulae (I-la) to (I- If) and (I-2a) to (I-2r):(I- la) (I- lb)SU BSTITUTE SH EET ( RU LE 26)(I-2e) (I-2f)SUBSTITUTE SHEET (RULE 26)(I-2o) (I-2p)SUBSTITUTE SHEET (RULE 26)(I-2q) (I-2r)In some embodiments, the compound is according to any of the following Formulae (I-lg) to (I-lo) and (I-2aa) to (I-2az):(I-lo)SUBSTITUTE SHEET (RULE 26)(I-2ak) (I-2al)SUBSTITUTE SHEET (RULE 26)(I-2au) (I-2av)SUBSTITUTE SHEET (RULE 26)(I-2ay) (I-2az)In some embodiments, the compound is according to any of the following Formulae (1-3) to (1-9):(1-9)SUBSTITUTE SHEET (RULE 26)In some embodiments, the compound is according to any of the following Formulae (I-3a) to (I-3k):In some embodiments, the compound is according to any of the following Formulae(I-4a) to (I-4bf):SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(1-4 al) (I-4am)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-4be) (I-4bf)In some embodiments, the compound is according to any of the following Formulae(I-5a) to (I-5u):(I-5e) (I-5f)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-5u)In some embodiments, the compound is according to any of the following Formulae(I-6a) to (I-6cw):(I-6i) (I-6j)SUBSTITUTE SHEET (RULE 26)(I-6u) (I-6v)SUBSTITUTE SHEET (RULE 26)(I-6ag) (I-6ah)SUBSTITUTE SHEET (RULE 26)(I-6at)(1-6 as)SUBSTITUTE SHEET (RULE 26)(i-6be) (I-6bf)SUBSTITUTE SHEET (RULE 26)(I-6bq) (I-6br)SUBSTITUTE SHEET (RULE 26)(I-6cc) (I-6cd)SUBSTITUTE SHEET (RULE 26)(I-6co) (I-6cp)SUBSTITUTE SHEET (RULE 26)(I-6cv) (I-6cw)In some embodiments, the compound is according to any of the following Formulae (I-7a) to (I-7co):SUBSTITUTE SHEET (RULE 26)(I-7m) (I-7n)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-7ak) (I-7al)SUBSTITUTE SHEET (RULE 26)(I-7)ax(1-7 aw)SUBSTITUTE SHEET (RULE 26)(I-7bi) (I-7bj)SUBSTITUTE SHEET (RULE 26)(I-7bu) (I-7bv)SUBSTITUTE SHEET (RULE 26)(I-7cg) (I-7ch)SUBSTITUTE SHEET (RULE 26)(I-7co)In some embodiments, the compound is according to any of the following Formulae (I-8a) to (I-8z):(I-8c) (I-8d)SUBSTITUTE SHEET (RULE 26)(I-80) (I-8p)SUBSTITUTE SHEET (RULE 26)(I-8y) (I-8z)In some embodiments, the compound is according to any of the following Formulae (I-9a) to (I-9z):SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(i-9y) (I-9z)In some embodiments, R13is Cy1B.SUBSTITUTE SHEET (RULE 26)In some embodiments, R13is (Ci-6 alkylene)Cy1B, (C2-6 alkenylene)Cy1B, or (C2-6 alkynylene)Cy1B. In some embodiments, the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R13is unsubstituted.In some embodiments, R13is (CR13AR13B)n3Cy1B.In some embodiments, each R13Ais H.In some embodiments, each R13Bis H.In some embodiments, n3 is 0.In some embodiments, n3 is 1.In some embodiments, n3 is 2.In some embodiments,In some embodiments,In some embodiments,In some embodiments,In some embodiments, Cy1Bis unsubstituted Ce-io aryl.In some embodiments, Cy1Bis unsubstituted phenyl.In some embodiments, Cy1Bis unsubstituted naphthyl, such as 1 -naphthyl or 2- naphthyl.In some embodiments, Cy1Bunsubstituted 5-10 membered heteroaryl.In some embodiments, Cy1Bis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl or unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.In some embodiments, Cy1Bis substituted Ce-io aryl.In some embodiments, Cy1Bis substituted phenyl.In some embodiments, Cy1Bis a biphenylyl (i.e., phenyl substituted by phenyl), such as 2-, 3-, or 4-biphenylyl.In some embodiments, Cy1Bis substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.In some embodiments, Cy1Bsubstituted 5-10 membered heteroaryl.In some embodiments, Cy1Bis substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl or substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.In some embodiments, Cy1Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCylB, halogen, and C1-6 haloalkyl; wherein each RCylBis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and Ce-io aryl or 5-10 membered heteroaryl, wherein each Ce-io aryl or 5-10 membered heteroaryl forming RC 1 Bis unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.SUBSTITUTE SHEET (RULE 26)In some embodiments, R13is selected from groups of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)In some embodiments, Rt 1 Bin the formula representing R13is Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen, such as fluorine or chlorine, preferably fluorine.In some embodiments, Rt 1 Bin the formula representing R13is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.In some embodiments, RC 1 Bin the formula representing R13is halogen, such as fluorine or chlorine, preferably fluorine.In some embodiments, no more than one R14is other than hydrogen.SUBSTITUTE SHEET (RULE 26)In some embodiments, no more than one R14is other than hydrogen and one R14is Ci- 6 alkyl, such as methyl.In some embodiments, each R14is hydrogen.In some embodiments, A11is N.In some embodiments, R15is hydrogen.In some embodiments, R15is Ci-6 alkyl such as methyl.In some embodiments, R15is hydroxyl.In some embodiments, R16is hydrogen.In some embodiments, R16is unsubstituted or substituted Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.In some embodiments, R16is unsubstituted Ci-6 alkyl such as methyl.In some embodiments, R16is substituted Ci-6 alkyl.In some embodiments, the substituted Ci-6 alkyl forming R16is substituted by 1, 2, 3,4 or 5, such as 1, 2, or 3, or, preferably 1, substituents selected from the group consisting of halogen, CN, C(0)NRcllRdnand C(0)0Ral1.In some embodiments, R16is (CH2)i-6C(0)0Ra11.In some embodiments, the Ral1defining R16is H or Ci-6 alkyl such as methyl.In some embodiments, the Ral1defining R16is H.In some embodiments, Ral1, Rbn, Rcl1and Rdn, Ral2, Rbl2, Rcl2and Rdl2are each independently selected from H and Ci-6 alkyl.In some embodiments, each Rel1and each Rel2is H.In some embodiments, the compounds of Formula (1-1), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.The compounds of Formula (1-1), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (1-1), 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (1-1), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (1-1) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.SUBSTITUTE SHEET (RULE 26)In certain aspects, the compound is one or more selected from the compounds of Formula (1-1) set forth in the Examples, including the compounds listed in Table 31, ie.g., the compounds with selectivity for MASP-2 over thrombin). In certain aspects, one or more of the variables defining the compounds of Formula (I) (such as Cy1A; RCylA; R11; R12; A11; R13; R14; R15; nl ; n2; n3; R13A; R13B; Cy1B; R16; R16A; R16B; Cyic; RCylc; Ral1, Rbn, Rcl1; Rdn;Rei i, Ral2, Rbl2, Rcl2; Rdl2; and Rel 1) is selected from the corresponding substituents in the compounds of Formula (1-1) in the Examples including the compounds listed in Table 31, preferably, those of the compounds with selectivity for MASP-2 over thrombin.In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group;hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O-alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1,SUBSTITUTE SHEET (RULE 26)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.B. Compounds of Formula IIA and IIBIn certain aspects, the present disclosure provides a compound of Formula (IIA) and(IIB)or a salt thereof, wherein:Cy2Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy2Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-io aryl or substituted 5-10 membered heteroaryl forming Cy2Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy2A, halogen, Ci-6 haloalkyl, C0C(0)NRc2C(=NRe21)NRc21Rd21, C(=NORa21)NRc21Rd21, C(=N0C(0)Rb21)NRc21Rd21,C(=NRe21)NRc21C(0)0Ra21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;each RCy2Ais independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming RCy2Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCy2Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21,SUBSTITUTE SHEET (RULE 26)NRC2iRd2iNRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21,S(0)2NRc21Rd21and oxo, and wherein each Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 2Ais independentlyunsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, OR321, SRa21, C(0)Rb21,C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21, NRc21Rd21, NRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;R21is H or C1-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the C1-6 alkyl forming R21is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21,C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21, NRc21Rd21, NRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R21is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21,NRC2iRd2iNRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21,S(0)2NRc21Rd21and oxo;R22is H or C1-6 alkyl; orR21and R22, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;A23is N or NR23;A24is CR24; N or NR24;A26is CR26or S;provided thatA23, A24and A26in Formula (IIA) are selected such that the ring comprising A23, A24and A26is a heteroaryl ring and the symbol = represents an aromatic ring (normalized) bond;R23is H or C1-6 alkyl;R24is H; C1-6 alkyl or phenyl;SUBSTITUTE SHEET (RULE 26)R25is Cy2B, (CR25AR25B)n25Cy2B, (Ci-6 alkylene)Cy2B, (C2-6 alkenylene)Cy2B, or (C2-6 alkynylene)Cy2B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R25is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21,S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;R26is H or C1-6 alkyl;each R25Ais H or C1-6 alkyl;each R25Bis H or C1-6 alkyl;n25 is 0, 1 or 2;Cy2Bis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy2Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; andwherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy2Bare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy2B, halogen, C1-6 haloalkyl, CN, ORa21, S®821, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21,C(=NRe21)NRc21C(0)0Ra21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;wherein each RC 2Bis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC 2Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 2Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR321, SRa21, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21,NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo; and wherein each C6-10 aryl, 5-10 memberedSUBSTITUTE SHEET (RULE 26)heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming Rtv2Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21, NRc21Rd21,NRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21,NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21,S(0)2NRc21Rd21and oxo;Ra2i, Rb21, Rc21and Rd21are each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ra21, Rb21, Rc21and Rd21are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa22, SRa22, C(0)Rb22, C(0)NRc22Rd22, C(0)0Ra22, 0C(0)Rb22,NRc22S(0)2Rb22, S(0)2NRc22Rd22and oxo;or Rc21and Rd21atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, OR322, SRa22, C(0)Rb22, C(0)NRc22Rd22, C(0)0Ra22,S(0)2Rb22, NRc22S(0)2Rb22, S(0)2NRc22Rd22and oxo;Ra22, Rb22, Rc22and Rd22are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ra22, Rb22, Rc22and Rd22are each optionally substituted with 1, 2 or 3 substituents independently selectedSUBSTITUTE SHEET (RULE 26)from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rc22and Rd22atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRe21and Re22are each, independently, H, CN or NO2.In some embodiments, Cy2Ais unsubstituted or substituted aryl.In some embodiments, Cy2Ais unsubstituted or substituted phenyl.In some embodiments, Cy2Ais substituted phenyl.In some embodiments, Cy2Ais substituted with at least one OR321or at least one C(=NRe21)NRc21Rd21, C(=NORa21)NRc21Rd21, C(=N0C(0)Rb21)NRc21Rd21, orC(=NRe21)NRc21C(0)0Ra21.In some embodiments, Cy2Ais substituted with at least one OR321and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy2Ais substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy2Ais substituted with at least one C(=NRe21)NRc21Rd21, C(=NORa21)NRc21Rd21, C(=N0C(0)Rb21)NRc21Rd21, C(=NRe21)NRc21C(0)0Ra21, preferably in the 4-position.In some embodiments, Cy2Ais substituted with at least one C(=NRe21)NRc21Rd21, preferably in the 4-position.In some embodiments, Cy2Ais substituted with at least one C(=NH)NH2, preferably in the 4-position.In some embodiments, Cy2Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)In some embodiments, in the formula defining Cy2A, each Rc-v2Ais independently Ci-6 alkyl, such as methyl, or halogen, such as Cl or Br, or amino.In some embodiments, Cy2Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)In some embodiments, Ra21is Ci-6 alkyl and Rb21is Ci-6 alkyl.In some embodiments, Cy2Ais unsubstituted or substituted heteroaryl, such as pyridin-3-yl, lH-pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.In some embodiments, Cy2Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)In some embodiments, each Rt 2Ain the formula defining Cy2Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferablyCl.In some embodiments, each Rt 2Aattached to nitrogen in the formula defining Cy2AisCi-6 alkyl, such as methyl or ethyl.In some embodiments, R21is Ci-6 alkyl.In some embodiments, R21is methyl.In some embodiments, R21is H.In some embodiments, R22is H.In some embodiments, R22is Ci-6 alkyl.In some embodiments, R22is methyl.In some embodiments, R21and R22, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.In some embodiments, the compound is of Formula (IIA).In some embodiments, the compound is according to any of the following Formulae (IIA- la) or (IIA-lb):SUBSTITUTE SHEET (RULE 26)(IIA-la) (IIA-lb)In some embodiments, the compound is according to any of the following Formulae (IIA-2) to (IIA-5):(IIA-4) (IIA-5)In some embodiments, the compound is according to any of the following Formulae (IIA-2a) to (IIA-5b):(IIA-3a) (IIA-3b)SUBSTITUTE SHEET (RULE 26)(IIA-5a) (IIA-5b)In some embodiments, the compound is of Formula (IIB).In some embodiments, the compound is according to any of the following Formulae(IIB-la) or (IIB-lb):(IIB-la) (IIB-lb)In some embodiments, R23is H.In some embodiments, R23is Ci-6 alkyl.In some embodiments, R24is H.In some embodiments, R24is Ci-6 alkyl.In some embodiments, R24is phenyl.In some embodiments, R25is Cy2B.In some embodiments, R25is (Ci-6 alkylene)Cy2B, (C2-6 alkenylene)Cy2B, or (C2-6 alkynylene)Cy2B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R25is unsubstituted or substituted.In some embodiments, R25is (Ci-6 alkylene)Cy2B, (C2-6 alkenylene)Cy2B, or (C2-6 alkynylene)Cy2B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R25is unsubstituted.In some embodiments, R25is (CR25AR25B)n25Cy2B.In some embodiments, each R25Ais H.SUBSTITUTE SHEET (RULE 26)In some embodiments, each R25Bis H.In some embodiments, n25 is 0.In some embodiments, n25 is 1.In some embodiments, n25 is 2.In some embodiments, R25is CffeCy2®.In some embodiments, R25is CffeCffeCy2®.In some embodiments, Cy2Bis unsubstituted Ce-io aryl.In some embodiments, Cy2Bis unsubstituted phenyl.In some embodiments, Cy2Bis unsubstituted naphthyl, such as 1 -naphthyl or 2- naphthyl.In some embodiments, Cy2Bunsubstituted 5-10 membered heteroaryl.In some embodiments, Cy2Bis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl or unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.In some embodiments, Cy2Bis substituted Ce-io aryl.In some embodiments, Cy2Bis substituted phenyl.In some embodiments, Cy2Bis a biphenylyl (i.e., phenyl substituted by phenyl), such as 2-, 3-, or 4-biphenylyl.In some embodiments, Cy2Bis substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.In some embodiments, Cy2Bis substituted 5-10 membered heteroaryl.In some embodiments, Cy2Bis substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl or substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.In some embodiments, Cy2Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy2B, halogen, and Ci-6 haloalkyl; wherein each RC 2Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming RC 2Bis unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.In some embodiments, R25is selected from groups of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)In some embodiments, Rt 2Bin the formula representing R25is Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen, such as fluorine or chlorine, preferably fluorine.In some embodiments, Rt 2Bin the formula representing R25is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.In some embodiments, RC 2Bin the formula representing R25is halogen, such as fluorine or chlorine, preferably fluorine.In some embodiments, Ra21, Rb21, Rc21, Rd21, Ra22, Rb22, Rc22, Rd22are each independently selected from H, Ci-6 alkyl.In some embodiments, each Re21and each Re22is H.The compounds of Formula (IIA) and (IIB), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use.In some embodiments, the compounds of Formula (IIA) and (IIB), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.The compounds of Formula (IIA) and (IIB), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (IIA) and (IIB), 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IIA) or (IIB), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (IIA) or (IIB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound orSUBSTITUTE SHEET (RULE 26)a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.In certain aspects, the compound is one or more selected from the compounds of Formula (IIA) and (IIB) set forth in the Examples including the compounds listed in Table 31, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of the variables defining the compounds of Formula (IIA) and (IIB) (such as Cy2A, RCy2A, Cy2B, RCy2B, A23, A24, A26, R21, R22, R23, R24, R25, R26, n25, Ra21, Rb21, Rc21, Rd21, Re21, Ra22, Rb22, Rc22, Rd22and Re22) is selected from the corresponding substituents in the compounds of Formula (IIA) and (IIB) in the Examples, including the compounds listed in Table 31, preferably, those of the compounds with selectivity for MASP-2 over thrombin.In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group;hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O-alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.SUBSTITUTE SHEET (RULE 26)In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin 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.C. Compounds of Formula IIIIn certain aspects, the present disclosure provides a compound of Formula (III).or a salt thereof, for use in treating a MASP-2-associated disease or disorder, wherein:Cy3Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy3Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy3Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3A, halogen, Ci-6 haloalkyl, CN, ORa31, S®831, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31,C(=NRe31)NRc31C(0)0Ra31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;each RCy3Ais independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming RCy3Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCy3Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31,S(0)2NRc31Rd31and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCy3Ais independentlySUBSTITUTE SHEET (RULE 26)unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, ORa31, SRa31, C(0)Rb31,R32is H or C1-6 alkyl; orR31and R32, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;R33is Cy3B, (CR33AR33B)n33Cy3B, (C1-6 alkylene)Cy3B, (C2-6 alkenylene)Cy3B, or (C2-6 alkynylene)Cy3B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R35is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31,S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;each R33Ais independently H or C1-6 alkyl;each R33Bis independently H or C1-6 alkyl; oror R33Aand R33Battached to the same carbon atom, independently of any other R33Aand R33Bgroups, together may form -(CH2)2-5-, thereby forming a 3-6 membered cycloalkyl ring;n33 is 0, 1, 2 or 3;SUBSTITUTE SHEET (RULE 26)Cy3Bis unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy3Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; andwherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy3Bare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3B, halogen, Ci-6 haloalkyl, CN, ORa31, S^31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31,0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc3 1Rd3 1. C(=NORa3')NRc3 1Rd3C(=NOC(0)Rb3')NRc3' Rd31.C(=NRe31)NRc31C(0)0Ra31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;wherein each Rt 3Bis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC 3Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 3Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31,NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 3Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa31, SRa31,S(0)2NRc31Rd31and oxo;R34is selected from H and Ci-6 alkyl;R35is selected from H, unsubstituted or substituted Ci-6 alkyl and Cy3C, wherein the substituted Ci-6 alkyl forming R35is substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy3C, halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31,SUBSTITUTE SHEET (RULE 26)C(0)0Ra31, 0C(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo; provided that no more than one of the substituents of R35is Cy3C;Cy3Cis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy3Cconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; andwherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy3Care substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3C, halogen, Ci-6 haloalkyl, CN, OR831, S®831, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31,0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc3 1Rd3 1. C(=NORa3')NRc3 1Rd3C(=NOC(0)Rb3')NRc3' Rd31.C(=NRe31)NRc31C(0)0Ra31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;wherein each Rt 3tis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Rt 3tconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 3Cis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR831, SR831, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31,NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 3Cis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OR831, SR831, C(0)Rb31, C(0)NRc31Rd31, C(0)0R831, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31,NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31,NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31,S(0)2NRc31Rd31and oxo;SUBSTITUTE SHEET (RULE 26)R36is selected from H and Ci-6 alkyl;Ra31, Rb31, Rc31and Rd31are each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ra31, Rb31, Rc31and Rd31are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa32, SRa32, C(0)Rb32, C(0)NRc32Rd32, C(0)0Ra32, 0C(0)Rb32,NRc32S(0)2Rb32, S(0)2NRc32Rd32and oxo;or Rc31and Rd31atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, ORa32, SRa32, C(0)Rb32, C(0)NRc32Rd32, C(0)0Ra32,haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ra32, Rb32, Rc32and Rd32are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rc32and Rd32atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituentsSUBSTITUTE SHEET (RULE 26)independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRe31and Re32are each, independently, H, CN or NO2.In some embodiments, Cy3Ais unsubstituted or substituted aryl.In some embodiments, Cy3Ais unsubstituted or substituted phenyl.In some embodiments, Cy3Ais substituted phenyl.In some embodiments, Cy3Ais substituted with at least one ORa31or at least one C(=NRe31)NRc31Rd31, C(=NORa31)NRc31Rd31, C(=N0C(0)Rb31)NRc31Rd31, orC(=NRe31)NRc31C(0)0Ra31.In some embodiments, Cy3Ais substituted with at least one ORa31and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy3Ais substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy3Ais substituted with at least one C(=NRe31)NRc31Rd31, C(=NORa31)NRc31Rd31, C(=N0C(0)Rb31)NRc31Rd31, C(=NRe31)NRc31C(0)0Ra31, preferably in the 4-position.In some embodiments, Cy3Ais substituted with at least one C(=NRe31)NRc31Rd31, preferably in the 4-position.In some embodiments, Cy3Ais substituted with at least one C(=NH)NH2, preferably in the 4-position.In some embodiments, Cy3Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)In some embodiments, Cy3Ais of any one of the following formulae:In some embodiments, in the formula defining Cy3A, Ra31is Ci-6 alkyl, such as methyl; Rb31is Ci-6 alkyl, such as methyl, or Rb31is Ci-6 haloalkyl, such as trifluoromethyl' and Rc31is alkyl such as methyl.In some embodiments, Cy3Ais unsubstituted or substituted heteroaryl.In some embodiments, Cy3Ais unsubstituted or substituted pyridin-3-yl, 1H- pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.In some embodiments, Cy3Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)In some embodiments, each Rt 3Ain the formula defining Cy3Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.In some embodiments, each Rt 3Aattached to nitrogen in the formula defining Cy3Ais Ci-6 alkyl, such as methyl or ethyl.In some embodiments, R31is Ci-6 alkyl.In some embodiments, R31is methyl.In some embodiments, R31is H.In some embodiments, R32is H.In some embodiments, R32is Ci-6 alkyl.In some embodiments, R32is methyl.In some embodiments, R31and R32, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.In some embodiments, the compound is according to any of the following Formulae(III- la) to (Ill-lh):(Ill-le) (Ill-lf)SUBSTITUTE SHEET (RULE 26)(Ill-lg) (Ill-lh)In some embodiments, R33is Cy3B.In some embodiments, R33is. (Ci-6 alkylene)Cy3B, (C2-6 alkenylene)Cy3B, or (C2-6 alkynylene)Cy3B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R35is unsubstituted.In some embodiments, R33is (C1-6 alkylene)Cy3B, (C2-6 alkenylene)Cy3B, or (C2-6 alkynylene)Cy3B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R35is substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)0Ra31, 0C(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31,NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo.In some embodiments, R33is Cy3B, (CR33AR33B)n33Cy3B.In some embodiments, each R33Ais H.In some embodiments, each R33Bis H.In some embodiments, n33 is 0.In some embodiments, n33 is 1.In some embodiments, n33 is 2.In some embodiments, n33 is 3.In some embodiments, R33is CFhCy3®In some embodiments, R33is CFkCFkCy3®In some embodiments, the compound is according to any of the following Formulae(III-2) to (III-4):(III-2) (III-3)SUBSTITUTE SHEET (RULE 26)(III-4)In some embodiments, the compound is according to any of the following Formulae(III-2a) to (III-2h):(III-2g) (III-2h)In some embodiments, the compound is according to any of the following Formulae(III-3a) to (III-3h):SUBSTITUTE SHEET (RULE 26)(III-3g) (III-3h)In some embodiments, the compound is according to any of the following Formulae(III-4a) to (III-4h):(III-4a) (III-4b)SUBSTITUTE SHEET (RULE 26)(III-4g) (III-4h)In some embodiments, R33is CtkCtkClrkCy3®In some embodiments, Cy3Bis unsubstituted Ce-io aryl.In some embodiments, Cy3Bis unsubstituted phenyl.In some embodiments, R33is CtbCtbPh.In some embodiments, Cy3Bis unsubstituted naphthyl, such as 1 -naphthyl or 2- naphthyl.In some embodiments, R33is CH2CH2-I -naphthyl or CH2CH2-2-naphthyl.In some embodiments, Cy3Bunsubstituted 5-10 membered heteroaryl.In some embodiments, Cy3Bis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo| / i |thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo| / i|thiophenyl. or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.In some embodiments, Cy3Bunsubstituted C3-10 cycloalkyl.In some embodiments, Cy3Bis unsubstituted cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Cy3Bunsubstituted 4-10 membered heterocycloalkyl.SUBSTITUTE SHEET (RULE 26)In some embodiments, Cy3Bis substituted C6-10 aryl.In some embodiments, Cy3Bis substituted phenyl.In some embodiments, Cy3Bis substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.In some embodiments, Cy3Bsubstituted 5-10 membered heteroaryl.In some embodiments, Cy3Bis substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.In some embodiments, Cy3Bsubstituted C3-10 cycloalkyl.In some embodiments, Cy3Bis substituted cyclopentyl, cyclohexyl, or cycloheptyl.In some embodiments, Cy3Bsubstituted 4-10 membered heterocycloalkylIn some embodiments, Cy3Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3B, halogen, and C1-6 haloalkyl; wherein each Rt 3Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming R3Bis unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.In some embodiments, R33is selected from the following groups: phenyl; benzyl;, 2- phenylethyl; 2,3-dihydro-lH-inden-2-yl; 2-(2-methylphenyl)ethyl; 2-(3-methylphenyl)ethyl; 2-(4-methylphenyl)ethyl; 2-(2,4-dimethylphenyl)ethyl; 2-(2,5-dimethylphenyl)ethyl; 2-(3,5- dimethylphenyl)ethyl; 2-(2-ethylphenyl)ethyl; 2-(3-ethylphenyl)ethyl; 2-(4- ethylphenyl)ethyl; 2-(2,4-diethylphenyl)ethyl; 2-(2,5-dimethylphenyl)ethyl; 2-(3,5- dimethylphenyl)ethyl; 2-(2-trifluoromethylphenyl)ethyl; 2-(3-trifluoromethylphenyl)ethyl; 2- (4-trifluoromethylphenyl)ethyl; 2-(2-fluorophenyl)ethyl; 2-(3-fluorophenyl)ethyl; 2-(4- fluorophenyl)ethyl; 2-(2,4-difluorophenyl)ethyl; 2-(2,5-difluorophenyl)ethyl; 2-(3,5- difluorophenyl)ethyl; 2-(2-chlorophenyl)ethyl; 2-(3-chlorophenyl)ethyl; 2-(4- chlorophenyl)ethyl; 2-(2,4-dichlorophenyl)ethyl; 2-(2,5-dichlorophenyl)ethyl; 2-(3,5- dichlorophenyl)ethyl; 2-(2-methoxyphenyl)ethyl; 2-(3-methoxyphenyl)ethyl; 2-(4- methoxyphenyl)ethyl; 2-(2,4-dimethoxyphenyl)ethyl; 2-(2,5-dimethoxyphenyl)ethyl; 2-(3,5- dimethoxyphenyl)ethyl; 2-(cyclopentyl)ethyl; 2-(cyclohexyl)ethyl; 2-(cycloheptyl)ethyl; 2- (2-(aminomethyl)phenyl)ethyl; 2-(3-(aminomethyl)phenyl)ethyl; 2-(4- (aminomethyl)phenyl)ethyl; 2-(2-cyanophenyl)ethyl; 2-(3-cyanophenyl)ethyl; and 2-(4- cyanophenyl)ethyl; and groups of the following formulae:SUBSTITUTE SHEET (RULE 26)In some embodiments, R34is hydrogen.In some embodiments, R34is Ci-6 alkyl, such as methyl.In some embodiments, R35is H.In some embodiments, R35is Cy3C.In some embodiments, R35is unsubstituted Ci-6 alkyl.In some embodiments, R35is substituted Ci-6 alkyl.In some embodiments, the substituted Ci-6 alkyl forming R35is substituted by at least one substituent, wherein the substituents of R35are independently selected from: 1, 2, or 3 substituents selected from the group consisting of Cy3C, halogen, CN, ORa31, SRa31, C(0)Rb31,S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo.In some embodiments, the substituted Ci-6 alkyl forming R35is substituted by at least one substituent, wherein the substituents include Cy3C.In some embodiments, the substituted Ci-6 alkyl forming R35is substituted by one substituent, wherein the substituent is Cy3C.In some embodiments, R35is (CH2)i-5Cy3C.In some embodiments, R35is CH2Cy3C.In some embodiments, Cy3Cis unsubstituted C6-10 aryl.In some embodiments, Cy3Cis unsubstituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl.In some embodiments, Cy3Cis unsubstituted 5-10 membered heteroaryl.In some embodiments, Cy3Cis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo[Z>]thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7-SUBSTITUTE SHEET (RULE 26)benzo| / ? I thiophenyl. or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, - 5-yl, -6-yl or -7-yl.In some embodiments, Cy3Cis unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.In some embodiments, Cy3Cis unsubstituted 4-10 membered heterocycloalkyl.In some embodiments, Cy3Cis substituted C6-10 aryl.In some embodiments, Cy3Cis substituted phenyl, or substituted naphthyl, such as substituted 1 -naphthyl or 2-naphthyl.In some embodiments, Cy3Csubstituted 5-10 membered heteroaryl.In some embodiments, Cy3Cis substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.In some embodiments, Cy3Cis substituted C3-10 cycloalkyl such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.In some embodiments, Cy3Cis substituted 4-10 membered heterocycloalkyl.In some embodiments, R36is H.In some embodiments, R36is C1-6 alkyl such as methyl.In some embodiments, Ra31, Rb31, Rc31, Rd31, Ra32, Rb32, Rc32and Rd32are each independently selected from H and C1-6 alkyl.In some embodiments, each Re31and each Re32is H.The compounds of Formula (III), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use.In some embodiments, the compounds of Formula (III), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.The compounds of Formula (III), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (III), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (III) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a saltSUBSTITUTE SHEET (RULE 26)thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.In certain aspects, the compound is one or more selected from the compounds of Formula (III) set forth in the Examples, including the compounds listed in Table 31, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of the variables defining the compounds of Formula (III) (such as Cy3A, RCy3A, Cy3B, RCy3B, Cy3C,Rd32and Re32) is selected from the corresponding substituents in the compounds of Formula (III) of the Examples, including the compounds listed in Table 31, preferably, those of the compounds with selectivity for MASP-2 over thrombin.In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group;hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O-alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.SUBSTITUTE SHEET (RULE 26)In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin 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.D. Compounds of Formula IVIn certain aspects, the present disclosure provides a compound of Formula (IV).or a salt thereof, for use in treating a MASP-2-associated disease or disorder, wherein:Cy4Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy4Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy4Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy4A, halogen, Ci-6 haloalkyl, CN, ORa41, S®841, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41, 0C(0)Rb41,0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41, NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41,NRc41S(0)2RM1, S(0)2NRc41Rd41and oxo;each RCy4Ais independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming RCy4Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCy4Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa41, SRa41, C(0)RM1, C(0)NRc41Rd41, C(0)ORa41, OC(0)Rb41, 0C(0)NRc41Rd41,NRC4iRd4i NRc41C(0)Rb41, NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41, C(=NRe41)NRc41Rd41, NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41,S(0)2NRc41Rd41and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCy4Ais independentlySUBSTITUTE SHEET (RULE 26)unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, ORa41, SRa41, C(0)Rb41,R42is H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or Cy4B; wherein each of the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, forming R42is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy4B, halogen, CN, ORa41, SRa41, C(0)Rb41,S(0)RM1, S(0)NRc41Rd41, S(0)2RM1, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; provided that no more than one of the substituents is Cy4B;Cy4Bis unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocycloalkyl forming Cy4Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl substituted C3-10 cycloalkyl, or 4- 10 membered heterocycloalkyl forming Cy4Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy4B, halogen, Ci-6 haloalkyl, CN, ORa41, S11341, C(0)Rb41,SUBSTITUTE SHEET (RULE 26)C(=N0C(0)Rb41)NRc41Rd41, C(=NRe41)NRc41C(0)0Ra41, NRc41C(=NRe41)NRc41Rd41, S(0)RM1, S(0)NRc41Rd41, S(0)2RM1, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;wherein each RC 4Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming RC 4Bconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, and wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 4Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa41, SRa41, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41, 0C(0)Rb41,NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; and \each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming each RC 4Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-e alkenyl, C2-e alkynyl, Ci-e haloalkyl, CN, ORa41, SRa41, C(0)Rb41,S(0)Rb41, S(0)NRc41Rd41, S(0)2RM1, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;or R41and R42, together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R41and R42are attached, form a 4-7 memberedheterocycloalkyl ring; which is optionally further substituted by 1, 2, 3, 4 or 5 substituents each independently selected from RCy4B, halogen, Ci-6 haloalkyl, CN, ORa41, S11341, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41, OC(0)RM1, 0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41,S(0)Rb41, S(0)NRc41Rd41, S(0)2RM1, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;R43is H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or Cy4C; wherein each of the Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R43is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy4C, halogen, CN, ORa41, SRa41, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41,S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo, provided that no more than one substituent of the Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R43is Cy4C;SUBSTITUTE SHEET (RULE 26)Cy4Cis unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocycloalkyl forming Cy4Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl substituted C3-10 cycloalkyl, or 4- 10 membered heterocycloalkyl forming Cy4Cis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy4C, halogen, C1-6 haloalkyl, CN, ORa41, S11341, C(0)RM1,S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;each RCy4Cis independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming RCy4Cconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCy4Cis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen,S(0)2NRc41Rd41and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming each RCy4Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-e alkenyl, C2-e alkynyl, Ci-e haloalkyl, CN, ORa41, SRa41, C(0)Rb41,alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-5UB5TITUTE SHEET (RULE 26)Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ra41, RM1, Rc41and Rd41are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa42, SRa42, C(0)Rb42, C(0)NRc42Rd42, C(0)0Ra42, 0C(0)Rb42,NRc42S(0)2Rb42, S(0)2NRc42Rd42and oxo;or Rc41and Rd41attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, ORa42, SRa42, C(0)Rb42, C(0)NRc42Rd42, C(0)0Ra42,S(0)2Rb42, NRc42S(0)2Rb42, S(0)2NRc42Rd42and oxo;Ra42, Rb42, Rc42and Rd42are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ra42, Rb42, Rc42and Rd42are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rc42and Rd42attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRe41and Re42are each, independently, H, CN or N02.In some embodiments, Cy4Ais unsubstituted or substituted aryl.In some embodiments, Cy4Ais unsubstituted or substituted phenyl.In some embodiments, Cy4Ais substituted phenyl.SUBSTITUTE SHEET (RULE 26)In some embodiments, Cy4Ais substituted with at least one ORa41or at least one C(=NRe41)NRc41Rd41, C(=NORa41)NRc41Rd41, C(=N0C(0)Rb41)NRc41Rd41, orC(=NRe41)NRc41C(0)0Ra41.In some embodiments, Cy4Ais substituted with at least one ORa41and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy4Ais substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.In some embodiments, Cy4Ais substituted with at least one C(=NRe41)NRc41Rd41,C(=NORa41)NRc41Rd41, C(=N0C(0)Rb41)NRc41Rd41, C(=NRe41)NRc41C(0)0Ra41, preferably in the 4-position.In some embodiments, Cy4Ais substituted with at least one C(=NRe41)NRc41Rd41, such as C(=NH)NH2, preferably in the 4-position.In some embodiments, Cy4Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)In some embodiments, in the formula defining Cy4A, Ra41is Ci-6 alkyl, such as methyl,Rb41is Ci-6 alkyl, such as methyl, Rb41is Ci-6 haloalkyl, such as trifluoromethyl, and Rc41is alkyl such as methyl.In some embodiments, Cy4Ais unsubstituted or substituted heteroaryl.In some embodiments, Cy4Ais unsubstituted or substituted pyridin-3-yl, 1H- pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.In some embodiments, Cy4Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)In some embodiments, each RC 4Ain the formula defining Cy4Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl.SUBSTITUTE SHEET (RULE 26)In some embodiments, each RC 4Aattached to nitrogen in the formula defining Cy4Ais Ci-6 alkyl, such as methyl or ethyl.In some embodiments, R41is Ci-6 alkyl.In some embodiments, R41is H.In some embodiments, R41is methyl.In some embodiments, R42is H.In some embodiments, R42is unsubstituted Ci-6 alkyl, such as methyl.In some embodiments, R42is Cy4B.In some embodiments, R42is substituted Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.In some embodiments, R42is substituted Ci-6 alkyl.In some embodiments, R42is substituted Ci-6 alkyl, wherein the Ci-6 alkyl forming R42is substituted by 1, 2, or 3 substituents selected from the group consisting of Cy4B, halogen, CN, ORa41, SRa41, C(0)Rb41, C(0)NRc41Rd41, C(0)0Ra41, 0C(0)Rb41,0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41, NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41, C(=NRe41)NRc41Rd41, NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; provided that no more than one of the substituents is Cy4B.In some embodiments, the substituted Ci-6 alkyl forming R42is substituted by at least one substituent, wherein the substituents include Cy4B.In some embodiments, the substituted Ci-6 alkyl forming R35is substituted by one substituent, wherein the substituent is Cy4B.In some embodiments, R42is (CH2)i-5Cy4B.In some embodiments, R42is CffeCy4®.In some embodiments, Cy4Bis unsubstituted C6-10 aryl such as unsubstituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl, Cy4Bis unsubstituted 5-10 membered heteroaryl, such as unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstitutedbenzo| / ? | thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl, Cy4Bis unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy4Bis unsubstituted 4-10 membered heterocycloalkyl.In some embodiments, Cy4Bis substituted C6-10 aryl such as substituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl, Cy4Bis substituted 5-10 membered heteroaryl, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, suchSUBSTITUTE SHEET (RULE 26)as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo| / ? |thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl, Cy4Bis substituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy4Bis substituted 4-10 membered heterocycloalkyl.In some embodiments, R41and R42, together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R41and R42are attached, form a 4-7 membered heterocycloalkyl ring; which is optionally further substituted by 1, 2, 3, 4 or 5 substituents each independently selected from RCy4B, halogen, C1-6 haloalkyl, CN, ORa41,S(0)2NRc41Rd41and oxo.In some embodiments, R41and R42, together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R41and R42are attached, form a 5 or 6 membered heterocycloalkyl ring.In some embodiments, the compound is according to any of the following Formulae(IV-1), (IV-2), (IV-la), (IV-lb), (IV-2a), or (IV-2b),(IV-la) (IV-lb)SUBSTITUTE SHEET (RULE 26)(IV-2a) (IV-2b)In some embodiments, R43is Cy4C.In some embodiments, R43is unsubstituted Ci-6 alkyl.In some embodiments, R43is substituted Ci-6 alkyl.In some embodiments, the substituted Ci-6 alkyl forming R43is substituted by at least one substituent independently selected from: 1, 2, or 3 substituents selected from the group consisting of Cy4C, halogen, CN, ORa41, SRa41, C(0)RM1, C(0)NRc41Rd41, C(0)0Ra41,S(0)2Rb41, NRc41S(0)2RM1, S(0)2NRc41Rd41and oxo.In some embodiments, the substituted Ci-6 alkyl forming R43is substituted by at least one substituent, wherein the substituents include Cy4C.In some embodiments, the substituted Ci-6 alkyl forming R43is substituted by one substituent, wherein the substituent is Cy4C.In some embodiments, R43is (CH2)i-5Cy4C.In some embodiments, R43is CH2Cy4C.In some embodiments, R43is CH2CH2Cy4G.In some embodiments, R43is CF2Cy4Cor CF2CH2Cy4G.In some embodiments, Cy4Cis unsubstituted Ce-io aryl, such as phenyl, 1 -naphthyl or 2-naphthyl.In some embodiments, Cy4Cis unsubstituted 5-10 membered heteroaryl, such as unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo[Z>]thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.In some embodiments, Cy4Cis unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.In some embodiments, Cy4Cis unsubstituted 4-10 membered heterocycloalkyl.SUBSTITUTE SHEET (RULE 26)In some embodiments, Cy4Cis substituted Ce-io aryl, such as substituted phenyl, substituted 1 -naphthyl or substituted 2-naphthyl.In some embodiments, Cy4Cis substituted 5-10 membered heteroaryl, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.In some embodiments, Cy4Cis substituted C3-10 cycloalkyl such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.In some embodiments, Cy4Cis substituted 4-10 membered heterocycloalkyl.In some embodiments, the compound is according to any of the following Formulae (IV-3)-(IV-7), (IV-3a), (IV-3b), (IV-5a), (IV-5b), (IV-7a), or (IV-7b):(IV-3a) (IV-3b)SUBSTITUTE SHEET (RULE 26)(IV-7a) (IV-7b)In some embodiments, Ra41, Rb41, Rc41, Rd41, Ra42, Rb42, Rc42, and Rd42are each independently selected from H and Ci-6 alkyl.In some embodiments, each Re41and each Re42is H.In some embodiments, the compounds of Formula (IV), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.The compounds of Formula (Iv), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (IV), 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IV), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (IV) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.In certain aspects, the compound is one or more selected from the compounds of Formula (IV) set forth in the Examples, including the compounds listed in Table 31, ( e.g . , the compounds with selectivity for MASP-2 over thrombin). In certain aspects, one or more of the variables defining the compounds of Formula (IV) (such as Cy4A, RCy4A, Cy4B, RCy4B, Cy4C, RCy4C, R41, R42, R43, Ra41, Rb41, Rc41, Rd41, Re41, Ra42, Rb42, Rc42, Rd42and Re42) is selected from the corresponding substituents in the compounds of Formula (IV) of the Examples, including the compounds listed in Table 31, preferably, those of the compounds with selectivity for MASP-2 over thrombin.SUBSTITUTE SHEET (RULE 26)In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group;hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O-alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin 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.E. Compounds of Formula VA, VB, VIA, VIB, VIIA and VIIB.1. Additional Chemical DefinitionsThe following definitions apply herein in the present section (II)(E) and the claims directed to the compounds of Formulae (VA), (VB), (VIA), (VIB), (VIIA) and (VIIB) disclosed herein.SUBSTITUTE SHEET (RULE 26)The term "alkoxy" refers to a straight or branched chain saturated or unsaturated hydrocarbon containing at least one oxygen atom in an ether group (e.g., EtO). The chain may contain an indicated number of carbon atoms. For example, "C1-C12 alkoxy" indicates that the group may have from 1 to 12 (inclusive) carbon atoms and at least one oxygen atom. Examples of C1-C12 alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.The term "alkyl" includes an aliphatic hydrocarbon chain that may be straight chain or branched. The chain may contain an indicated number of carbon atoms: For example, C1-C12 indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. If not otherwise indicated, an alkyl group about 1 to about 20 carbon atoms. In one aspect, alkyl groups have 1 to about 12 carbon atoms in the chain. In another aspect, alkyl groups ("lower alkyl") have 1 to about 6 carbon atoms in the chain. Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1 -butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2- methylbutyl, l,l-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, cyclopentyl, or cyclohexyl. In one aspect, an alkyl group can exclude methyl (e.g., 2 to 6 carbon atoms in the chain).The term "aryl" as used herein includes cyclic aromatic carbon ring systems containing from 6 to 18 carbons. Examples of an aryl group include, but are not limited to, phenyl, naphthyl, anthracenyl, tetracenyl, biphenyl and phenanthrenyl.The terms "arylalkyl" and "aralkyl," which are used interchangeably, include an alkyl group as defined herein where at least one hydrogen substituent has been replaced with an aryl group as defined herein. Examples include, but are not limited to, benzyl, 1 -phenylethyl, 4-methylbenzyl, and 1,1, -dimethyl- l-phenylmethyl.The term "cycloalkyl" as used herein includes a cyclic hydrocarbon group that may contain an indicated number of carbon atoms: For example, C3-C 12 indicates that the group may have from 3 to 12 (inclusive) carbon atoms in it. If not otherwise indicated, a cycloalkyl group includes about 3 to about 20 carbon atoms. In one aspect, cycloalkyl groups have 3 to about 12 carbon atoms in the group. In another aspect, cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examples may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, or iodo. In one aspect, "halo" includes fluoro or chloro (preferably chloro).The term "heteroaryl" includes mono and bicyclic aromatic groups of about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms) containing at least one heteroatom. HeteroatomSUBSTITUTE SHEET (RULE 26)as used in the term heteroaryl refers to oxygen, sulfur and nitrogen. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Examples include, but are not limited to, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, l,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, l,2,4-triazinyl, and benzothiazolyl.As used herein, "heterocyclyl" includes a non-aromatic saturated monocyclic or multicycbc ring system of about 4 to about 10 ring atoms (e.g., 5 to about 8 ring atoms, or 5 to about 6 ring atoms), in which one or more of the atoms in the ring system is an element or elements other than carbon, e.g., nitrogen, oxygen or sulfur. A heterocyclyl group optionally comprises at least one sp2-hybridized atom (e.g., a ring incorporating a carbonyl, endocyclic olefin, or exocyclic olefin). In some embodiments, a nitrogen or sulfur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, l,3-dioxolanyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.As used herein, the term "hydroxyalkyl" includes an alkyl group where at least one hydrogen substituent has been replaced with an alcohol (-OH) group. In certain aspects, the hydroxyalkyl group has one alcohol group. In certain aspects, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, and 1 -hydroxy ethyl.The term "hypertonic" refers to a formulation with an osmotic pressure above that of human (i.e., greater than 350 mOsm / KglHhO).When any two substituent groups or any two instances of the same substituent group are "independently selected" from a list of alternatives, the groups may be the same or different. For example, if Raand Rbare independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two Ragroups and two Rbgroups could have all groups be alkyl group (e.g., four different alkyl groups). Alternatively, the first Racould be alkyl, the second Racould be fluoro, the first Rbcould be hydroxyalkyl, and the second Rbcould be amino (or any other substituents taken from the group).SUBSTITUTE SHEET (RULE 26)Alternatively, both Raand the first Rbcould be fluoro, while the second Rbcould be alkyl (i.e.. some pairs of substituent groups may be the same, while other pairs may be different).As used herein, the term "salt" refers to acid or base salts of a compound, e.g., ZNA or another 2-(acylamino)imidazole. Illustrative examples of pharmaceutically acceptable salts are cationic salts such as alkali and alkaline earth metal (such as sodium, lithium, potassium, calcium, and magnesium) salts, ammonium (ammonium, trimethyl ammonium,diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium) salts, mineral acid(hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic carboxylic acid (acetic acid, propionic acid, glutamic acid, citric acid, and the like) salts, organic sulfonic acid (methanesulfonic acid) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's, Pharmaceutical Sciences (current edition), MackPublishing Co., Easton, PA, which is incorporated herein by reference.The terms "a salt thereof," "salt thereof," or "salts thereof' can be applied to any preceding member of an associated Markush group. For example, a group consisting of A, B, C, and salts thereof would include within its scope embodiments that were a salt of A, embodiments that were a salt of B, and embodiments that were a salt of C.2. Compounds of Formula VA and VBIn certain aspects, the present disclosure provides a compound is of the Formula (VA) or (VB):or a salt thereof; wherein:A1is a member selected from the group consisting of -(C=NH)-,-(C=NORa)-, -[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting of-NFh,-NH(C=0)Ra, and - NH(C=0)ZRb;SUBSTITUTE SHEET (RULE 26)when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is-NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2 or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3- C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form a heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;A2is a member selected from the group consisting of C3-C6 heteroaryl, G, aryl, and C2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of -NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is Ce aryl, Y2is selected from the group consisting of aminomethyl, hydroxy, and halo, and A2is substituted with m additional R1groups;when A2is C2-C6 alkyl, Y2is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;L is -(0)P-(C(R2a)(R2b))q-,each R2aor R2bis a member independently selected from the group consisting of hydrogen and fluoro;p is an integer from 0 to 1;q is an integer from 1 to 2;R3is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R3and R4join to form an azetidine, pyrrolidine, or piperidine ring;R4is a member selected from the group consisting of hydrogen and C1-C6 alkyl; or, alternatively, R4and R3join to form an azetidine, pyrrolidine, or piperidine ring;SUBSTITUTE SHEET (RULE 26)R5is a member selected from the group consisting of C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents; or, alternatively, R5and R6join to form a heterocyclic ring with from 0 to 3 R13substituents;R6is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R6and R5join to form a heterocyclylic ring with from 0 to 3 R13substituents; andeach R13is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, (C6-C10 aryl)Ci-C6 alkyl, carboxy(Ci-C6 alkyloxy), heteroaryl, (C6-C10 heteroaryl)Ci-C6 alkyl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring.In certain aspects, the present disclosure provides a compound is of the Formula (VA) or (VB):or a salt thereof; wherein:A1is a member selected from the group including -(C=NH)-,-(C=NORa)-,-[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group including -NH2, -NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is -NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2 or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group including C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from theSUBSTITUTE SHEET (RULE 26)group including C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group including C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group including O and S;A2is a member selected from the group including C3-C6 heteroaryl, G, aryl, and C2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group including -NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra, -(C=NH)NH(C=0)ZRb, - (C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and -{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is G, aryl, Y2is selected from the group including aminomethyl, hydroxy, and halo, and A2is substituted with m additional R1groups;when A2is C2-C6 alkyl, Y2is selected from the group including -NH(C=NH)NH2, -NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group including C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;L is -(0)P-(C(R2a)(R2b))q-,each R2aor R2bis a member independently selected from the group including hydrogen and fluoro;p is an integer from 0 to 1;q is an integer from 1 to 2;R3is a member selected from the group including hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R3and R4join to form an azetidine, pyrrolidine, or piperidine ring;R4is a member selected from the group including hydrogen and C1-C6 alkyl; or, alternatively, R4and R3join to form an azetidine, pyrrolidine, or piperidine ring;R5is a member selected from the group including C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents; or, alternatively, R5and R6join to form a heterocyclic ring with from 0 to 3 R13substituents;R6is a member selected from the group including hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13SUBSTITUTE SHEET (RULE 26)substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R6and R5join to form a heterocyclic ring with from 0 to 3 R13substituents; andeach R13is a member independently selected from the group including C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring,with the proviso that the compound is not melagatran.In certain aspects, the compound is of Formula VA.In certain aspects, A1is -(C=NH)-. In certain aspects, A1is -NH(C=0)Ra. In certain aspects, A1is - NH(C=0)ZRb. In certain aspects, Z is O, S, or N.In certain aspects, A1is -(C=NH)-. In certain aspects, Y1is -NH2. In certain aspects, Y1is -NH(C=0)RaIn certain aspects, Y1is - NH(C=0)ZRbIn certain aspects, A1is -(C=NORa)-. In certain aspects, Y1is -NH2. In certain aspects, Y1is -NH(C=0)Ra. In certain aspects, Y1is - NH(C=0)ZRb.In certain aspects, Raor Rbis C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In certain aspects, Raor Rbis C3-C10 cycloalkyl, such as cyclohexyl, cyclopentyl, or cyclopropyl. In certain aspects, Raor Rbis C6-C10 aryl, such as phenyl or substituted phenyl (e.g., 4-methoxy phenyl). In certain aspects, Raor Rbis C7-C12 arylalkyl, such as benzyl or 4-methoxybenzyl.In certain aspects, A1is a fused heteroaryl. In certain aspects, A1is a quinolone. In certain aspects, A1is an isoquinoline. In certain aspects, A1is a benzimidazole. In certain aspects, Y1is -NH2.In certain aspects, Y1is-NFh.In certain aspects, the compound is of Formula VB.In certain aspects, A2is Ce aryl. In certain aspects, A2is C3-C6 heteroaryl.In certain aspects, A2is substituted with m additional R1groups, such as halo, hydroxyl, C2-C6 alkyl, or C1-C4 methoxy,In certain aspects, Y2is halo (e.g., chloro). In certain aspects, Y2is 3-chloro. In certain aspects, Y2is aminomethyl (e.g., 4-aminomethyl).In certain aspects, A2is C2-C6 alkyl.In certain aspects, Y2is -NH(C=NH)NH2.In certain aspects, Y2is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb. In certain aspects, Y2isSUBSTITUTE SHEET (RULE 26)-NH(C=NH)NH2. In certain aspects, Y2is -NH(C=NH)NH(C=0)Ra. In certain aspects, Y2is -NH(C=NH)NH(C=0)ZRb.In certain aspects, the compound has an R3stereochemistry ofIn certain aspects, R3is a member selected from the group including hydrogen or methyl. In certain aspects, R3is hydrogen. In certain aspects, R3is methyl.In certain aspects, R4is a member selected from the group including hydrogen or methyl. In certain aspects, R4is hydrogen.In certain aspects, R3and R4join to form an azetidine, pyrrolidine, or piperidine ring. In certain aspects, R3and R4join to form a pyrrolidine ring. In certain aspects, R3and R4join to form a piperidine ring.In certain aspects, R5is a member selected from the group including 2,3-dihydro-lH- inden-2-yl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenethyl, and phenpropyl with from 0 to 3 R13substituents.In certain aspects, R5is a member selected from the group including phenethyl, 4- methylphenethyl, 4-chlorophenethyl, 4-fluorophenethyl, and phenpropyl. In certain aspects, R5is a member selected from the group including phenethyl, 4-methylphenethyl, 4- chlorophenethyl, 4-fluorophenethyl, 3-methylphenethyl, 3-chlorophenethyl, 3- fluorophenethyl, 2-methylphenethyl, 2-chlorophenethyl, 2-fluorophenethyl, phenpropyl, 4- methylphenpropyl, 4-chlorophenpropyl, 4-fluorophenpropyl, 3-methylphenpropyl, 3- chlorophenpropyl, 3-fluorophenpropyl, 2-methylphenpropyl, 2-chlorophenpropyl, and 2- fluorophenpropyl.In certain aspects, R6is a member selected from the group including amino(Ci-C8 alkyl). and C7-C12 arylalkyl with from 0 to 3 R13substituents,In certain aspects, R6is a member selected from the group including hydrogen and carboxymethyl.In certain aspects, R6and R5join to form a pyrrolidine, octahydro-lH-indole, 3- phenylpyrrolidine, piperidine, l,2,3,4-tetrahydroisoquinoline, 2,5-dihydro-lH-pyrrole, or l,2,3,6-tetrahydropyridine ring.In certain aspects, R1is hydroxyl or C1-C6 alkoxy. In certain aspects, R1is hydroxyl ( e.g ., 2-hydroxy; 3-hydroxy). In certain aspects, R1is methoxy (e.g., 2-methoxy).SUBSTITUTE SHEET (RULE 26)In certain aspects, m is 0. In certain aspects, m is 1. In certain aspects, n is 0. In certain aspects, n is 1. In certain aspects, both m and n are 0.In certain aspects, p is 0. In certain aspects, p is 1.In certain aspects, q is 1. In certain aspects, p is 0 and q is 1.In certain aspects, each R2aor R2bis hydrogen. In certain aspects, L is methylene. In certain aspects, L is ethylene.In certain aspects, the compound of Formula (VA) is selected from compounds of Formulae (VC), (VD), (VE) and (VF):and salts thereof; wherein:R7is a member selected from the group including hydrogen, hydroxyl, and C1-C6 alkyl;R8is a member selected from the group including hydrogen and C1-C6 alkyl; and each m and n is an independently selected integer from 0 to 2.In certain aspects, the compound is of Formula (VC). In certain aspects, the compound is of Formula (VD). In certain aspects, the compound is of Formula (VE). In certain aspects, the compound is of Formula (VF).In certain aspects, R7is hydrogen. In certain aspects, R8is hydrogen.The compounds of Formula (VA) and (VB), and embodiments thereof, including compounds of Formula (VC), (VD), (VE) and (VF), are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (VA) and (VB), 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of aSUBSTITUTE SHEET (RULE 26)compound of Formula (VA) or (VB), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (VA) or (VB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.In certain aspects, the compound is one or more selected from the compounds of Formula (VA) and (VB) in the Examples, including the compounds listed in Table 31, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of R1, Ra, Rb, R2a, R2b, R3, R4, R5, R6, or R13is selected from the corresponding substituents in the compounds of (VA) and (VB) in the Examples, including the compounds listed in Table 31 preferably, those of the compounds with selectivity for MASP-2 over thrombin.In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group;hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006,SUBSTITUTE SHEET (RULE 26)12, 73-91. Prodrugs for the amidine group include amidoximes, O-alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin 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 30:1.3. Compounds of Formula (VIA) and (VIB)In certain aspects, the present disclosure provides a MASP-2 inhibitory compound for therapeutic use, wherein the compound is of the Formula (VIA) or (VIB):or a salt thereof; wherein:A1is a member selected from the group consisting of -(C=NH)-,-(C=NORa)-, -[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting of-NFk, - NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is -NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NFh or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3- C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;SUBSTITUTE SHEET (RULE 26)A2is a member selected from the group consisting of C3-C6 heteroaryl andC2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of -NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is C2-C6 alkyl, Y2is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;X and X2are each a member selected from the group consisting of NR8, CH, and CR10(preferably, NR8); or, alternatively, the X and X2R10groups join to form a fused G, aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents;each R8is a member independently selected from the group consisting of hydrogen and C1-G5 alkyl;each R10is a member independently selected from the group consisting of C1-C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R13substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R10groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents;r is an integer from 0 to 4; andeach R13is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci- C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring or a salt thereof.In certain aspects, the compound is of Formula (VIA).In certain aspects, the compound is of Formula (VIB).In certain aspects, the compound is of Formula (VIC) or (VID):SUBSTITUTE SHEET (RULE 26)or a salt thereof.In certain aspects, each R7is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; and m is an integer from 0 to 2.In certain aspects, (i) the compound is of Formula (VIA) or a salt thereof, and m is 0; or (ii) the compound is (VIB) or a salt thereof, and r is 0.In certain aspects, X is NR8.In certain aspects, R8is hydrogen.In certain aspects, X2is CH or CR10.In certain aspects, R10is a member independently selected from the group consisting of C1-C6 alkyl, C6 aryl with from 0 to 3 R13substituents, C1-C6 alkoxy, and C2-C9 alkoxy alkyl.In certain aspects, two R10groups join to form a fused Ce aryl ring with from 0 to 3 R13substituents.

[0003] In certain aspects, R7is hydrogen.

[0004] In certain aspects, R3is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R3is methyl.

[0005] In certain aspects, Z is O.

[0006] In certain aspects, R11is (R14)(R14)N(CO)-.

[0007] In certain aspects, R11is (R14)(H)N(CO)-.

[0008] In certain aspects, R14is C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C8cycloalkylalkyl.

[0009] In certain aspects, R12is hydrogen or C7-C14 arylalkyl.

[0010] In certain aspects, R1is hydroxyl or C1-C6 alkoxy.

[0011] In certain aspects, each R2aor R2bis hydrogen.

[0012] In certain aspects, L is methylene.

[0013] In certain aspects, A1is -(C=NH)-. In certain aspects, Y1is -NH2. In certain aspects, Y1is -NH(C=0)Ra. In certain aspects, Y1is - NH(C=0)ZRb.

[0014] In certain aspects, A1is -(C=NORa)-. In certain aspects, Y1is -NH2. In certain aspects, Y1is -NH(C=0)Ra. In certain aspects, Y1is - NH(C=0)ZRb.

[0015] In certain aspects, A1is -(C=NH)-. In certain aspects, A1is -NH(C=0)Ra. In certain aspects, A1is - NH(C=0)ZRb. In certain aspects, Z is O, S, or N.

[0016] In certain aspects, A1is a fused heteroaryl. In certain aspects, A1is a quinolone. In certain aspects, A1is an isoquinoline. In certain aspects, A1is a benzimidazole. In certain aspects, Y1is -NH2.SUBSTITUTE SHEET (RULE 26)

[0017] In certain aspects, Raor Rbis C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In certain aspects, Raor Rbis C3-C10 cycloalkyl, such as cyclohexyl, cyclopentyl, or cyclopropyl. In certain aspects, Raor Rbis C6-C10 aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In certain aspects, Raor Rbis C7-C12 arylalkyl, such as benzyl or 4-methoxybenzyl.

[0018] In certain aspects, R7is hydrogen.

[0019] In certain aspects, the compound is of Formula (VIB).

[0020] In certain aspects, A2is C3-C6 heteroaryl.

[0021] In certain aspects, A2is substituted with m additional R1groups, such as halo, C2-C6 alkyl, or C1-C4 methoxy,

[0022] In certain aspects, Y2is selected from the group consisting of - NH(C=NH)NH2,-NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb. In certain aspects, Y2is-NH(C=NH)NH2. In certain aspects, Y2is -NH(C=NH)NH(C=0)Ra. In certain aspects, Y2is -NH(C=NH)NH(C=0)ZRb.

[0023] In certain aspects, Y2is halo (e.g., chloro, such as 3-chloro). In certain aspects, Y2is aminomethyl (e.g., 4-aminomethyl).

[0024] In certain aspects, A2is C2-C6 alkyl.

[0025] In certain aspects, X is NR8(e.g., NH or NMe). In certain aspects, X is CH. In certain aspects, X is CR10(e.g., CMe).

[0026] In certain aspects, each Z is a member independently selected from the group consisting of O and NR8; and each R8is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl. In certain aspects, one Z or each Z is NR8. In certain aspects, each R8is hydrogen.

[0027] In certain aspects, X2is NR8(e.g., NH or NMe). In certain aspects, B is CH. In certain aspects, X2is CR10(e.g., CMe).

[0028] In certain aspects, the compound has an R3stereochemistry of

[0029] In certain aspects, R3is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R3is hydrogen. In certain aspects, R3is methyl.

[0030] In certain aspects, R1is hydroxyl or C1-C6 alkoxy. In certain aspects, R1is hydroxyl (e.g. , 2-hydroxy; 3-hydroxy). In certain aspects, R1is methoxy (e.g. , 2-methoxy).SUBSTITUTE SHEET (RULE 26)

[0031] In certain aspects, m is 0. In certain aspects, m is 1. In certain aspects, n is 0.In certain aspects, n is 1. In certain aspects, both m and n are 0.

[0032] In certain aspects, p is 0. In certain aspects, p is 1.

[0033] In certain aspects, q is 1. In certain aspects, p is 0 and q is 1.

[0034] In certain aspects, each R2aor R2bis hydrogen. In certain aspects, L is methylene In certain aspects, L is ethylene.

[0035] In certain aspects, each R10is a member independently selected from the group consisting of C1-C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R13substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R10groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents. In certain aspects, an R10is amino. In certain aspects, an R10and an R1are amino.

[0036] In certain aspects, r is an integer from 0 to 5 (i.e., 0, 1, 2, 3, 4, or 5). In certain aspects, r is an integer from 0 to 4 (i.e., 0, 1, 2, 3, and 4). In certain aspects, r is an integer from 0 to 3 (i.e., 0, 1, 2, or 3).

[0037] In certain aspects, each R13is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, Ci- C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring or a salt thereof. In certain aspects, R13is phenyl. In certain aspects, R13is substituted phenyl.The compounds of Formula (VIA) and (VIB), and embodiments thereof, including compounds of Formula (VIC) and (VID), are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (VIA) and (VIB), 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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIA) and (VIB), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (VIA) and (VIB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.SUBSTITUTE SHEET (RULE 26)

[0038] In certain aspects, the compound is one or more selected from the compounds of Formula (VIA) and (VIB) in the Examples, including the compounds listed in Table 31, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of R1, Ra, Rb, R2a, R2b, R3, R4, R5, R6, or R13is selected from the corresponding substituents in the compounds of (VIA) and (VIB) in the Examples, including the compounds listed in Table 31 preferably, those of the compounds with selectivity for MASP-2 over thrombin.

[0039] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.

[0040] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0041] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

[0042] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1,SUBSTITUTE SHEET (RULE 26)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: 1.4. Compounds of Formula VIIA and VIIB

[0043] In certain aspects, the present disclosure provides a MASP-2 inhibitory compound for therapeutic use, wherein the compound is of the Formula (VIIA) or (VIIB):or a salt thereof; wherein:A1is a member selected from the group consisting of -(C=NH)-,-(C=NORa)-, -[C=NO(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting of-NFh, - NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=NO(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is -NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3- C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;SUBSTITUTE SHEET (RULE 26)A2is a member selected from the group consisting of C3-C6 heteroaryl andC2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of -NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is C2-C6 alkyl, Y2is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;L is -(0)P-(C(R2a)(R2b))q-,each R2aor R2bis a member independently selected from the group consisting of hydrogen and fluoro;p is an integer from 0 to 1;q is an integer from 1 to 2;R3is a member selected from the group consisting of hydrogen, C1-C6 alkyl, and carboxy(Ci-C6 alkyl);each R11is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, halo, and (R14)(R14)N(CO)-; or, alternatively, two R11groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents;r is an integer from 0 to 4; andeach Z is a member independently selected from the group consisting of O and NR8; each R8is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl;each R12is a member independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C7-C14 arylalkyl with from 0 to 3 R13substituents;each R13is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl ring; andSUBSTITUTE SHEET (RULE 26)each R14is a member independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C7-C14 arylalkyl, and heteroaryl(Ci-C6 alkyl); or, alternatively, two R13groups join to form a fused heterocyclyl ring.In certain aspects, the compound is of Formula (VIIA).In certain aspects, the compound is of Formula (VIIB).

[0044] In certain aspects, the compound is of Formula (VIIC):in which each R7is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl.

[0045] In certain aspects, R7is hydrogen.

[0046] In certain aspects, X is NR8.

[0047] In certain aspects, R8is hydrogen.

[0048] In certain aspects, X2is CH or CR10.

[0049] In certain aspects, R10is a member independently selected from the group consisting of C1-C6 alkyl, C6 aryl with from 0 to 3 R13substituents, C1-C6 alkoxy, and C2-C9 alkoxy alkyl.

[0050] In certain aspects, two R10groups join to form a fused Cc, aryl ring with from 0 to 3 R13 substituents.

[0051] In certain aspects, R7is hydrogen.

[0052] In certain aspects, R3is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R3is methyl.

[0053] In certain aspects, Z is O.

[0054] In certain aspects, R11is (R14)(R14)N(CO)-.

[0055] In certain aspects, R11is (R14)(H)N(CO)-.

[0056] In certain aspects, R14is C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C8cycloalkylalkyl.

[0057] In certain aspects, R12is hydrogen or C7-C14 arylalkyl.

[0058] In certain aspects, R1is hydroxyl or C1-C6 alkoxy.

[0059] In certain aspects, each R2aor R2bis hydrogen.SUBSTITUTE SHEET (RULE 26)

[0060] In certain aspects, L is methylene.

[0061] In certain aspects, A1is -(C=NH)-. In certain aspects, Y1is -Nth. In certain aspects, Y1is -NH(C=0)Ra. In certain aspects, Y1is - NH(C=0)ZRb.

[0062] In certain aspects, A1is -(C=NORa)-. In certain aspects, Y1is -Nth. In certain aspects, Y1is -NH(C=0)Ra. In certain aspects, Y1is - NH(C=0)ZRb.

[0063] In certain aspects, A1is -(C=NH)-. In certain aspects, A1is -NH(C=0)Ra. In certain aspects, A1is - NH(C=0)ZRb. In certain aspects, Z is O, S, or N.

[0064] In certain aspects, A1is a fused heteroaryl. In certain aspects, A1is a quinolone. In certain aspects, A1is an isoquinoline. In certain aspects, A1is a benzimidazole. In certain aspects, Y1is -Nth.

[0065] In certain aspects, Raor Rbis C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In certain aspects, Raor Rbis C3-C10 cycloalkyl, such as cyclohexyl, cyclopentyl, or cyclopropyl. In certain aspects, Raor Rbis C6-C10 aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In certain aspects, Raor Rbis C7-C12 arylalkyl, such as benzyl or 4-methoxybenzyl.

[0066] In certain aspects, R7is hydrogen.

[0067] In certain aspects, the compound is of Formula (VIIB).

[0068] In certain aspects, A2is C3-C6 heteroaryl.

[0069] In certain aspects, A2is substituted with m additional R1groups, such as halo, C2-C6 alkyl, or C1-C4 methoxy,

[0070] In certain aspects, Y2is selected from the group consisting of - NH(C=NH)NH2,-NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb. In certain aspects, Y2is-NH(C=NH)NH2. In certain aspects, Y2is -NH(C=NH)NH(C=0)Ra. In certain aspects, Y2is -NH(C=NH)NH(C=0)ZRb.

[0071] In certain aspects, Y2is halo (e.g., chloro, such as 3-chloro). In certain aspects, Y2is aminomethyl (e.g., 4-aminomethyl).

[0072] In certain aspects, A2is C2-C6 alkyl.

[0073] In certain aspects, X is NR8(e.g., NH or NMe). In certain aspects, X is CH. In certain aspects, X is CR10(e.g., CMe).

[0074] In certain aspects, each Z is a member independently selected from the group consisting of O and NR8; and each R8is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl. In certain aspects, one Z or each Z is NR8. In certain aspects, each R8is hydrogen.SUBSTITUTE SHEET (RULE 26)

[0075] In certain aspects, X2is NR8(e.g., NH or NMe). In certain aspects, B is CH. In certain aspects, X2is CR10(e.g., CMe).

[0076] In certain aspects, the compound has an R3stereochemistry of

[0077] In certain aspects, R3is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R3is hydrogen. In certain aspects, R3is methyl.

[0078] In certain aspects, R1is hydroxyl or C1-C6 alkoxy. In certain aspects, R1is hydroxyl (e.g., 2-hydroxy; 3-hydroxy). In certain aspects, R1is methoxy (e.g., 2-methoxy).

[0079] In certain aspects, m is 0. In certain aspects, m is 1. In certain aspects, n is 0.In certain aspects, n is 1. In certain aspects, both m and n are 0.

[0080] In certain aspects, p is 0. In certain aspects, p is 1.

[0081] In certain aspects, q is 1. In certain aspects, p is 0 and q is 1.

[0082] In certain aspects, each R2aor R2bis hydrogen. In certain aspects, L is methylene In certain aspects, L is ethylene.

[0083] In certain aspects, each R10is a member independently selected from the group consisting of C1-C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R13substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R10groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents. In certain aspects, an R10is amino. In certain aspects, an R10and an R1are amino.

[0084] In certain aspects, r is an integer from 0 to 5 (i.e., 0, 1, 2, 3, 4, or 5). In certain aspects, r is an integer from 0 to 4 (i.e., 0, 1, 2, 3, and 4). In certain aspects, r is an integer from 0 to 3 (i.e., 0, 1, 2, or 3).

[0085] In certain aspects, each R13is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, Ci- C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring or a salt thereof. In certain aspects, R13is phenyl. In certain aspects, R13is substituted phenyl.The compounds of Formula (VIIA) and (VIIB), and embodiments thereof, including compounds of Formula (VIIC) and (VIID), are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (VIIA) and (VIIB), and embodiments thereof,SUBSTITUTE SHEET (RULE 26)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 of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIIA) and (VIIB), or an embodiment thereof, optionally in the form of a salt.In some embodiments the compound Formula (VIIA) and (VIIB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0086] In certain aspects, the compound is one or more selected from the compounds of Formula (VIIA) and (VIIB) in the Examples, including the compounds listed in Table 31, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of R1, Ra, Rb, R2a, R2b, R3, R4, R5, R6, or R13is selected from the corresponding substituents in the compounds of (VIIA) and (VIIB) in the Examples, including the compounds listed in Table 31 preferably, those of the compounds with selectivity for MASP- 2 over thrombin.

[0087] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers ordiastereomers.

[0088] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. 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, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).SUBSTITUTE SHEET (RULE 26)

[0089] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

[0090] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin 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.F. Compounds Defined by Reference to Binding RulesIn certain aspects, the present disclosure provides compounds having MASP-2 inhibitory activity, especially for therapeutic use. The compound with MASP-2 inhibitory activity interacts with the MASP-2 serine protease domain in an enzyme-inhibitor complex with a plurality of intermolecular interactions. In certain aspects, the molecule is described with complete specificity and description by the number and type(s) of intermolecular interactions within a MASP-2 binding site, using an empirically derived rule set such as an interaction rule set.

[0091] In certain aspects, the compounds with MASP-2 inhibitory activity interact with the MASP-2 serine protease domain as an enzyme-inhibitor complex. The compound having MASP-2 inhibitory activity has between 1 and 100 intermolecular interactions between itself and MASP-2 such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100, or more intermolecular interactions with the serine protease domain of MASP-2 (residues 445-686 of SEQ ID NO: 1). These intermolecular interactions types can be a hydrogen-bond, an ionic bond, an electrostatic bond, p-p interactions, a van der Waals interaction, binding of a water molecule or combinations thereof. The numbers within the various types of intermolecular interactions are counted to reach a total.SUBSTITUTE SHEET (RULE 26)

[0092] In certain aspects, a plurality of the same type of intermolecular interactions exists. For example, the enzyme-inhibitor complex may have 1-40 hydrogen-bonds, 1-40 ionic bonds, 1-40 electrostatic bonds, 1-40 p-p interactions, 1-40 van der Waals interactions, 1-40 binding of water molecules and combinations of thereof, wherein each of the foregoing1-40 range means 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or more interactions. In certain aspects, a plurality or multiple intermolecular interactions may exist with the same amino acid within the binding site.

[0093] In certain instances, an inhibitory molecule is described by a rule set. The compound with MASP-2 inhibitory activity interacts with the MASP-2 serine protease domain in an enzyme-inhibitor complex with a plurality of intermolecular interactions or rules. In certain aspects, the molecule is described with complete structural and functional specificity and description by the number and type(s) of intermolecular interactions. These rules have been empirically derived and discovered using crystallographic data with a number of enzyme-inhibitor complex co-crystals. In certain instances, the crystallographic data are from at least 1, 10, 20, 30, 40, 50, up to 100 enzyme-inhibitor complex crystals. For example, 30 co-crystals can be used, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or even more enzyme-inhibitor complex crystals can be used to generate a set of rules. Using the co-crystal structural information, it is possible to describe the binding site and inhibitory compounds within Angstrom detail and definition.

[0094] In certain instances, a plurality of amino acids within the MASP-2 serine protease domain are involved in the intermolecular interactions. Amino acids within the MASP-2 serine protease domain (amino acid residues 445-686 of SEQ ID NO: l) include, but are not limited to, ASP 627, SER 628, SER 654, GLY 656, GLN 665, SER 657, PHE 529, TYR 607, TRP 655, GLY 667, SER 633, ARG 630, CYS 629, HIS 483, PRO 606, PRO 608, SER 611, VAL 653, MET 658, TYR 669, ASN 659, CYS 660, GLN 665.

[0095] In certain aspects, the number of amino acids within the serine protease domain that interact with a compound having MASP-2 inhibitory activity or that make up a rule set is about 1-50, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, or 50 amino acid residues within the MASP-2 serine protease domain.

[0096] In certain instances, an inhibitor of the present disclosure is bound to MASP-2, rendering MASP-2 inactive. The amino acids of MASP-2 interact through intermolecularSUBSTITUTE SHEET (RULE 26)interactions with the inhibitor compound and the types of interactions are now described in more detail.

[0097] In certain aspects, the type of interactions include a hydrogen bond (H-bond). The enzyme-inhibitor complex may include 1-40 intermolecular H-bonds with one or more of the following 8 amino acids: ASP 627, SER 628, SER 654, GLY 656, GLN 665, ARG 630, PRO 606 and SER 657. The enzyme-inhibitor complex may include 1-40 intermolecular H- bonds with one or more of the following 6 amino acids: ASP 627, SER 628, SER 654, GLY 656, GLN 665 and SER 657. The 1-40 intermolecular H-bonds can include one or more atoms of the inhibitor with one or more atoms of ASP 627, SER 628, SER 654, GLY 656, GLN 665, ARG 630, PRO 606 and SER 657. The 1-40 intermolecular H-bonds can include one or more atoms of the inhibitor with one or more atoms of ASP 627, SER 628, SER 654, GLY 656, GLN 665 and SER 657. Each amino acid can have more than one H-bond interaction with an inhibitor. In certain instances, the same atom can be hydrogen bonded to one or more partners. In other words, a single atom of an inhibitory molecule can interact with 2 or more atoms on the protein. In certain instances, there are 1-10 H-bonds, or 2-8 H- bonds, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 H-bonds per compounds.

[0098] In certain aspects, the type of interactions include an ionic and / or an electrostatic interaction. The enzyme-inhibitor complex may include 1-10 intermolecular ionic and / or electrostatic interactions with ASP 627 or ARG 630. The enzyme-inhibitor complex may include 1-10 intermolecular ionic and / or electrostatic interactions with ASP 627. ASP 627 can have more than one ionic and or electrostatic interaction with an inhibitor.

[0099] In certain other aspects, the type of interaction is binding of a water molecule with ASP 627, GLN 665, SER 657, ASN 659, SER 628, GLU 662, ARG 630, VAL 668,TYR 602, TYR 607. The enzyme-inhibitor complex may include 1-30 bound water molecules 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 2526, 27, 28, 29 or 30 to various amino acids, other water molecules, to the compounds or combinations thereof.

[0100] In certain other instances, the type of interaction includes one or more (e.g., a plurality or 1-40) p-p interactions with one or more of the following amino acids PHE 529, TYR 607, and / or TRP 655, 1, 2 or 3 amino acids. Each of the foregoing amino acids can have more than one p-p interaction.In certain aspects, the type of interaction also includes one or more such as 1-40, van der Waals interactions with ALA 468, ALA 469, HIS 483, ASP 526, ALA 527, GLY 528,PHE 529, LEU 575, PRO 606, TYR 607, PRO 608, SER 611, ASP627, SER 628, CYS 629,SUBSTITUTE SHEET (RULE 26)ARG 630, GLY 631, ASP 632, SER 633, GLY634, GLY 635, VAL 653, SER 654, TRP 655, GLY656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, TYR 669 and combinations thereof, which interactions are specific MASP-2 amino acids within the serine protease domain of MASP-2.

[0101] In certain aspects, the type of interaction also includes one or more such as 1- 40, van der Waals interactions with HIS 483, PHE 529, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, SER 633, VAL 653, SER 654, TRP 655, GLY 656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667 and TYR 669 and combinations thereof, which interactions are specific MASP-2 amino acids within the serine protease domain of MASP-2.In certain aspects, the MASP-2 inhibitory compound can be a compound as described elsewhere herein, including the compounds of Formulae (I), (II), (III), (IV), (V), (VI) or (VII), or any of the embodiments thereof.

[0102] In certain aspects, compounds having MASP-2 inhibitory activity comprise the compounds of Formula (VIII):

[0103] In certain aspects, the compounds of the disclosure can have 5 segments identified as Mi, M2, M3, M4 and Ms. The segments or regions bind the active binding site of MASP-2. In certain aspects, the various segments bind with affinity to the active site. The inhibitor recognition site or pocket includes the binding site for the inhibitor. Using the nomenclature of Schechter and Berger, R1-RG denotes the peptide residues of the scissile bond of the substrate (inhibitor), whereas Sl-STdenote the corresponding enzyme binding pocket for these segments. The inhibitor-MASP-2 interactions extends beyond the Sl site and includes additional binding of the inhibitor to MASP-2. In one aspect, M1-M5 may substantially bind to one or more binding pockets of MASP-2. These binding pockets correspond to ST, Sl, S2, S3, and S41.SUBSTITUTE SHEET (RULE 26)

[0104] In certain aspects, the disclosure provides compounds wherein Mi is a member selected from the group consisting of:wherein each R1is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo (e.g., chloro);each n is an independently selected integer from 0 to 4;R7is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; andR8is a member selected from the group consisting of hydrogen and C1-C6 alkyl.

[0105] In certain aspects, M5 has the formula:R5is a member selected from the group including C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents; or, alternatively, R5and R6join to form a heterocyclic ring with from 0 to 3 R13substituents;R6is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R6and R5join to form a heterocyclic ring with from 0 to 3 R13substituents; andeach R13is a member independently selected from the group including C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring.

[0106] In certain aspects, M2 -4 has the formula:SUBSTITUTE SHEET (RULE 26)wherein R3is a member selected from the group including hydrogen, C1-C6 alkyl, Ci- C6 fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R3and R4join to form an azetidine, pyrrolidine, or piperidine ring; andR4is a member selected from the group including hydrogen and C1-C6 alkyl; or, alternatively, R4and R3join to form an azetidine, pyrrolidine, or piperidine ring.

[0107] In certain aspects, the compounds having MASP-2 inhibitory activity of Formula VIII have Formula VIIIA as follows:(VIIIA)

[0108] Various interactions between a compound of Formula VIIIA and the MASP-2 active site may exist as is shown in Schemes 1 and 2 below:SCHEME 1SUBSTITUTE SHEET (RULE 26)SCHEME 2Segment Mi of the compounds of Formula (VIIIA) can have an interaction which is an ionic type interaction between an ASP 627 carboxyl group and a positive (protonatable group) moiety in a compound of Formula (VIIIA). For example, as shown above, a nitrogen on the amidine can be a protonatable moiety and ionically interact with ASP 627.

[0109] In certain other aspects, with respect to hydrogen bonding analysis, certain of the compounds of the disclosure interact through intermolecular hydrogen bonding with one or more of the following amino acids: ASP 627, SER 628, SER 654, GLY 656, GLN 665, ARG630, PRO606, SER 633, CYS660 and SER 657 in MASP-2. In certain aspects, the compounds interact through intermolecular hydrogen bonding with one or more of the following acids: ASP 627, SER 628, SER 654, GLY 656, GLN 665 and SER 657 in MASP- 2In certain aspects, the compound binds via H-bonds with 1, 2, 3, 4, 5 or all of the following residues: ASP 627, SER 628, SER 654, GLY 656, GLN 665, ARG630, PRO606,SER 633, CYS660 and SER 657.

[0110] In certain aspects, the compound binds via H- bonds with 1, 2, 3, 4, 5 or all of the following residues: ASP 627, SER 628, SER 654, GLY 656, GLN 665 and SER 657. There may be more than one H-bond per amino acid. In certain aspects, the number of hydrogen bonds between an inhibitory molecule and the active site can be 1-40. In certain aspects, one amino acid (e.g., GLY 656) may have more than 1SUBSTITUTE SHEET (RULE 26)hydrogen bond. A compound of the disclosure may have about 1 to about 10 hydrogen bonds, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 H-bonds.

[0111] In general, although crystal structural information does not directly show or detect hydrogen bonding, the LigPlot+ software used to describe the co-crystal structural information does include algorithms to evaluate the presence of (or "predict") such H- bonding based on, e.g., bond distances. Therefore, throughout the disclosure when a H-bond is said to be present and described, it may be said to have been evaluated by software to be present based on the crystallographic data.In certain aspects, the compound binds via ionic or electrostatic interactions or hydrogen bonding to ASP 627 or ARG630. In certain aspects, the compound does not bind via ionic interaction with ASP 627 or ARG630. In certain aspects, the compound does bind via ionic interaction with ASP 627 or ARG630.

[0112] In certain aspects, the compound binds via ionic or electrostatic interactions or hydrogen bonding to ASP 627. In certain aspects, the compound does not bind via ionic interaction with ASP 627. In certain aspects, the compound does bind via ionic interaction with ASP 627.

[0113] As shown above, a hydrogen from a compound of Formula (VIIIA) in segment Mi hydrogen-bonds with SER 628 and another hydrogen from the compound hydrogen-bonds with SER 657. In addition, hydrogens on SER 628 and another on SER 657 hydrogen-bonds with nitrogens on the compound in segment Mi. In general, a hydrogen bond is a partially electrostatic attraction between a hydrogen (H) which is bound to a more electronegative atom such as nitrogen (N) or oxygen (O) and another adjacent atom bearing a lone pair of electrons.

[0114] As shown, in certain aspects, atoms in segment M3 interact with SER 654. In certain aspects, an atom such as a nitrogen in segment M3hydrogen bonds with SER 654. In addition, in certain aspects, an atom such as nitrogen in M3is both a hydrogen bonding acceptor and donor with GLY 656. In another aspect, an atom such as an oxygen in segment M3interacts with a water molecule.

[0115] In certain aspects, an inhibitory compound interacts via a water molecule. The water molecule may be bound to both the compound and an amino acid residue, only the compounds, only the amino acid or a combination thereof. The water molecule may bridge by binding Mi and 1, 2, 3, 4, 5, 6, or 7 MASP-2 residues ASP 627, GLN 665, SER 657, ASN 659, SER 628, GLU 662, ARG 630, VAL 668, TYR 602, TYR 607, VAL 668.

[0116] In certain aspects, the M4 segment of a compound interacts through p-p stacking interactions with either TYR 607 and / or PHE 529 and in the vicinity of TRP 655. InSUBSTITUTE SHEET (RULE 26)certain other aspects, the compound interacts via p-p interactions with 1, 2, 3 or all of the following residues: PHE 529, TYR 607, and TRP 655. In certain aspects, p-p interactions of the edge-face or T-type interaction are present.

[0117] In yet certain other aspects, in order to minimize interactions with serine proteases other than MASP-2, such as thrombin, bulky aromatic groups at segment i of the compounds increase specificity for MASP-2 over thrombin.In yet certain other aspects, to minimize interactions with serine proteases other than MASP-2, such as thrombin, methylated chloroazaindole Mi segments of the compounds increase specificity for MASP-2 over thrombin.In yet certain other aspects, to minimize interactions with serine proteases other than MASP-2, such as thrombin, large substituents such as glutaminyl derivatives or small substituents such as fluorine on the glycine carbon or substitutions on the Nitrogen atom of the center glycine of M3 moieties increase specificity for MASP-2 over thrombinIn yet certain other aspects, to minimize interactions with serine protease other than MASP-2, such as thrombin, planar aromatic groups such as 5-membered rings such as pyrazole connecting the M3region with the M4 segments of the compounds increase specificity for MASP-2 over thrombin.

[0118] In certain aspects, a compound binds via 3 H-bonds with 2 residues: SER 654 and GLY 656. In certain aspects, there are two (2) H-bonds to GLY 656. For example, in certain instances, only 3 hydrogen bonds exist between the compound and the active site of MASP-2. In certain aspects, p-p stacking interaction (T-type or edge-face) can occur with either TYR 607 or PHE 529 and in the vicinity of TRP 655. In other aspects, no ionic bonds exist between the inhibitory compound and the active site of MASP-2. In other aspects, ionic bonds exist between the inhibitory compound and the active site of MASP-2.

[0119] In certain aspects, FIGs. 1-57 show certain of the amino acids of MASP-2 having arcs with radiating lines showing interactions, such as van der Waals interactions, with atoms of inhibitors of the present disclosure.In certain aspects, the compound interacts via van der Waals contacts to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all of the following residues: ALA 468, ALA 469, HIS 483, ASP 526, ALA527, GLY528, PHE 529, LEU 575, PRO 606, TYR 607, PRO608, SER 611, ASP627, SER 628, CYS 629, ARG 630, GLY 631, ASP 632, SER 633, GLY634, GLY 635, VAL 653, SER 654, TRP 655, GLY656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, TYR 669 and combinations thereof.SUBSTITUTE SHEET (RULE 26)

[0120] In certain aspects, the compound interacts via van der Waals contacts to 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all of the following residues: GLY 667, SER 657, GLY 656, TRP 655, SER 654, SER 633, ARG 630, CYS 629, SER 628, ASP 627, PHE 529, HIS 483, PRO 606, TYR 607, PRO 608, SER 611, VAL 653, MET 658, TYR 669, ASN 659, CYS 660, GLN 665 and combinations thereof.

[0121] FIGs. 1-57 represent 2D ligand-MASP-2 interaction diagrams for specific compounds of this disclosure. These figures are schematic depictions of atoms from various compounds with those of MASP-2 amino acids as computed by LigPlot+ + software settings for hydrogen-bond calculation parameters employing models derived from the corresponding crystallographic MASP-2-compound co-structures. Atoms for amino acids that interact with compound atoms as well as compound atoms that have sufficient 2fo-fc electron density from crystallographic data are depicted. MASP-2 amino acid residue numbering (MASP-2 AA#) is according to Uniprot accession code 000187, atom numbering for amino acids (AA atom) according to conventions established by the Protein Data Bank and correspond to those in Table Al (Appendix). Hydrogen bonds and polar contacts are depicted as broken lines with distances provided in units of Angstrom.

[0122] Turning now to FIG. 1, an illustration of MASP-2 CCP2-SP amino acid interactions with (1129) through hydrogen bonds.

[0123] As shown therein, six different hydrogen bonds are present between the (1129) compound atoms and the MASP-2 amino acid residue atoms. In addition, a total of four water molecules are shown in this area of the active site to be included within the crystal structure, two of which are shown to be participating in hydrogen bonding, either with one or more atoms of the (1129) compound, or as a bridging water molecule between particular (1129) compound atoms and MASP-2 amino acid residue atoms. As shown therein, an amidine nitrogen Nl 9 interacts with an oxygen OD1 of ASP 627 as a hydrogen bond donor. As used herein, when it is stated that the nitrogen acts as a "hydrogen bond donor" it means that a hydrogen (H) bound to a more electronegative atom such as nitrogen (N) is electrostatically attracted to an adjacent atom bearing a lone pair of electrons such as an oxygen. NitrogenSUBSTITUTE SHEET (RULE 26)N19 also interacts with an oxygen of SER628 as a hydrogen bond donor. In addition, N20 of the amidine interacts with oxygen OE1 of GLN 665 and O of SER 657 as a hydrogen bond donor. The nitrogen N10 of the amide bond interacts by H-bonding as a donor with an oxygen of SER 654. Further, oxygen 007 interacts by H-bonding with the nitrogen of GLY 656 as a hydrogen bond acceptor. Similarly, as above, when it is stated that an oxygen acts as a "hydrogen bond acceptor," it means that a hydrogen (H) bound to a more electronegative atom such as nitrogen (N) is electrostatically attracted to or "accepted by" an adjacent atom such as oxygen bearing a lone pair of electrons. The oxygen 008 interacts with a water molecule near TRP 655. The oxygen of 026 interacts with a water molecule, as does the secondary amine N21, while the same water molecule further interacts with oxygen 03 of a nearby buffer molecule succinic acid (Sinl). In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0124] FIG. 2 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1034) through hydrogen bonds. As shown therein, seven different hydrogen bonds are present between the (1034) compound atoms and the MASP-2 amino acid residue atoms. The figure does not depict the presence of any water molecules in the crystal structure. The amidine nitrogen N19 interacts with an oxygen of SER657 as a hydrogen bond donor. N19 also interacts with oxygen OE1 of GLN665 as a hydrogen bond donor. Nitrogen N20 interacts with oxygen OE1 of GLN665, an oxygen of SER628, and the OD1 oxygen of ASP627 as a hydrogen bond donor. N10 nitrogen interacts with oxygen of SER654 by H- bonding as a donor. Oxygen 007 interacts with a nitrogen on GLY656 by H-bonding as an acceptor. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).SUBSTITUTE SHEET (RULE 26)

[0125] FIG. 3 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1024) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between atoms of the (1024) compound and MASP-2 residue atoms. In addition, a total of six water molecules are shown in the active site depicted to be included within the crystal structure, four of which are shown to be participating in hydrogen bonding, either with one or more atoms of the (1024) compound, or as a bridging water molecule between particular (1024) compound atoms and MASP-2 amino acid residue atoms. As shown therein, the 02 oxygen interacts with a nitrogen of GLY 656 as a hydrogen bond acceptor. Nitrogen Nl interacts with two different water molecules near TRP 655, one of which also interacts with oxygen 01. Nitrogen N2 interacts with another water molecule. The N3 nitrogen interacts with an oxygen of SER 654 as a hydrogen bond donor. Amidine nitrogen N4 interacts with an oxygen of SER628 by H-bonding as a donor and OD2 oxygen of ASP 627 by H-bonding as a donor. The other amidine nitrogen N5 interacts with an oxygen of SER 657 as a hydrogen bond donor and a nearby water molecule. The same water molecule that is interacting with nitrogen N5 also interacts with oxygen OG of SER 657, an oxygen of GLN 665 via a hydrogen bond, and oxygen OD2 of ASP 627 as a bridging water molecule. In addition, the compound binds via ionic or electrostatic interaction ASP 627 (not shown).

[0126] FIG. 4 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1059) through hydrogen bonds. As shown therein, eight different H-bonds between the (1059) compound atoms and the MASP-2 residue atoms. In addition, a total of six water molecules are shown in the active site depicted to be included within the crystal structure,SUBSTITUTE SHEET (RULE 26)four of which are shown to be participating in hydrogen bonding, either with one or more atoms of the (1059) compound, or as a bridging water molecule between particular (1059) compound atoms and MASP-2 amino acid residue atoms. As shown therein, the amine nitrogen of the benzimidazole moiety, N6, forms hydrogen bonds as a donor with the OD2 oxygen of ASP 627, an oxygen of GLN 665, and the oxygen OG of SER 657. Nitrogen N6 may also interact with a water molecule. The same water molecule that is interacting with nitrogen N6 also interacts with oxygen OG of SER657 and an oxygen of ASN 659 as a bridging water molecule. The hydrogen of the benzimidazole can tautomerize between N4 and N5. Although there is only one hydrogen, software shows that the benzimidazole nitrogen N4 interacts as a H-bond donor with oxygen OD1 of ASP 627 and the other imidazole nitrogen N5 interacts with an oxygen of SER 657 as a hydrogen bond donor.Nitrogen Nl interacts with an oxygen of SER 654 as a hydrogen bond donor. Oxygen 01 interacts with a nearby water molecule, which is a bridging water molecule that further interacts with nitrogen NH1 of ARG 630 (an encircled cross) and nitrogen N3 of (1059). The N3 nitrogen interacts with another water molecule near TRP 655 as well as an oxygen ofGLY 656 as a hydrogen bond donor. Oxygen 02 interacts with the nitrogen of GLY 656 as a hydrogen bond acceptor. The N2 nitrogen interacts with a water molecule close to PHE 529. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown). The molecule labeled So4l designates a sulfate ion.

[0127] FIG. 5 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1088) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between atoms of the (1088) compound and atoms of the MASP-2 amino acid residues. In addition, a total of 17 water molecules are shown to be included within the active site of the crystal structure, seven of which are shown to be participating in hydrogen bonding with compound (1088), either with one or more atoms of the (1088), or as a bridging water molecule between particular (1088) compound atoms and MASP-2 amino acid residue atoms. As shown therein, nitrogen N31, the primary amine nitrogen of the isoquinoline moiety,SUBSTITUTE SHEET (RULE 26)interacts with the OG oxygen of SER 628 and the OD1 oxygen of ASP 627 as a hydrogen bond donor. The N3l nitrogen also interacts with a nearby water molecule. The same water molecule that is interacting with nitrogen N31 also interacts with oxygen OG of SER628 and an oxygen of VAL 668 as a bridging water molecule. The nitrogen of the isoquinoline ring, N29, forms a hydrogen bond as a donor with oxygen OD2 of ASP 627 and also forms a contact with a nearby water molecule. The same water molecule that is interacting with nitrogen N29 also interacts with oxygen OD2 of ASP 627, both a nitrogen and oxygen OG of SER 657, and an oxygen atom of GLN665 as a bridging water molecule. Nitrogen N01 interacts with an oxygen of SER654 as a hydrogen bond donor. Nitrogen N05 interacts with a water molecule near GLY 656 and PHE 529, and oxygen 003 also interacts with two different water molecules that are located between PHE 529 and SER 654. Oxygen 007 interacts with the nitrogen of GLY 656 as a hydrogen bond acceptor. The N18 nitrogen interacts with two different water molecules, in which one of the water molecules also interacts with nitrogen NH1 of ARG 630 as a bridging water molecule. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0128] FIG. 6 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1036) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the (1036) compound atoms and the atoms of the MASP-2 residues. In addition, a total of four water molecules are shown to be included within the crystal structure, three of which are shown to be participating in hydrogen bonding, either with one or more atoms of the (1036) compound, or as a bridging water molecule between particular (1036) compound atoms and MASP-2 amino acid residue atoms. As shown therein, an ami dine nitrogen N26 interacts with an oxygen of SER 657 as a hydrogen bond donor. Nitrogen N26 also interacts with a water molecule. The same water molecule that is interacting with nitrogen N26 also interacts with oxygen OG of SER 657, an oxygen of ASN 659, an oxygen of GLN 665, and oxygen OD2 of ASP 627 as a bridging water molecule. In addition, N27 of the ami dine forms hydrogen bonds as a donor with oxygen OD2 of ASP 627 and an oxygen of SER 628.Nitrogen Nl 7 interacts with an oxygen of SER 654 as a hydrogen bond donor and oxygenSUBSTITUTE SHEET (RULE 26)016 interacts with a water molecule positioned between ARG 630 and SER 654. Oxygen 029 interacts with a nitrogen of GLY 656 as a hydrogen bond acceptor and the nitrogen of the pyrrolidine moiety, N03, interacts with a water molecule. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0129] FIG. 7 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1081) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between atoms of the (1081) compound and atoms of the MASP-2 amino acid residues. In addition, a single water molecule is shown to be included within the crystal structure, which is shown to be participating in hydrogen bonding as a water molecule, bridging between one atom of the compound and multiple MASP-2 amino acid residue atoms. As shown therein, an amidine nitrogen N26 interacts with an oxygen of SER 657 as a hydrogen donor. Nitrogen N26 also interacts with a water molecule. The same water molecule that is interacting with nitrogen N26 also interacts with oxygen OG of SER 657, an oxygen atom of GLN665, an oxygen atom of ASN 659, and oxygen OD2 of ASP 627 as a bridging water molecule. The other amidine nitrogen, N27, interacts with an oxygen of SER 628 as a hydrogen bond donor. Nitrogen Nl 7 interacts with an oxygen of SER 654 as a hydrogen bond donor and nitrogen N03 interacts with an oxygen of GLY 656 as a hydrogen bond donor. In addition, the compound binds via ionic or electrostatic interaction ASP 627 (not shown).

[0130] FIG. 8 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1063) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between the (1063) compound atoms and the MASP-2 amino acid residue atoms. In addition, a total of two water molecules are shown to be included within the crystal structure, one ofSUBSTITUTE SHEET (RULE 26)which is shown to be participating in hydrogen bonding with one atom of the (1063) compound. As shown therein, the amidine nitrogen N5 interacts with an oxygen of SER 657 as a hydrogen bond donor and the other amidine nitrogen N4 interacts with an oxygen of SER 628 as a hydrogen bond donor. Nitrogen N3 interacts with an oxygen of SER 654 as a hydrogen bond donor, oxygen 02 interacts with a nearby water molecule, and oxygen 01 interacts with the nitrogen of GLY 656 as a hydrogen bond acceptor. In addition, the compound binds via ionic or electrostatic interaction ASP 627 (not shown).

[0131] FIG. 9 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1065) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between the (1065) compound atoms and the MASP-2 residue atoms. In addition, a total of seven water molecules are shown to be included within the crystal structure, five of which are shown to be participating in hydrogen bonding, either with one or more atoms of the (1065) compound, or as a bridging water molecule between particular (1065) compound atoms and MASP-2 amino acid residue atoms. As shown therein, the amidine nitrogen N28 interacts with two different bridging water molecules, in which one of said water molecules further interacts with an oxygen atom of SER 657, while the second water molecule interacts with a nitrogen atom of SER 657, an oxygen OH of TYR 602, an oxygen atom of GLN 665, and oxygen OD2 of ASP 627. Nitrogen N28 also forms a hydrogen bond as a donor with oxygen OD2 of ASP 627. The other amidine nitrogen N29 interacts as a hydrogen bond donor with the OD1 oxygen of ASP627. Nitrogen N29 also interacts with a nearby water molecule, bridging between N29, an oxygen atom of VAL 668, and oxygen OG of SER6 28. Nitrogen N14 interacts with an oxygen of SER 654 as a hydrogen bond donor and oxygen 013 interacts with a water molecule. The same water molecule that is interacting with 013 also interacts with an oxygen atom of ARG 630 as a bridging water molecule. Oxygen 009 interacts with the nitrogen of GLY 656 as a hydrogen bond acceptor and the nitrogen of the piperidine moiety, N06, interacts with a nearby water molecule. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).SUBSTITUTE SHEET (RULE 26)

[0132] FIG. 10 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1030) through hydrogen bonds. As shown therein, five different H-bonds are present between the (1030) compound atoms and the MASP-2 atoms. In addition, a total of three water molecules are shown to be included within the crystal structure, two of which are shown to be participating in hydrogen bonding with two different atoms of the compound. As shown therein, the amidine nitrogen N4 interacts with an oxygen of SER 657 as a hydrogen bond donor and the other amidine nitrogen N5 interacts with oxygen OG of SER 628 as a hydrogen bond donor. Nitrogen N3 interacts with an oxygen of SER 654 as a hydrogen bond donor, oxygen 01 interacts with a water molecule near PHE 529, and nitrogen N2 interacts with another nearby water molecule. Oxygen 02 interacts with the nitrogen of GLY 656 as a hydrogen bond acceptor, while the nitrogen of the pyrrole moiety, Nl, interacts with the oxygen of GLY 656 as a hydrogen bond donor. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0133] FIG. 11 is an illustration of MASP-2 CCP2-S amino acid interactions with (1037) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between the (1037) molecule atoms and the MASP-2 amino acid residue atoms. The figure does not depict the presence of any water molecules in the crystal structure. An amidine nitrogen Nl 8 interacts with an oxygen of SER 657 as a hydrogen bond donor. The other amidine nitrogen Nl 9 forms a hydrogen bond as a donor with oxygen OD2 of ASP 627. Nitrogen 09 interacts with an oxygen of SER 654 as a hydrogen donor and oxygen 004SUBSTITUTE SHEET (RULE 26)interacts relatively weakly as a hydrogen acceptor with the nitrogen of GLY 656. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0134] FIG. 12 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1118) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the atoms of (1118) and the atoms of MASP-2 amino acids. In addition, a total of 17 water molecules are shown to be included within the crystal structure, five of which are shown to be participating in hydrogen bonding, either with single atoms of the (1118) compound, or as a bridging water molecule between particular (1118) compound atoms and MASP-2 amino acid residue atoms. As shown therein, one of the amidine nitrogens, N4, interacts with an oxygen of SER 657 as a hydrogen bond donor. Nitrogen N4 also interacts with a bridging water molecule, bridging between N4, oxygen OG of SER 657, an oxygen atom of GLN 665, oxygen OD2 of ASP 627, and an oxygen atom of ASN 659. The other amidine nitrogen N5 interacts with oxygen OG of SER 628 as a hydrogen bond donor.Nitrogen N3 forms a hydrogen bond as a donor with an oxygen of SER 654 and oxygen 02 interacts with two different water molecules close to PHE 529. Nitrogen N2 interacts with a nearby water molecule as well. Oxygen 01 interacts with the nitrogen atom of GLY 656 as a hydrogen bond acceptor, while nitrogen Nl interacts with the oxygen atom of GLY 656 as a hydrogen bond donor. Nitrogen Nl also interacts with a water molecule. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0135] FIG. 13 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1090) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the (1090) atoms and the MASP-2 residue atoms. In addition, a total of two water molecules are shown to be included within the crystal structure, both of which are shown toSUBSTITUTE SHEET (RULE 26)be participating in hydrogen bonding, either with a single atom of (1090) or as a water molecule, bridging between one atom of the (1090) compound and multiple MASP-2 amino acid residue atoms. As shown therein, nitrogen N5, the amine nitrogen of the isoquinoline moiety, interacts with a nearby water molecule. This water molecule also interacts with oxygen OG of SER 657 and an oxygen atom of GLN 665 as a bridging water molecule. Nitrogen N5 also interacts with an oxygen of SER 657 as a hydrogen bond donor. The nitrogen of the isoquinoline ring, N4, interacts with oxygen OD2 of ASP 627 as a hydrogen bond donor. Nitrogen N2 interacts with an oxygen of SER 654 as a hydrogen bond donor and oxygen 01 interacts with a nearby water molecule positioned next to SER 654. Oxygen 02 interacts with the nitrogen atom of GLY 656 as a hydrogen bond acceptor and the nitrogen of the pyrrolidine moiety, Nl, interacts with the oxygen atom of GLY 656 as a hydrogen bond donor.

[0136] FIG. 14 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1007) through hydrogen bonds. As shown therein, four different hydrogen bonds exist between the (1007) compound atoms and the MASP-2 amino acid residue atoms. In addition, a total of three water molecules are shown to be included within the crystal structure, all of which are shown to be participating in hydrogen bonding, either with single atoms of the (1007) compound, or as a bridging water molecule between particular (1007) compound atoms and MASP-2 amino acid residue atoms. As shown therein, nitrogen N5, the amine nitrogen of the pyridine moiety, interacts with OD2 oxygen of ASP 627 and an oxygen of SER 657 as a hydrogen bond donor. The nitrogen of the pyridine ring, Nl, interacts with an oxygen of SER 628 as a hydrogen bond donor. Nitrogen Nl also interacts with a water molecule. This water molecule bridges between Nl of (1007), oxygen OD1 of ASP 627, oxygen OG of SER 628, as well as the other oxygen atom of SER628. Nitrogen atom N2 interacts with an oxygen of SER 654 as a hydrogen bond donor and nitrogen atomN4 interacts with two different water molecules, one of which is a bridging water molecule which interacts with NH1 of ARG 630. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).SUBSTITUTE SHEET (RULE 26)

[0137] FIG. 15 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1021) through hydrogen bonds. As shown therein, two different hydrogen bonds are present between (1021) and MASP-2 amino acid atoms. In addition, a single water molecule is shown to be included within the crystal structure, which is shown to be participating in hydrogen bonding as a water molecule, bridging between one atom of the (1021) compound and an atom of a MASP-2 amino acid residue. As shown therein, the amide nitrogen Nl interacts with an oxygen of SER 654 as a hydrogen bond donor. The amino nitrogen N3 interacts with a bridging water molecule which also interacts with the phenolic OH-group of TYR 607. Oxygen 01 interacts with the nitrogen of GLY 656 as a hydrogen bond acceptor. In addition, the compound does not bind via ionic or electrostatic interaction to ASP 627.

[0138] FIG. 16 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1097) through hydrogen bonds. As shown therein, six different H-bonds are present between the (1097) compound atoms and the MASP-2 residue atoms. In addition, a total of five water molecules are shown to be included within the crystal structure, four of which are shown to be participating in hydrogen bonding, either with one or more atoms of the (1097) compound, or as a bridging water molecule between particular (1097) compound atoms and MASP-2 amino acid residue atoms. As shown therein, an amidine nitrogen, N6, interacts with an oxygen of SER 657 as a hydrogen bond donor. Nitrogen N6 also interacts with a bridging water molecule that is positioned between and interacting with oxygen OG of SER 657 and an oxygen atom of GLN665. In addition, N5 of the amidine interacts with oxygen OD2 of ASP 627 and an oxygen atom of SER 628 as a hydrogen bond donor. Nitrogen N4 forms a hydrogen bond as a donor with an oxygen of SER 654 and nitrogen N3 interacts with a nearby water molecule. Oxygen 01 (in the backbone) and nitrogen Nl in the piperidinyl ring of the fused tetrahydro-pyrido-indole system interact with the same bridging water moleculeSUBSTITUTE SHEET (RULE 26)positioned between HIS 483 and GLY 656. The Nl nitrogen also interacts with the oxygen of GLY 656 as a hydrogen bond donor and the 02 oxygen interacts with the nitrogen atom of the GLY 656 as a hydrogen bond acceptor. Nitrogen N2 in the indole ring of the fused tetrahydro-pyrido-indole system interacts with a water molecule shown between TRP 655 and SER 657. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).

[0139] FIG. 17 is an illustration of MASP-2 CCP2-SP amino acid interactions with (1089) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between atoms of the (1089) compound and the atoms of the MASP-2 amino acid residues. In addition, a total of nine water molecules are shown to be included within the crystal structure, three of which are shown to be participating in hydrogen bonding, either with single atoms of the (1089) compound, or as a bridging water molecule between particular (1089) compound atoms and MASP-2 amino acid residue atoms. As shown therein, nitrogen N5, the primary amine nitrogen of the isoquinoline moiety, interacts with an oxygen atom of SER 657 as a hydrogen bond donor. The N5 nitrogen also interacts with a bridging water molecule that is positioned between and interacting with oxygen OG of SER 657, an oxygen atom of GLN 665, and oxygen OD2 of ASP627. The nitrogen of the isoquinoline ring, N4, interacts with oxygen OD2 of ASP 627 as a hydrogen bond donor. Nitrogen N3 forms a hydrogen bond as a donor with an oxygen of SER654 and oxygen 01 interacts with a nearby water molecule. The oxygen 02 forms a hydrogen bond as an acceptor with the nitrogen atom of GLY 656, while the pyrrolidinyl nitrogen Nl interacts with the oxygen atom of GLY 656 as a hydrogen bond donor. Nitrogen Nl also interacts with a nearby water molecule. In addition, the compound binds via ionic or electrostatic interaction to ASP 627 (not shown).melagatranSUBSTITUTE SHEET (RULE 26)

[0140] FIG. 18 is an illustration of MASP-2 CCP2-SP amino acid interactions with melagatran via hydrogen bonds. As shown therein, two different H-bonds exist between the atoms of melagatran and the atoms of the MASP-2 residues. The figure does not depict the presence of any water molecules in the crystal structure. One of the amidine nitrogens, N25, interacts with an oxygen of SER 657 as a hydrogen bond donor and the other amidine nitrogen N24 interacts with an oxygen of SER 628 as a hydrogen bond donor. In addition, the compound binds via ionic or electrostatic interactions or hydrogen bonding to ASP 627 (not shown).

[0141] FIG. 19 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound 14 via hydrogen bonds. The compound binds covalently to SER 633 with opening of the oxazin-4-one ring. The carbonyl oxygen atom 02 of the resulting ester linkage forms a hydrogen bond with nitrogen NE2 of HIS 483 as a hydrogen bond acceptor. Furthermore, the same carbonyl oxygen atom also forms a hydrogen bond with water molecule 66 as a hydrogen bond acceptor.

[0142] FIG. 20 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (54) via hydrogen bonds. As shown therein, two different H-bonds exist between the atoms of compound (54) and the atoms of the MASP-2 residues. The carbonyl oxygen atom 009, interacts with an oxygen of SER 628 as a hydrogen bond acceptor and the amino nitrogen atom N15 interacts with a carbonyl oxygen of SER 657 as a hydrogen bond donor. In addition, one water molecule is included within the crystal structure, which is shown to be participating as a bridging water molecule between the carbonyl oxygen atom 009 of compound (54) and MASP-2 amino acid residue atoms of SER 628, TRP 655 and VAL 668.FIG. 21 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1042) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between the compound (1042) atoms and the MASP-2 amino acid residue atoms.SUBSTITUTE SHEET (RULE 26)As shown therein, an amidine nitrogen N21 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The other amidine nitrogen N22 interacts with a carbonyl oxygen O of SER 628 as a hydrogen bond donor and with a carboxylate group oxygen OD1 of ASP 627 as a hydrogen bond donor. The amino group nitrogen N03 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor.FIG. 22 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (2018) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (2018) compound atoms and the MASP-2 amino acid residue atoms. As shown therein, one of the ami dine nitrogens, N4, interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor and with a carbonyl oxygen OE1 of SER 657 as a hydrogen bond donor. The other amidine nitrogen N5 interacts with an oxygen of SER 628 as a hydrogen bond donor. The amide nitrogen N3 interacts with the carbonyl oxygen O of SER 654 as a hydrogen bond donor, and with the hydroxyl oxygen OG of SER 633 as a hydrogen bond acceptor. The carbonyl oxygen 02 interacts with the nitrogen N of GLY 656 as a hydrogen bond acceptor. A total of four water molecules are shown in this area of the active site to be included within the crystal structure, two of which are shown to be participating in hydrogen bonding with one or more atoms of the compound (2018) compound, or as a bridging water molecule between particular compound (2018) compound atoms and MASP-2 amino acid residue atoms. A sulfate ion is also present in the crystal structure and interacts with amide nitrogen N6 of compound (2018) as a hydrogen bond acceptor.SUBSTITUTE SHEET (RULE 26)FIG. 23 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1149) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (1149) atoms and the MASP-2 amino acid residue atoms. As shown therein, an ami dine nitrogen Nl interacts with a carboxylate oxygen OD2 of ASP 627 as a hydrogen bond donor. The other amidine nitrogen N2 interacts with the carbonyl oxygen O of SER 657 as a hydrogen bond donor and can interact with a hydroxyl oxygen OG of SER 657 as a hydrogen bond donor, or with the sulfur atom SG of CYS 660 as a hydrogen bond donor. The amide nitrogen N3 interacts with carbonyl oxygen O of SER 654 as a hydrogen bond donor. The carbonyl oxygen 02 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, one water molecule is shown to be included within the crystal structure in this area of the active site, which participates in hydrogen bonding with the carbonyl oxygen 01 of the compound (1149).FIG. 24 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1031) through hydrogen bonds. As shown therein, three different hydrogen bonds are present between the compound (1031) and the MASP-2 amino acid residue atoms. The carbonyl oxygen 004 interacts with a guanidine nitrogen NE of ARG 630 as a hydrogen bond acceptor. The carbonyl oxygen 009 interacts with a guanidine nitrogen NH1 of ARG 630 as a hydrogen bond acceptor. The amino group nitrogen Nl 1 interacts with a carbonyl oxygen O of GLY 656 as a hydrogen bond donor.SUBSTITUTE SHEET (RULE 26)FIG. 25 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1153) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (1153) compound atoms and the MASP-2 amino acid residue atoms. As shown therein, an ami dine nitrogen Nl interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor and with a carboxylate oxygen OD2 of ASP 627 as a hydrogen bond donor. The other amidine nitrogen N2 interacts with a hydroxyl oxygen OG of SER 628 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with guanidine nitrogen NH2 of ARG 630 as a hydrogen bond acceptor. The amine nitrogen N5 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 02 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, one water molecule is shown to be included within the crystal structure in this area of the active site, which participates in hydrogen bonding with amide nitrogen N3 of the compound (1153).FIG. 26 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1025) through hydrogen bonds. As shown therein, three different hydrogen bonds are present between the compound (1025) atoms and the MASP-2 amino acid residue atoms. Amine nitrogen N09 interacts with carboxylate oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 628 as a hydrogen bond donor. The pyridine nitrogen N05 also interacts with carbonyl oxygen O of SER 628 as a hydrogen bond donor.SUBSTITUTE SHEET (RULE 26)FIG. 27 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1012) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the compound (1012) atoms and the MASP-2 amino acid residue atoms. As shown therein, an amine nitrogen N5 interacts with a carboxylate oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen Nl interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, a total of eleven water molecules are shown in this area of the active site to be included within the crystal structure, three of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1012), or as a bridging water molecule between particular compound (1012) atoms and MASP-2 amino acid residue atoms. One of the water atoms forms a bridge between the pyridine nitrogen N4 and the carboxylate carbon OD1 of ASP 627 and the hydroxyl oxygen OG of SER 628. A chloride ion is also present in the crystal structure, bridging Nl of compound (1012) to NH2 of ARG630 and a water molecule 141.FIG. 28 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1078) through hydrogen bonds. As shown therein, three different hydrogen bonds are present between the compound (1078) atoms and the MASP-2 amino acid residue atoms. The carbonyl oxygen 02 interacts with a guanidine nitrogen NH2 of ARG 630 as a hydrogen bond acceptor. The amide nitrogen N2 also interacts with the guanidine nitrogen NH2 ofSUBSTITUTE SHEET (RULE 26)ARG 630, but as a hydrogen bond donor. The amide nitrogen Nl interacts with carbonyl oxygen O of SER 654 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen N of GLY 656 as a hydrogen bond acceptor.FIG. 29 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1145) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the compound (1145) compound atoms and the MASP-2 amino acid residue atoms. As shown therein, an ami dine nitrogen N5 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The other ami dine nitrogen N4 interacts with a carbonyl oxygen O of SER 628 as a hydrogen bond donor. Amide nitrogen Nl interacts with carbonyl oxygen atom O of SER 654 as a hydrogen bond donor. The amine nitrogen N3 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 02 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, two water molecules are shown to be included within the crystal structure in this area of the active site, which participates in hydrogen bonding with the phenolic hydroxyl 01 and amide nitrogen N2 of the compound (1145).FIG. 30 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1050) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between the compound (1050) atoms and the MASP-2 amino acid residue atoms.SUBSTITUTE SHEET (RULE 26)As shown therein, an ami dine nitrogen N4 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The amide nitrogen N2 interacts with a carbonyl oxygen O of SER 654 as a hydrogen bond donor. The amino group nitrogen N5 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 02 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, three water molecules are shown to be included within the crystal structure in this area of the active site, each of which participate in hydrogen bonding with the compound (1050).FIG. 31 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1253) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (1253) atoms and the MASP-2 amino acid residue atoms. Amine nitrogen N07 interacts with carboxylate oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The pyridine nitrogen N01 may interact with carbonyl oxygen O of SER 628 as a hydrogen bond donor and is in H-bonding distance to a water molecule 16 which it may interact with as an acceptor or donor. Amide nitrogen N10 interacts with carbonyl oxygen O of SER 654 as a hydrogen bond donor. Piperidine nitrogen N22 interacts with carbonyl oxygen O of GLY 656 as a hydrogen bond donor. Carbonyl oxygen 017 interacts with a nitrogen N of GLY 656 as a hydrogen bond acceptor. Six water molecules are shown to be included within the crystal structure in this area of the active site, four of which are involved in hydrogen bonding, either with one or more atoms of the compound (1253), or as a bridging water molecule between particular compound (1253) atoms and MASP-2 amino acid residue atoms.SUBSTITUTE SHEET (RULE 26)FIG. 32 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1257) through hydrogen bonds. As shown therein, four different hydrogen bonds are present between the compound (1257) compound atoms and the MASP-2 amino acid residue atoms. As shown therein, an amine nitrogen N08 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The pyridine nitrogen N01 may interact with carbonyl oxygen O of SER 628 as a hydrogen bond donor and is in H-bonding distance to a water molecule which it may interact with as an acceptor or donor. The amide nitrogen N10 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen Nl 8 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. In addition, a total of thirteen water molecules are shown in this area of the active site to be included within the crystal structure, four of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1257), or as a bridging water molecule between particular compound (1257) atoms and MASP-2 amino acid residue atomsFIG. 33 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1297) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (1297) atoms and the MASP-2 amino acid residue atoms The amino group nitrogen N5 interacts with a carboxyl group oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl group oxygen O of SER 657 as a hydrogen bond donor. The pyridine nitrogen N4 interacts with a carbonyl oxygen O of SER 628 as a hydrogen bond donor. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The piperidine nitrogen Nl interacts with a carbonyl oxygen ofSUBSTITUTE SHEET (RULE 26)GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, a total of four water molecules are shown in this area of the active site to be included within the crystal structure, which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1297), or as a bridging water molecule between particular compound (1297) atoms and MASP-2 amino acid residue atoms.FIG. 34 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1304) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (1304) atoms and the MASP-2 amino acid residue atoms. An amine nitrogen N5 interacts with a carboxyl group oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The pyridine nitrogen N4 may interact with carbonyl oxygen O of SER 628 as a hydrogen bond donor and is in H-bonding distance to a water molecule which it may interact with as an acceptor or donor. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, a total of eleven water molecules are shown to be included within the crystal structure in this area of the active site, three of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1304), or as a bridging water molecule between particular compound (1304) atoms and MASP-2 amino acid residue atoms. A chloride ion is also present in the crystal structure in this area of the active site, which interacts with the pyrrolidine nitrogen N2 as a hydrogen bond acceptor.SUBSTITUTE SHEET (RULE 26)FIG. 35 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1306) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the compound (1306) atoms and the MASP-2 amino acid residue atoms. As shown therein, one of the amidine nitrogens, N5, interacts with a carbonyl oxygen of SER 657 as a hydrogen bond donor and the other amidine nitrogen N4 interacts with a carbonyl group oxygen of SER 628 as a hydrogen bond donor and with a carboxyl group oxygen OD2 of ASP 627 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor.FIG. 36 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1307) through hydrogen bonds. As shown therein, three different hydrogen bonds are present between the compound (1307) atoms and the MASP-2 amino acid residue atoms. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. Two water molecules are shown to be included within the crystal structure in this area of the active site, both of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1307), or as a bridging water molecule between particular compound (1307) atoms and MASP-2 amino acid residue atoms. The phenolic oxygen atom forms an intramolecular H-bond with 02 serving as an H- bond donor and it interacts as a hydrogen bond acceptor with a water molecule that furtherSUBSTITUTE SHEET (RULE 26)interacts with a nitrogen atom NH1 of ARG 630 as a hydrogen bond acceptor and a carbonyl oxygen of SER 657 as a hydrogen bond donor.FIG. 37 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1328) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the compound (1328) atoms and the MASP-2 amino acid residue atoms. The amino group nitrogen N5 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The pyridine nitrogen N4 interacts with a carbonyl oxygen O of SER 628 as a hydrogen bond donor. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, one water molecule is shown in this area of the active site to be included within the crystal structure in this area of the active site, which participates in hydrogen bonding with the pyrrolidine nitrogen (N2) of the compound (1328).FIG. 38 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1334) through hydrogen bonds. As shown therein, three different hydrogen bonds are present between the compound (1334) atoms and the MASP-2 amino acid residue atoms. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. Nine water molecules are shown to be included within the crystal structure in this area of the active site, five of which are shown to be participating inSUBSTITUTE SHEET (RULE 26)hydrogen bonding, either with one or more atoms of the compound (1334), or as a bridging water molecule between particular compound (1334) atoms and MASP-2 amino acid residue atoms.FIG. 39 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1335) through hydrogen bonds. As shown therein, six different hydrogen bonds are present between the compound (1335) atoms and the MASP-2 amino acid residue atoms. An amidine nitrogen N6 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor and with an amide group carbonyl oxygen OE1 of GLN 665 as a hydrogen bond donor. The other amidine nitrogen N5 interacts with a hydroxyl group oxygen OG of SER 628 as a hydrogen bond donor. The amide nitrogen Nl interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The amino group nitrogen N3 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, four water molecules are shown in this area of the active site to be included within the crystal structure, three of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1335), or as a bridging water molecule between particular compound (1335) atoms and MASP-2 amino acid residue atoms.FIG. 40 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1338) through hydrogen bonds. As shown therein, six different hydrogen bondsSUBSTITUTE SHEET (RULE 26)are present between the compound (1338) atoms and the MASP-2 amino acid residue atoms. An amino group nitrogen N5 interacts with a carboxyl group oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The pyridine nitrogen N4 may interact with carbonyl oxygen O of SER 628 as a hydrogen bond donor and is in H-bonding distance to a water molecule which it may interact with as an acceptor or donor. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, a total of seventeen water molecules are shown to be included within the crystal structure in this area of the active site, three of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1338), or as a bridging water molecule between particular compound (1338) atoms and MASP-2 amino acid residue atoms.FIG. 41 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1345) through hydrogen bonds. As shown therein, seven different hydrogen bonds are present between the compound (1345) atoms and the MASP-2 amino acid residue atoms. An amidine nitrogen N6 interacts with a carbonyl oxygen O of SER 657 as a hydrogen bond donor and with a carbonyl oxygen OE1 of GLN 665 as a hydrogen bond donor. The other amidine nitrogen N5 interacts with a carbonyl oxygen O of SER 628 as a hydrogen bond donor. The amide nitrogen Nl interacts with a carbonyl oxygen O of SER 654 as a hydrogen bond donor. The secondary amine nitrogen N3 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with guanidine nitrogen NH1 of ARG 630 as a hydrogen bond acceptor. The carbonyl oxygen 02 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, one water molecule is shown to be included within the crystal structure in this area of the active site, which participates in hydrogen bonding as a hydrogen bond donor with carbonyl oxygen 03 of the compound (1345).SUBSTITUTE SHEET (RULE 26)FIG. 42 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1351) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the compound (1351) atoms and the MASP-2 amino acid residue atoms. An amino group nitrogen N5 interacts with a carboxylate group oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. The amide nitrogen N3 interacts with a carbonyl oxygen of SER 654 as a hydrogen bond donor. The pyrrolidine nitrogen N2 interacts with a carbonyl oxygen of GLY 656 as a hydrogen bond donor. The carbonyl oxygen 01 interacts with a nitrogen atom of GLY 656 as a hydrogen bond acceptor. In addition, a total of eight water molecules are shown to be included within the crystal structure in this area of the active site, five of which are shown to be participating in hydrogen bonding, either with one or more atoms of the compound (1351), or as a bridging water molecule between particular compound (1351) atoms and MASP-2 amino acid residue atoms.FIG. 43 is an illustration of MASP-2 CCP2-SP amino acid interactions with compound (1353) through hydrogen bonds. As shown therein, five different hydrogen bonds are present between the compound (1353) atoms and the MASP-2 amino acid residue atoms. As shown therein, an amino group nitrogen N5 interacts with a carboxylate group oxygen OD2 of ASP 627 as a hydrogen bond donor and also with a carbonyl oxygen O of SER 657 as a hydrogen bond donor. Th...

Claims

What is claimed is:

1. A small molecule compound with MASP-2 inhibitory activity, for therapeutic use in the treatment of a MASP-2-associated disease or disorder, wherein the compound has one or more of the following interactions (a) to (e):a) the compound binds via H-bonds with one or more of PRO 606, ASP 627, SER 628, ARG 630, SER 633, SER 654, GLY 656, SER 657, CYS 660 and GLN 665 in MASP-2;b) the compound binds via ionic or electrostatic interactions or hydrogen bonding to one or more of ASP 627 and ARG 630 in MASP-2;c) the compound interacts via a water molecule in MASP-2 to one or more of TYR 602, TYR 607, ASP 627, SER 628, SER 657, ASN 659, GLU 662, TRP 655, GLY656, CYS660, GLN 665, TYR 666, VAL 668, and ARG 630 in MASP-2;d) the compound interacts via t-p interactions with one or more of PHE 529, TYR 607, and TRP 655 in MASP-2; ande) the compound interacts via van der Waals contacts to one or more of ALA 468, ALA 469, HIS 483, ASP 526, ALA 527, GLY 528, PHE 529, LEU 575, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, GLY 631, ASP 632, SER 633, GLY 634, GLY 635, VAL 653, SER 654, TRP 655, GLY656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, and TYR 669 in MASP-2,wherein the compound is not an endogenous MASP-2 ligand.

2. A small molecule compound with MASP-2 inhibitory activity, for therapeutic use in the treatment of a MASP-2-associated disease or disorder, wherein the compound has one or more of the following interactions (a) to (e):a) the compound binds via H-bonds with one or more of ASP 627, SER 628, SER 654, GLY 656, GLN 665, and SER 657 in MASP-2;b) the compound binds via ionic or electrostatic interactions or hydrogen bonding to ASP 627 in MASP-2;c) the compound interacts via a water molecule in MASP-2 to one or more of ASP 627, GLN 665, SER 657, ASN 659, SER 628, GLU 662, VAL 668, TYR607, TYR602, ARG630 in MASP-2;SUBSTITUTE SHEET (RULE 26)d) the compound interacts via p-p interactions with one or more of PHE 529, TYR 607, and TRP 655 in MASP-2; ande) the compound interacts via van der Waals contacts to one or more of HIS 483, PHE 529, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, SER 633, VAL 653, SER 654, TRP 655, GLY 656, SER 657,MET 658, ASN 659, CYS 660, GLN 665, GLY 667 and TYR 669 in MASP-2,wherein the compound is not an endogenous MASP-2 ligand.

3. The compound of claim 1 or 2, wherein the compound has 1, 2, 3, 4, or 5 of theinteractions (a)-(e).

4. The compound of any one of claims 1 to 3, wherein the compound binds via H-bonds with one or more of the following: PRO 606, ASP 627, SER 628, SER 633, SER 654, GLY 656, SER 657, CYS 660 and GLN 665 in MASP-2.

5. The compound of any one of claims 1 to 4, wherein the compound binds via H-bonds with one or more of the following: ASP 627, SER 628, SER 654, GLY 656, GLN 665 and SER 657 in MASP-2.

6. The compound of any one of claims 1 to 5, wherein the compound binds via 1-10 H- bonds.

7. The compound of any one of claims 1 to 6, wherein the compound binds via 3 H- bonds to SER 654 and GLY 656, wherein there are two H-bonds to GLY 656 in MASP-2.

8. The compound of any one of claims 1 to 7, wherein the compound binds via ionic or electrostatic interactions or hydrogen bonding to one or both of ASP 627 and ARG 630 in MASP-2.

9. The compound of any one of claims 1 to 8, wherein the compound binds via ionic or electrostatic interactions or hydrogen bonding to ASP 627 in MASP-2.

10. The compound of any one of claims 1 to 7, wherein the compound does not bind via ionic interactions to ASP 627 or ARG 630 in MASP-2.SUBSTITUTE SHEET (RULE 26)11. The compound of any one of claims 1 to 7, wherein the compound does not bind via ionic interactions to ASP 627 in MASP-2.

12. The compound of any one of claims 1 to 11, wherein the compound binds via a water molecule in MASP-2 to one or more of TYR 602, TYR 607, ASP 627, SER 628,SER 657, ASN 659, GLU 662, TRP 655, GLY656, CYS660, GLN 665, TYR 666, VAL 668, and ARG 630 in MASP-2.

13. The compound of any one of claims 1 to 12, wherein the compound binds via a water molecule in MASP-2 to one or more of ASP 627, GLN 665, SER 657, ASN 659, SER 628, GLU 662, VAL 668, TYR 607, TYR 602, and ARG 630.

14. The compound of any one of claims 1 to 13, wherein the compound binds via 1-20 water molecule(s) in MASP-2.

15. The compound of any one of claims 1 to 14, wherein the compound binds via 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 water molecule(s) in MASP-2.

16. The compound of any one of claims 1 to 15, wherein the compound interacts via p-p interactions with one or more of PHE 529, TYR 607, and TRP 655 in MASP-2.

17. The compound of any one of claims 1 to 16, wherein the compound interacts via van der Waals contacts to one or more of ALA 468, ALA 469, HIS 483, ASP 526,ALA 527, GLY 528, PHE 529, LEU 575, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, GLY 631, ASP 632, SER 633, GLY634, GLY 635, VAL 653, SER 654, TRP 655, GLY 656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, and TYR 669 in MASP-2.

18. The compound of any one of claims 1 to 17, wherein the compound interacts via van der Waals contacts to one or more of HIS 483, PHE 529, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, SER 633, VAL 653, SER 654, TRP 655, GLY 656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667 and TYR 669 in MASP-2.

19. The compound of any one of claims 1 to 18, wherein the compound has the Formula (VIII):SUBSTITUTE SHEET (RULE 26)(VIII).

20. The compound of claim 19, wherein Mi is a member selected from the groupconsisting ofwherein each R1is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each n is an independently selected integer from 0 to 4;R7is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; andR8is a member selected from the group consisting of hydrogen and C1-C6 alkyl.21 The compound of claim 19 or 20, wherein Ms has the formula:wherein R5is a member selected from the group consisting of C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents; or, alternatively, R5and R6join to form a heterocyclic ring with from 0 to 3 R13substituents; andR6is a member selected from the group consisting of hydrogen, C 1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R6and R5join to form a heterocyclic ring with from 0 to 3 R13substituents.SUBSTITUTE SHEET (RULE 26)22 The compound of any one of claims 1 to 21, wherein the compound has the Formula(VIIIA):(VIIIA).

23. The compound of any one of claims 1 to 22, wherein the compound has a molecular weight of about 300 g / mole to about 600 g / mole.

24. The compound of any one of claims 1 to 23, wherein the compound has a lower Ki for MASP-2 compared to thrombin.

25. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 1 to 24 and a pharmaceutically acceptable carrier or excipient.

26. A small molecule compound for use in the treatment of MASP-2-associated diseases or disorders, wherein the compound comprises a combination of pharmacophore elements comprising:(a) an Sl pharmacophore group comprising CA1 and Nl pharmacophore elements or CA1 and C5 pharmacophore elements;(b) an S2 pharmacophore group comprising H4 and 02 pharmacophore elements; and(c) an S3 pharmacophore group comprising a C2 pharmacophore element and an N2 or H3 pharmacophore element;wherein:C2 and C5 are hydrophobic groups;CA1 is an aromatic ring;H3 and H4 are hydrogen bond donors;Nl and N2 are positive ionizable groups; and02 is a hydrogen bond acceptor;SUBSTITUTE SHEET (RULE 26)wherein C2, C5, CA1, H3, H4, Nl, N2, and 02 have coordinates in the ranges given in Table 3.

27. The compound of claim 26, wherein C2, C5, CA1, H3, H4, Nl, N2, and 02 have coordinates in the ranges given in Table 4.

28. The compound of claim 26 or 27, wherein C2, C5, CA1, H3, H4, Nl, N2, and 02 have coordinates in the ranges given in Table 5.

29. The compound of any one of claims 26 to 28, wherein the Sl pharmacophore group comprises CA1 and Nl pharmacophore elements.

30. The compound of claim 29, wherein the Sl pharmacophore group further comprises a C3 pharmacophore element, wherein C3 is a hydrophobic group and has coordinates in the ranges given in Table 6.

31. The compound of claim 30, wherein C3 has coordinates in the ranges given in Table7.

32. The compound of claim 31, wherein C3 has coordinates in the ranges given in Table833. The compound of any one of claims 26 to 32, wherein the Sl pharmacophore group comprises CA1 and C5 pharmacophore elements.

34. The compound of claim 33, wherein the Sl pharmacophore group further comprises 1, 2, or 3 pharmacophore elements selected from the group consisting of C7, H2 and 04, wherein:C7 is a hydrophobic group;H2 is a hydrogen bond donor; and04 is a hydrogen bond acceptor; andwherein C7, H2 and 04 have the coordinates in the ranges given in Table 9.

35. A compound according to claim 34, wherein C7, H2 and 04 have coordinates in the ranges given in Table 10.

36. The compound of claim 35, wherein C7, H2 and 04 have coordinates in the ranges given in Table 11.SUBSTITUTE SHEET (RULE 26)37. The compound of any one of claims 33 to 36, wherein the Sl pharmacophore group comprises a C7 pharmacophore element.

38. The compound of any one of claims 33 to 37, wherein the Sl pharmacophore group comprises an H2 pharmacophore element.

39. The compound of any one of claims 33 to 38, wherein the Sl pharmacophore group comprises an 04 pharmacophore element.

40. The compound of any one of claims 26 to 39, wherein the S2 pharmacophore group further comprises 1 or 2 pharmacophore elements selected from the group consisting of CA6 and 01, wherein:CA6 is an aromatic ring;01 is a hydrogen bond acceptor;wherein CA6 and 01 have coordinates in the ranges given in Table 12.

41. The compound of claim 40, wherein CA6 and 01 have coordinates in the ranges given in Table 13.

42. The compound of claim 41, wherein CA6 and 01 have coordinates in the ranges given in Table 14.

43. The compound of any one of claims 40 to 42, wherein the Sl pharmacophore group comprises a CA6 pharmacophore element.

44. The compound of any one of claims 40 to 43, wherein the Sl pharmacophore group comprises an 01 pharmacophore element.

45. The compound of any one of claims 26 to 44, wherein the S3 pharmacophore group comprises C2 and N2 pharmacophore elements.

46. The compound of claim 45, wherein the S3 pharmacophore group further comprises an H3 pharmacophore element.

47. The compound of any one of claims 26 to 46, wherein the compound furthercomprises an S4 pharmacophore group; whereinthe S4 pharmacophore group comprises a C4, CA2, CA4 or CA5 pharmacophore element; whereinSUBSTITUTE SHEET (RULE 26)C4 is a hydrophobic group; andCA2, CA4, and CA5 are aromatic rings; andwherein C4, CA2, CA4, and CA5 have coordinates in the ranges given in Table 15.

48. The compound of claim 47, wherein C4, CA2, CA4, and CA5 have coordinates in the ranges given in Table 16.

49. The compound of claim 48, wherein C4, CA2, CA4, and CA5 have coordinates in the ranges given in Table 17.

50. The compound of any one of claims 47 to 49, wherein the S4 pharmacophore group comprises C4.

51. The compound of any one of claims 47 to 50, wherein the S4 pharmacophore group comprises CA2.

52. The compound of claim 51, wherein the S4 pharmacophore group further comprises 1, 2, 3, or 4 additional pharmacophore elements selected from the group consisting of C6, C7, CA4 and CA5, wherein:C6 and C7 are hydrophobic groups; andCA4 and CA5 are aromatic rings; andwherein C6, C7, CA4, and CA5 have coordinates in the ranges given in Table18.

53. The compound of claim 52, wherein C6, C7, CA4, and CA5 have coordinates in the ranges given in Table 19.54 The compound of claim 53, wherein C6, C7, CA4, and CA5 have coordinates in the ranges given in Table 20.

55. The compound of any one of claims 47 to 54, wherein the S4 pharmacophore group comprises a C6 pharmacophore element.

56. The compound of any one of claims 47 to 55, wherein the S4 pharmacophore group comprises a C7 pharmacophore element.SUBSTITUTE SHEET (RULE 26)57. The compound of any one of claims 47 to 56, wherein the S4 pharmacophore group comprises a CA4 pharmacophore element.

58. The compound of any one of claims 47 to 57, wherein the S4 pharmacophore group comprises a CA5 pharmacophore element.

59. The compound of any one of claims 26 to 58, wherein the compound furthercomprises an RM pharmacophore group; wherein the RM pharmacophore group comprises a CA3 pharmacophore element, wherein CA3 is an aromatic ring that has coordinates in the ranges given in Table 21.

60. The compound of according to claim 59, wherein CA3 has coordinates in the ranges given in Table 22.

61. The compound of claim 60, wherein CA3 has coordinates in the ranges given in Table 23.

62. The compound of any one of claims 59 to 61, wherein the RM pharmacophore group further comprises 1 or 2 additional pharmacophore elements selected from the group consisting of Hl and 03, wherein:Hl is a hydrogen bond donor; and03 is a hydrogen bond acceptor; andwherein Hl and 03 have coordinates in the ranges given in Table 24.

63. The compound of claim 62, wherein Hl and 03 have coordinates in the ranges given in Table 25.

64. The compound of claim 63, wherein Hl and 03 have coordinates in the ranges given in Table 26.

65. The compound of any one of claims 62 to 64, wherein the RM pharmacophore group comprises Hl.

66. The compound of any one of claims 62 to 65, wherein the RM pharmacophore group comprises 03.SUBSTITUTE SHEET (RULE 26)67. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 26 to 66 and a pharmaceutically acceptable carrier or excipient.68 A compound of Formula (1-1):or a salt thereof, wherein:Cy1Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5- 10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy1Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy1Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCylA, halogen, Ci-6 haloalkyl, CN, ORa11, SRa11, C(0)Rbn,C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, 0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, C(=NORall)NRcllRdn, C(=NOC(0)Rbll)NRcllRdn, C(=NRell)NRcllC(0)ORa11, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;each RCylAis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10- membered heterocycloalkyl forming RCylAconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCylAis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, OC(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn,S(0)2NRcllRdnand oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCylAis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected fromSUBSTITUTE SHEET (RULE 26)halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa11, SRa11,S(0)2NRcllRdnand oxo;R11is H or C1-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the C1-6 alkyl forming R11is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, ORa11, SRa11, C(0)Rbn,S(0)2NRcllRdnand oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R11is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn,S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;R12is H or Ci-6 alkyl; orR11and R12, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;A11is CR13R15or N;each R13is independently Cy1B, (CR13AR13B)n3Cy1B, (Ci-6 alkylene)Cy1B, (C2-6 alkenylene)Cy1B, (C2-6 alkynylene)Cy1Bor OCy1B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R13is unsubstituted or substituted by 1,2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn, OC(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn,S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo;each R14is independently selected from H and Ci-6 alkyl;R15is selected from H, R13, Ci-6 alkyl and OH;a pair of R14groups attached to adjacent carbon atoms, or a pairing of R14and R15groups attached to adjacent carbon atoms, may, independently of otherSUBSTITUTE SHEET (RULE 26)occurrences of R14, together be replaced a bond connecting the adjacent carbon atoms to which the pair of R14groups or pairing of R14and R15groups is attached, such that the adjacent carbon atoms are connected by a double bond; ora pair of R14groups attached to the same carbon atom, or a pairing of R13and R15groups attached to the same carbon atom, may, independently of other occurrences of R14, and together with the carbon atom to which the pair of R14groups or pairing of R13and R15groups is attached together form a spiro-fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4- 10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein the spiro-fused C3-10 cycloalkyl or 4- 10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11,OC(0)Rbn, OC(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbl1, NRcllS(0)2Rbl1, S(0)2NRcllRdl1and oxo; orpairs of R14groups attached to adjacent carbon atoms, or a pairing of R14and R15groups attached to adjacent carbon atoms, may, independently of other occurrences of R14, together with the adjacent carbon atoms to which the pair of R14groups or pairing of R14and R15groups is attached, form a fused C3-10 cycloalkyl or 4- 10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein the fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11,OC(0)Rbn, 0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcllRdnand oxo; ora grouping of four R14groups attached to two adjacent carbon atoms, or a grouping of two R14, one R13and one R15groups attached to two adjacent carbon atoms, may, independently of other occurrences of R14, together with the two adjacent carbon atoms to which the grouping of four R14groups or grouping of two R14, one R13and one R15groups are attached, form a fused C6-10 aryl or 5-10 memberedSUBSTITUTE SHEET (RULE 26)heteroaryl, C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, and wherein the fused Ce-io aryl or 5-10 membered heteroaryl, C3-10 cycloalkyl or 4- 10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, OC(0)NRcl lRdn, NRcl lRdn, NRcl lC(0)Rbn, NRcllC(0)NRcl lRdn, NRcl lC(0)ORa11, C(=NRel l)NRcl lRdn, NRcl lC(=NRel l)NRcl lRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcl lS(0)2Rbn, S(0)2NRcl lRdnand oxo;nl is 1 or 2;n2 is 0, 1 or 2;provided that the sum of nl and n2 is 1, 2 or 3;provided that if nl is 1 or n2 is 0, then A11is CR13R15;n3 is 0, 1 or 2;each R13Ais independently H or C1-6 alkyl;each R13Bis independently H or C1-6 alkyl; oror R13Aand R13Battached to the same carbon atom, independently of any other R13Aand R13Bgroups, together may form -(CH2)2-5-, thereby forming a 3-6 membered cycloalkyl ring;Cy1Bis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, orunsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy1Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy1Bare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from Rcy1B, halogen, Ci-e haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcl lRdn,C(0)ORa11, OC(0)Rbn, OC(0)NRcl lRdn, NRcllRdn, NRcl lC(0)Rbn,NRcl lC(0)NRcl lRdn, NRcl lC(0)ORa11, C(=NRel l)NRcl lRdn, C(=NORal l)NRcl lRdn, C(=NOC(0)Rbl l)NRcl lRdn, C(=NRell)NRcl lC(0)ORa11, NRcl lC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcl lRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcl lRdnand oxo;SUBSTITUTE SHEET (RULE 26)wherein each Rt 1 Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC 1 Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 1 Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, OC(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn,S(0)2NRcllRdnand oxo; and wherein each Ce-io aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 1 Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn, OC(0)NRcllRdn, NRcllRdn,S(0)2NRcllRdnand oxo;R16is H, Cyic, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R16is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cyic, halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, 0C(0)Rbn, 0C(0)NRcllRdn, NRcllRdn, NRcllC(0)Rbn, NRcllC(0)NRcllRdn, NRcllC(0)ORa11, C(=NRell)NRcllRdn, NRcllC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcllRdn, S(0)2Rbn, NRcllS(0)2Rbl1, S(0)2NRcllRdnand oxo, provided that no more than one of the substituents of R16is Cyic;Cyicis unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, orunsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cyicconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cyicare substituted with 1, 2, 3, 4 or 5 substituents each independently selected fromSUBSTITUTE SHEET (RULE 26)RCylc, halogen, Ci-e haloalkyl, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcl lRdn,C(0)0Ral1, 0C(0)Rbn, 0C(0)NRcl lRdn, NRcllRdn, NRcl lC(0)Rbn,NRcl lC(0)NRcl lRdn, NRcl lC(0)0Ral 1, C(=NRel l)NRcl lRdn, C(=NORal l)NRcl lRdn, C(=N0C(0)Rbl l)NRcl lRdl 1, C(=NRell)NRcl lC(0)0Ral 1, NRcl lC(=NRell)NRcllRdn, S(0)Rbn, S(0)NRcl lRdn, S(0)2Rbn, NRcllS(0)2Rbn, S(0)2NRcl lRdnand oxo; wherein each Rt 1 cis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Rt 1 cconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCylcis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa11, SRa11, C(0)Rbn, C(0)NRcllRdn, C(0)ORa11, OC(0)Rbn, 0C(0)NRcl lRdn, NRcl lRdn, NRcllC(0)Rbn, NRcl lC(0)NRcl lRdn, NRcl lC(0)ORa11, C(=NRel l)NRcl lRdn,NRcl lC(=NRel l)NRcllRdn, S(0)Rbn, S(0)NRcl lRdn, S(0)2Rbn, NRcl lS(0)2Rbn, S(0)2NRcl lRdnand oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCylcis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa11, SRa11,S(0)2NRcl lRdnand oxo;REii i, Rb1 1 RCI 1independently selected from H, Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ral 1, Rbn, Rcl 1and Rdnare each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa12, SRa12, C(0)Rbl2, C(0)NRcl2Rdl2, C(0)ORa12, OC(0)Rb12,0C(0)NRcl2Rdl2, NRcl2Rd12, NRcl2C(0)Rbl2, NRcl2C(0)NRcl2Rdl2, NRcl2C(0)0Ral2,SUBSTITUTE SHEET (RULE 26)C(=NRel2)NRcl2Rd12, NRcl2C(=NRel2)NRcl2Rd12, S(0)Rbl2, S(0)NRcl2Rdl2,S(0)2Rbl2, NRcl2S(0)2Rbl2, S(0)2NRcl2Rdl2and oxo;or Rcl1and Rdnatached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-6 alkyl, halo, CN, ORa12, SRa12, C(0)Rbl2, C(0)NRcl2Rdl2, C(0)0Ral2, 0C(0)Rbl2, 0C(0)NRcl2Rdl2, NRcl2Rd12, NRcl2C(0)Rbl2, NRcl2C(0)NRcl2Rdl2, NRcl2C(0)0Ral2, C(=NRel2)NRcl2Rd12,l2Rd12, S(0)Rbl2, S(0)NRcl2Rdl2, S(0)2Rbl2, NRcl2S(0)2Rbl2, oxo;l2and Rdl2are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl- Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ral2, Rbl2, Rcl2and Rdl2are each optionally substituted with 1, 2 or 3 substituents independently selected from OH,CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rcl2and Rdl2atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRel1and Re12are each, independently, H, CN or N02.

69. The compound or salt thereof of claim 68, wherein the compound is of Formula (1-2):SUBSTITUTE SHEET (RULE 26)70. The compound or salt thereof of claim 68 or 69, wherein Cy1Ais unsubstituted or substituted aryl.

71. The compound or salt thereof of claim 70, wherein Cy1Ais unsubstituted orsubstituted phenyl.

72. The compound or salt thereof of claim 71, wherein Cy1Ais substituted phenyl.

73. The compound or salt thereof of any one of claims 68 to 72, wherein Cy1Aissubstituted with at least one ORa11or at least one C(=NRell)NRcl lRdn,C(=NORal l)NRcl lRdn, C(=NOC(0)Rbll)NRcl lRdn, or C(=NRel l)NRcl lC(0)ORa11.

74. The compound or salt thereof of any one of claims 68 to 73, wherein Cy1Aissubstituted with at least one ORa11and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

75. The compound or salt thereof of any one of claims 68 to 74, wherein Cy1Aissubstituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

76. The compound or salt thereof of any one of claims 68 to 75, wherein Cy1Aissubstituted with at least one C(=NRel l)NRcl lRdn, C(=NORall)NRcl lRdn,C(=NOC(0)Rbl l)NRcl lRdn, C(=NRell)NRcl lC(0)ORa11, preferably in the 4-position.

77. The compound or salt thereof of claim 76, wherein Cy1Ais substituted with at least one C(=NRell)NRcllRdn, preferably in the 4-position.

78. The compound or salt thereof of claim 77, wherein Cy1Ais substituted with at least one C(=NH)NH2, preferably in the 4-position.SUBSTITUTE SHEET (RULE 26)79. The compound or salt thereof of claim 72, wherein Cy1Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)80. The compound or salt thereof of claim 79, wherein, in the formula defining Cy1A, each RCylAis independently Ci-6 alkyl, such as methyl, or halogen, such as Cl or Br, or ammo.

81. The compound or salt thereof of claim 72, wherein Cy1Ais of any one of thefollowing formulae:

82. The compound or salt thereof of claim 81, wherein, in the formula defining Cy1A, Ral1is Ci-6 alkyl, such as methyl, Rbnis Ci-6 alkyl, such as methyl, Rbnis Ci-6 haloalkyl, such as trifluoromethyl, and Rcl1is alkyl such as methyl.

83. The compound or salt thereof of claim 68 or 69, wherein Cy1Ais unsubstituted or substituted heteroaryl.

84. The compound or salt thereof of claim 83, wherein Cy1Ais unsubstituted orsubstituted pyridin-3-yl, lH-pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6- yl.

85. The compound or salt thereof of claim 83, wherein Cy1Ais of any one of thefollowing formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)86. The compound or salt thereof of claim 85, wherein each RC 1 Lin the formula defining Cy1Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.

87. The compound or salt thereof of claim 85 or 86, wherein each Rt 1 Lattached tonitrogen in the formula defining Cy1Ais Ci-6 alkyl, such as methyl or ethyl. 88 The compound or salt thereof of any one of claims 68 to 87, wherein R11is Ci-6 alkyl.

89. The compound or salt thereof of claim 88, wherein R11is methyl.

90. The compound or salt thereof of any one of claims 68 to 87, wherein R11is H.

91. The compound or salt thereof of any one of claims 68 to 90, wherein R12is H.

92. The compound or salt thereof of any one of claims 68 to 90, wherein R12is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.

93. The compound or salt thereof of any one of claims 68 to 87, wherein R11and R12, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.

94. The compound or salt thereof of any one of claims 68 to 93, wherein nl is 1.

95. The compound or salt thereof of any one of claims 68 to 93, wherein nl is 2.

96. The compound or salt thereof of any one of claims 68 to 95, wherein n2 is 0.SUBSTITUTE SHEET (RULE 26)97. The compound or salt thereof of any one of claims 68 to 95, wherein n2 is 1.

98. The compound or salt thereof of any one of claims 68 to 95, wherein n2 is 2.

99. The compound or salt thereof of any one of claims 68 to 98, wherein the compound is according to any of the following Formulae (I-la) to (I- If) and (I-2a) to (I-2r):(I-2a) (I-2b)SUBSTITUTE SHEET (RULE 26)(I-2k) (1-21)SUBSTITUTE SHEET (RULE 26)(I-2q) (I-2r)The compound or salt thereof of any one of claims 68 to 99, wherein the compound is according to any of the following Formulae (I-lg) to (I-lo) and (I-2aa) to (I-2az):(I-li) (i-ij)SUBSTITUTE SHEET (RULE 26)(I-2ae) (I-2af)SUBSTITUTE SHEET (RULE 26)(I-2aq) (I-2ar)SUBSTITUTE SHEET (RULE 26)(I-2ay) (I-2az)The compound or salt thereof of any one of claims 68 to 100, wherein the compound is according to any of the following Formulae (1-3) to (1-9):SUBSTITUTE SHEET (RULE 26)102. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-3a) to (I-3k).(I-3g) (I-3h)SUBSTITUTE SHEET (RULE 26)103. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-4a) to (I-4bf):(I-4g) (I-4h)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-4at) (I-4au)SUBSTITUTE SHEET (RULE 26)(I-4be) (I-4bf)104. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-5a) to (I-5u):SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-5u)105. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-6a) to (I-6cw):(I-6c) (I-6d)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-6bk) (I-6bl)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-6ci) (I-6cj)SUBSTITUTE SHEET (RULE 26)(I-6ct) (I-6cu)SUBSTITUTE SHEET (RULE 26)(I-6cv) (I-6cw)106. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-7a) to (1-7 co).(I-7i) (I-7j)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-7aq) (I-7ar)SUBSTITUTE SHEET (RULE 26)(I-7bf)(I-7be)SUBSTITUTE SHEET (RULE 26)(I-7br)(I-7bq)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(I-7co)SUBSTITUTE SHEET (RULE 26)107. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-8a) to (I-8z):(I-8k) (1-81)SUBSTITUTE SHEET (RULE 26)(I-8w) (I-8x)SUBSTITUTE SHEET (RULE 26)(i-8y) (I-8z)108. The compound or salt thereof of any one of claims 68 to 101, wherein the compound is according to any of the following Formulae (I-9a) to (I-9z):(I-9i) (I-9j)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)(i-9y) (I-9z)109. The compound or salt thereof of any one of claims 68 to 108, wherein R13is Cy1B.110 The compound or salt thereof of any one of claims 68 to 108, wherein R13is (Ci-6 alkylene)Cy1B, (C2-6 alkenylene)Cy1B, or (C2-6 alkynylene)Cy1B.111 The compound or salt thereof according to claim 110, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R13is unsubstituted.112 The compound or salt thereof of any one of claims 68 to 108, wherein R13is(CR13AR13B)n3Cy1B.

113. The compound or salt thereof according claim 112, wherein each R13Ais H.

114. The compound or salt thereof according claim 112, wherein each R13Bis H.

115. The compound or salt thereof of any one of claims 68 to 114, wherein n3 is 0.

116. The compound or salt thereof of any one of claims 68 to 114, wherein n3 is 1.

117. The compound or salt thereof of any one of claims 68 to 114, wherein n3 is 2.

118. The compound or salt thereof of any one of claims 68 to 114, wherein R13is (CTkV 2Cy1B.

119. The compound or salt thereof of any one of claims 68 to 114, wherein R13isCH2Cy1B.SUBSTITUTE SHEET (RULE 26)120. The compound or salt thereof of any one of claims 68 to 114, wherein R13is CH2CH2Cy1B121. The compound or salt thereof of any one of claims 68 to 108, wherein R13is OCy1B.

122. The compound or salt thereof of any one of claims 68 to 121, wherein Cy1Bisunsubstituted Ce-io aryl.

123. The compound or salt thereof according to claim 122, wherein Cy1Bis unsubstituted phenyl.

124. The compound or salt thereof according to claim 122, wherein Cy1Bis unsubstituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

125. The compound or salt thereof of any one of claims 68 to 124, wherein Cy1Bunsubstituted 5-10 membered heteroaryl.

126. The compound or salt thereof according to claim 125, wherein Cy1Bis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl or unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

127. The compound or salt thereof of any one of claims 68 to 121, wherein Cy1Bissubstituted Ce-io aryl.

128. The compound or salt thereof according to claim 127, wherein Cy1Bis substituted phenyl.

129. The compound or salt thereof according to claim 128, wherein Cy1Bis a biphenylyl (i.e., phenyl substituted by phenyl), such as 2-, 3-, or 4-biphenylyl.

130. The compound or salt thereof according to claim 129, wherein Cy1Bis substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

131. The compound or salt thereof of any one of claims 68 to 121, wherein Cy1Bsubstituted 5-10 membered heteroaryl.

132. The compound or salt thereof according to claim 131, wherein Cy1Bis substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl or substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.SUBSTITUTE SHEET (RULE 26)133. The compound or salt thereof of any one of claims 127 to 132, wherein Cy1Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCylB, halogen, and Ci-6 haloalkyl;wherein each RC 1 Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming Rt 1 Bis unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.134 The compound or salt thereof of any one of claims 68 to 133, wherein R13is selected from groups of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)135. The compound or salt thereof of claim 134, wherein RC 1 Bin the formula representing R13is Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen, such as fluorine or chlorine, preferably fluorine.136 The compound or salt thereof of claim 134, wherein Rt 1 Bin the formula representing R13is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.SUBSTITUTE SHEET (RULE 26)137. The compound or salt thereof of claim 134, wherein Rtv 1 Bin the formula representing R13is halogen, such as fluorine or chlorine, preferably fluorine.

138. The compound or salt thereof of any one of claims 68 to 137, wherein no more than one R14is other than hydrogen.

139. The compound or salt thereof according to claim 138, wherein no more than one R14is other than hydrogen and one R14is Ci-6 alkyl, such as methyl.

140. The compound or salt thereof according to claim 139, wherein each R14is hydrogen.

141. The compound or salt thereof of any one of claims 68 to 140, wherein A11is N.

142. The compound or salt thereof of any one of claims 68 to 141, wherein R15ishydrogen.

143. The compound or salt thereof of any one of claims 68 to 141, wherein R15is Ci-6 alkyl such as methyl.

144. The compound or salt thereof of any one of claims 68 to 141, wherein R15is hydroxyl.

145. The compound or salt thereof of any one of claims 68 to 144, wherein R16ishydrogen.

146. The compound or salt thereof of any one of claims 68 to 144, wherein R16isunsubstituted or substituted Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.

147. The compound or salt thereof according to claim 146, wherein R16is unsubstituted Ci-6 alkyl such as methyl.

148. The compound or salt thereof according to claim 146, wherein R16is substituted Ci-6 alkyl.

149. The compound or salt thereof according to claim 148, wherein the substituted Ci-6 alkyl forming R16is substituted by 1, 2, 3, 4 or 5, such as 1, 2, or 3, or, preferably 1, substituents selected from the group consisting of halogen, CN, C(0)NRcllRdnand C(0)0RaUSUBSTITUTE SHEET (RULE 26)150. The compound or salt thereof according to claim 149, wherein R16is (CH2)I- 6C(0)0RaU151. The compound or salt thereof according to claim 150, wherein the Ral1defining R16is H or Ci-6 alkyl such as methyl.

152. The compound or salt thereof according to claim 150, wherein the Ral1defining R16is H.

153. The compound or salt thereof of any one of claims 68 to 152, wherein Ral1, Rbn, Rcl1and Rdn, Ral2, Rbl2, Rcl2and Rdl2are each independently selected from H and Ci-6 alkyl.

154. The compound or salt thereof of any one of claims 68 to 85153 wherein each Rel1and each Rel2is H.

155. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 68 to 154 and a pharmaceutically acceptable carrier or excipient.

156. A compound of Formula (IIA) or (IIB):or a salt thereof, wherein:Cy2Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5- 10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy2Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy2Aare substituted with 1, 2, 3, 4 or 5 substituents each independentlySUBSTITUTE SHEET (RULE 26)selected from RCy2A, halogen, Ci-6 haloalkyl, CN, ORa21, SRa21, C(0)Rb21,S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;each RCy2Ais independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10- membered heterocycloalkyl forming RCy2Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCy2Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21, NRc21Rd21, NRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21,NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCy2Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OR321, SR321,S(0)2NRc21Rd21and oxo;R21is H or Ci-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the Ci-6 alkyl forming R21is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OR321, SR321, C(0)Rb21,S(0)2NRc21Rd21and oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R21is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OR321, SR321, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21, NRc21Rd21, NRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21,SUBSTITUTE SHEET (RULE 26)C(=NRe21)NRc21Rd21, NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21,S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;R22is H or Ci-6 alkyl; orR21and R22, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;A23is N or NR23;A24is CR24; N or NR24;A26is CR26or S;provided thatA23, A24and A26in Formula (IIA) are selected such that the ring comprising A23, A24and A26is a heteroaryl ring and the symbol = represents an aromatic ring (normalized) bond;R23is H or Ci-6 alkyl;R24is H; Ci-6 alkyl or phenyl;R25is Cy2B, (CR25AR25B)n25Cy2B, (Ci-6 alkylene)Cy2B, (C2-6 alkenylene)Cy2B, or (C2-6 alkynylene)Cy2B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R25is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, c21Rd21,R26is H or Ci-6 alkyl;each R25Ais H or Ci-6 alkyl;each R25Bis H or Ci-6 alkyl;n25 is 0, 1 or 2;Cy2Bis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy2Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy2Bare substituted with 1, 2, 3, 4 or 5 substituents each independently selected fromSUBSTITUTE SHEET (RULE 26)R2B. halogen, Ci-e haloalkyl, CN, ORa21, SRa21, C(0)Rb21, C(0)NRc21Rd21,S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo;wherein each RC 2Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC 2Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 2Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR321, SR321, C(0)Rb21, C(0)NRc21Rd21, C(0)ORa21, OC(0)Rb21, 0C(0)NRc21Rd21, NRc21Rd21, NRc21C(0)Rb21, NRc21C(0)NRc21Rd21, NRc21C(0)0Ra21, C(=NRe21)NRc21Rd21,NRc21C(=NRe21)NRc21Rd21, S(0)Rb21, S(0)NRc21Rd21, S(0)2Rb21, NRc21S(0)2Rb21, S(0)2NRc21Rd21and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 2Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa21, SR321,S(0)2NRc21Rd21and oxo;are each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl- Ci-3 alkyl forming Ra21, Rb21, Rc21and Rd21are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, OR322, SR322,SUBSTITUTE SHEET (RULE 26)NRc22C(=NRe22)NRc22Rd22, S(0)Rb22, S(0)NRc22Rd22, S(0)2Rb22, NRc22S(0)2Rb22, S(0)2NRc22Rd22and oxo;or Rc21and Rd21atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-6 alkyl, halo, CN, OR322, SRa22, C(0)Rb22, C(0)NRc22Rd22, C(0)0Ra22, 0C(0)Rb22, 0C(0)NRc22Rd22, NRc22Rd22, NRc22C(0)Rb22, NRc22C(0)NRc22Rd22, NRc22C(0)0Ra22, C(=NRe22)NRc22Rd22,22Rd22, S(0)Rb22, S(0)NRc22Rd22, S(0)2Rb22, NRc22S(0)2Rb22, oxo;22and Rd22are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl- Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ra22, Rb22, Rc22and Rd22are each optionally substituted with 1, 2 or 3 substituents independently selected from OH,CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rc22and Rd22atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRe21and Re22are each, independently, H, CN or N02.

157. The compound or salt thereof according to claim 156, wherein Cy2Ais unsubstituted or substituted aryl.

158. The compound or salt thereof according to claim 157, wherein Cy2Ais unsubstituted or substituted phenyl.SUBSTITUTE SHEET (RULE 26)159. The compound or salt thereof according to claim 158, wherein Cy2Ais substituted phenyl.

160. The compound or salt thereof of any one of claims 156 to 159, wherein Cy2Aissubstituted with at least one OR321or at least one C(=NRe21)NRc21Rd21,C(=NORa21)NRc21Rd21, C(=N0C(0)Rb21)NRc21Rd21, or C(=NRe21)NRc21C(0)0Ra21.

161. The compound or salt thereof of any one of claims 156 to 160, wherein Cy2Aissubstituted with at least one OR321and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

162. The compound or salt thereof of any one of claims 156 to 161, wherein Cy2Aissubstituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

163. The compound or salt thereof of any one of claims 156 to 162, wherein Cy2Aissubstituted with at least one C(=NRe21)NRc21Rd21, C(=NORa21)NRc21Rd21,C(=N0C(0)Rb21)NRc21Rd21, C(=NRe21)NRc21C(0)0Ra21, preferably in the 4-position.

164. The compound or salt thereof according to claim 163, wherein Cy2Ais substituted with at least one C(=NRe21)NRc21Rd21, preferably in the 4-position.

165. The compound or salt thereof according to claim 164, wherein Cy2Ais substituted with at least one C(=NH)NH2, preferably in the 4-position.

166. The compound or salt thereof according to claim 159, wherein Cy2Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)167. The compound or salt thereof according to claim 166, wherein, in the formuladefining Cy2A, each RC 2Ais independently Ci-6 alkyl, such as methyl, or halogen, such as Cl or Br, or amino.

168. The compound or salt thereof according to claim 159, wherein Cy2Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)169. The compound or salt thereof according to claim 168, wherein R321is Ci-6 alkyl and Rb21is Ci-6 alkyl.

170. The compound or salt thereof according to claim 156, wherein Cy2Ais unsubstituted or substituted heteroaryl, such as pyridin-3-yl, lH-pyrrolo[2,3-b]pyridine-5-yl, or 1H- benzo[d]imidazol-6-yl.

171. The compound or salt thereof according to claim 170, wherein Cy2Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)172. The compound or salt thereof according to claim 171, wherein each Rt 2Ain the formula defining Cy2Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl.

173. The compound or salt thereof according to claim 171 or 172, wherein each Rt 2Aattached to nitrogen in the formula defining Cy2Ais Ci-6 alkyl, such as methyl or ethyl.

174. The compound or salt thereof of any one of claims 156 to 173, wherein R21is Ci-6 alkyl.

175. The compound or salt thereof according to claim 174, wherein R21is methyl.

176. The compound or salt thereof of any one of claims 156 to 173, wherein R21is H.

177. The compound or salt thereof of any one of claims 156 to 176, wherein R22is H.

178. The compound or salt thereof of any one of claims 156 to 176, wherein R22is Ci-6 alkyl.

179. The compound or salt thereof according to claim 178, wherein R22is methyl.

180. The compound or salt thereof of any one of claims 156 to 179, wherein R21and R22, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.

181. The compound or salt thereof of any one of claims 156 to 180, wherein the compound is of Formula (IIA).182 The compound or salt thereof according to claim 181, wherein the compound is according to any of the following Formulae (IIA-la) or (IIA-lb):SUBSTITUTE SHEET (RULE 26)(IIA-la) (IIA-lb)183. The compound or salt thereof of any one of claims 181 or 182, wherein the compound is according to any of the following Formulae (IIA-2) to (IIA-5):(IIA-4) (IIA-5)184. The compound or salt thereof according to claim 183, wherein the compound is according to any of the following Formulae (IIA-2a) to (IIA-5b):(IIA-3a) (IIA-3b)SUBSTITUTE SHEET (RULE 26)(IIA-5a) (IIA-5b)185. The compound or salt thereof of any one of claims 156 to 180, wherein the compound is of Formula (PB).

186. The compound or salt thereof according to claim 185, wherein the compound is according to any of the following Formulae (IIB-la) or (IIB-lb):(IIB-la) (IIB-lb) 187. The compound or salt thereof of any one of claims 156 to 184, wherein R23is H.

188. The compound or salt thereof of any one of claims 156 to 184, wherein R23is Ci-6 alkyl.

189. The compound or salt thereof of any one of claims 156 to 188, wherein R24is H.

190. The compound or salt thereof of any one of claims 156 to 188, wherein R24is Ci-6 alkyl.

191. The compound or salt thereof of any one of claims 156 to 188, wherein R24is phenyl.

192. The compound or salt thereof of any one of claims 156 to 191, wherein R25is Cy2B.SUBSTITUTE SHEET (RULE 26)193. The compound or salt thereof of any one of claims 156 to 191, wherein R25is (Ci-6 alkylene)Cy2B, (C2-6 alkenylene)Cy2B, or (C2-6 alkynylene)Cy2B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R25is unsubstituted or substituted.

194. The compound or salt thereof of any one of claims 156 to 193, wherein R25is (Ci-6 alkylene)Cy2B, (C2-6 alkenylene)Cy2B, or (C2-6 alkynylene)Cy2B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R25is unsubstituted.

195. The compound or salt thereof of any one of claims 156 to 194, wherein R25is(CR25AR25B)n25Cy2B.

196. The compound or salt thereof according to claim 195, wherein each R25Ais H.

197. The compound or salt thereof according to claim 194 or 195, wherein each R25Bis H.

198. The compound or salt thereof of any one of claims 194 to 196, wherein n25 is 0.

199. The compound or salt thereof of any one of claims 194 to 196, wherein n25 is 1.

200. The compound or salt thereof of any one of claims 194 to 196, wherein n25 is 2.

201. The compound or salt thereof of any one of claims 194 to 196, wherein R25isCH2Cy2B.

202. The compound or salt thereof of any one of claims 194 to 196, wherein R25isCH2CH2Cy2B.

203. The compound or salt thereof of any one of claims 156 to 202, wherein Cy2Bisunsubstituted Ce-io aryl.

204. The compound or salt thereof according to claim 203, wherein Cy2Bis unsubstituted phenyl.

205. The compound or salt thereof according to claim 203, wherein Cy2Bis unsubstituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

206. The compound or salt thereof of any one of claims 156 to 202, wherein Cy2Bunsubstituted 5-10 membered heteroaryl.SUBSTITUTE SHEET (RULE 26)207. The compound or salt thereof according to claim 206, wherein Cy2Bis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl or unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

208. The compound or salt thereof of any one of claims 156 to 202, wherein Cy2Bissubstituted C6-10 aryl.

209. The compound or salt thereof according to claim 208, wherein Cy2Bis substituted phenyl.

210. The compound or salt thereof according to claim 209, wherein Cy2Bis a biphenylyl (i.e., phenyl substituted by phenyl), such as 2-, 3-, or 4-biphenylyl.

211. The compound or salt thereof according to claim 208, wherein Cy2Bis substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

212. The compound or salt thereof of any one of claims 156 to 202, wherein Cy2Bissubstituted 5-10 membered heteroaryl.

213. The compound or salt thereof according to claim 212, wherein Cy2Bis substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl or substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

214. The compound or salt thereof of any one of claims 208 to 213, wherein Cy2Bissubstituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy2B, halogen, and Ci-6 haloalkyl;wherein each RC 2Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming Rt 2Bis unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.215 The compound or salt thereof of any one of claims 156 to 214, wherein R25is selected from groups of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)216. The compound or salt thereof of claim 215, wherein Rt 2Bin the formula representing R25is Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen, such as fluorine or chlorine, preferably fluorine.

217. The compound or salt thereof of claim 215, wherein Rt 2Bin the formula representing R25is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.

218. The compound or salt thereof of claim 215, wherein RC 2Bin the formula representing R25is halogen, such as fluorine or chlorine, preferably fluorine.

219. The compound or salt thereof of any one of claims 156 to 218, wherein Ra21, Rb21, Rc21. Rd21, R322, Rb22, Rc22, Rd22are each independently selected from H, Ci-6 alkyl.

220. The compound or salt thereof of any one of claims 156 to 219, wherein each Re21and each Re22is H.

221. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 156 to 220 and a pharmaceutically acceptable carrier or excipient.

222. A compound of Formula (III):SUBSTITUTE SHEET (RULE 26)or a salt thereof, for use in treating a MASP-2-associated disease or disorder, wherein:Cy3Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5- 10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy3Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-io aryl or substituted 5-10 membered heteroaryl forming Cy3Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3A, halogen, Ci-6 haloalkyl, CN, ORa31, SRa31, C(0)Rb31,C(=N0C(0)Rb3 1)N Rc3' Rd3 1. C(=NRe31)NRc3'C(0)0Ra3 1. NRc31C(=NRe3')NRc3' Rd3 1.S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;each RCy3Ais independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10- membered heterocycloalkyl forming RCy3Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RCy3Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa31, SRa31, C(0)Rb31,S(0)2NRc31Rd31and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RCy3Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;SUBSTITUTE SHEET (RULE 26)R31is H or Ci-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the Ci-6 alkyl forming R31is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, ORa31, SRa31, C(0)Rb31,S(0)2NRc31Rd31and oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R31is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)0Ra31, 0C(0)Rb31,(0)0Ra31,R32is H or Ci-6 alkyl; orR31and R32, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;R33is Cy3B, (CR33AR33B)n33Cy3B, (Ci-6 alkylene)Cy3B, (C2-6 alkenylene)Cy3B, or (C2-6 alkynylene)Cy3B, wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R35is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31,C(=NRe31)NRc31Rd31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31,S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;each R33Ais independently H or Ci-6 alkyl;each R33Bis independently H or Ci-6 alkyl; oror R33Aand R33Battached to the same carbon atom, independently of any other R33Aand R33Bgroups, together may form -(CH2)2-5-, thereby forming a 3-6 membered cycloalkyl ring;n33 is 0, 1, 2 or 3;Cy3Bis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, orunsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atomsSUBSTITUTE SHEET (RULE 26)of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy3Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-io aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy3Bare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3B, halogen, Ci-e haloalkyl, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31,C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31,NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, C(=NORa31)NRc31Rd31, C(=NOC(0)Rb3 1)N Rc3' Rd3 1. C(=NRe31)NRc3'C(0)ORa3 1. NRc3 lC(=NRc3 l)NRc3 lRd3 1. S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo; wherein each Rt 3Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming R3Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 3Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa31, SRa31, C(0)Rb31,S(0)2NRc31Rd31and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 3Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;R34is selected from H and Ci-6 alkyl;R35is selected from H, unsubstituted or substituted Ci-6 alkyl and Cy3C, wherein the substituted Ci-6 alkyl forming R35is substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy3C, halogen, CN, ORa31, SRa31,SUBSTITUTE SHEET (RULE 26)NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo; provided that no more than one of the substituents of R35isCy3C;Cy3Cis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, orunsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy3Cconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy3Care substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3C, halogen, Ci-e haloalkyl, CN, OR831, SRa31, C(0)Rb31, C(0)NRc31Rd31,C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31,NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, C(=NORa31)NRc31Rd31, C(=NOC(0)Rb3 1)N Rc3' Rd3 1. C(=NRe31)NRc3'C(0)ORa3 1. NRc3 lC(=NRc3 l)NRc3 lRd3 1. S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo; wherein each Rt 3tis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming RC 3Cconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 3Cis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa31, SRa31, C(0)Rb31,S(0)2NRc31Rd31and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 3Cis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)ORa31, OC(0)Rb31, 0C(0)NRc31Rd31, NRc31Rd31, NRc31C(0)Rb31, NRc31C(0)NRc31Rd31, NRc31C(0)0Ra31, C(=NRe31)NRc31Rd31, NRc31C(=NRe31)NRc31Rd31, S(0)Rb31, S(0)NRc31Rd31, S(0)2Rb31, NRc31S(0)2Rb31, S(0)2NRc31Rd31and oxo;SUBSTITUTE SHEET (RULE 26)R36is selected from H and Ci-6 alkyl;Ra31, Rb31, Rc31and Rd31are each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ra31, Rb31, Rc31and Rd31are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa32, SRa32, C(0)Rb32, C(0)NRc32Rd32, C(0)0Ra32, 0C(0)Rb32,S(0)2Rb32, NRc32S(0)2Rb32, S(0)2NRc32Rd32and oxo;or Rc31and Rd31atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5 -membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-6 alkyl, halo, CN, ORa32, SRa32, C(0)Rb32, C(0)NRc32Rd32, C(0)0Ra32, 0C(0)Rb32, 0C(0)NRc32Rd32, NRc32Rd32, NRc32C(0)Rb32, NRc32C(0)NRc32Rd32, NRc32C(0)0Ra32, C(=NRe32)NRc32Rd32,NRc32C(=NRe32)NRc32Rd32, S(0)Rb32, S(0)NRc32Rd32, S(0)2Rb32, NRc32S(0)2Rb32, S(0)2NRc32Rd32and oxo;REI32, Rb32 f^c32anc| RCI32are each independently selected from H, Ci-6alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl- Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ra32, Rb32, Rc32and Rd32are each optionally substituted with 1, 2 or 3 substituents independently selected from OH,CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;SUBSTITUTE SHEET (RULE 26)or Rc32and Rd32atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRe31and Re32are each, independently, H, CN or NO2.

223. The compound or salt thereof according to claim 222, wherein Cy3Ais unsubstituted or substituted aryl.

224. The compound or salt thereof according to claim 223, wherein Cy3Ais unsubstituted or substituted phenyl.

225. The compound or salt thereof according to claim 224, wherein Cy3Ais substituted phenyl.

226. The compound or salt thereof of any one of claims 222 to 225, wherein Cy3Aissubstituted with at least one ORa31or at least one C(=NRe31)NRc31Rd31,C(=NORa31)NRc31Rd31, C(=N0C(0)Rb31)NRc31Rd31, or C(=NRe31)NRc31C(0)0Ra31.

227. The compound or salt thereof of any one of claims 222 to 226, wherein Cy3Aissubstituted with at least one ORa31and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

228. The compound or salt thereof of any one of claims 222 to 227, wherein Cy3Aissubstituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

229. The compound or salt thereof of any one of claims 222 to 228, wherein Cy3Aissubstituted with at least one C(=NRe31)NRc31Rd31, C(=NORa31)NRc31Rd31,C(=N0C(0)Rb31)NRc31Rd31, C(=NRe31)NRc31C(0)0Ra31, preferably in the 4-position.

230. The compound or salt thereof according to claim 229, wherein Cy3Ais substituted with at least one C(=NRe31)NRc31Rd31, preferably in the 4-position.SUBSTITUTE SHEET (RULE 26)231. The compound or salt thereof according to claim 230, wherein Cy3Ais substituted with at least one C(=NH)NH2, preferably in the 4-position.

232. The compound or salt thereof according to claim 225, wherein Cy3Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)233. The compound or salt thereof according to claim 225, wherein Cy3Ais of any one of the following formulae:

234. The compound or salt thereof according to claim 233, wherein, in the formuladefining Cy3A, Ra31is Ci-6 alkyl, such as methyl; Rb31is Ci-6 alkyl, such as methyl, or Rb31is Ci-6 haloalkyl, such as trifluoromethyl' and Rc31is alkyl such as methyl.

235. The compound or salt thereof according to claim 222, wherein Cy3Ais unsubstituted or substituted heteroaryl.

236. The compound or salt thereof according to claim 235, wherein Cy3Ais unsubstituted or substituted pyridin-3-yl, lH-pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol- 6-yl.

237. The compound or salt thereof according to claim 234 or 235, wherein Cy3Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)238. The compound or salt thereof according to claim 237, wherein each Rt 3Ain the formula defining Cy3Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.

239. The compound or salt thereof according to claim 237 or 238, wherein each R3Aattached to nitrogen in the formula defining Cy3Ais Ci-6 alkyl, such as methyl or ethyl.

240. The compound or salt thereof of any one of claims 222 to 239, wherein R31is Ci-6 alkyl.

241. The compound or salt thereof according to claim 240, wherein R31is methyl.

242. The compound or salt thereof of any one of claims 222 to 241, wherein R31is H.

243. The compound or salt thereof of any one of claims 222 to 242, wherein R32is H.

244. The compound or salt thereof of any one of claims 222 to 242, wherein R32is Ci-6 alkyl.

245. The compound or salt thereof according to claim 244, wherein R32is methyl.

246. The compound or salt thereof of any one of claims 222 to 239, wherein R31and R32, together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.

247. The compound or salt thereof of any one of claims 222 to 246, wherein the compound is according to any of the following Formulae (Ill-la) to (Ill-lh):SUBSTITUTE SHEET (RULE 26)(Ill- la) (III- lb)(Ill-lg) (Ill-lh)248. The compound or salt thereof of any one of claims 222 to 247, wherein R33is Cy3B.

249. The compound or salt thereof of any one of claims 222 to 247, wherein R33is (Ci-6 alkylene)Cy3B, (C2-6 alkenylene)Cy3B, or (C2-6 alkynylene)Cy3B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R35is unsubstituted.

250. The compound or salt thereof of any one of claims 222 to 249, wherein R33is. (C1-6 alkylene)Cy3B, (C2-6 alkenylene)Cy3B, or (C2-6 alkynylene)Cy3B, wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R35is substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, ORa31, SRa31, C(0)Rb31, C(0)NRc31Rd31, C(0)0Ra31, 0C(0)Rb31,(0)0Ra31,251. The compound or salt thereof of any one of claims 222 to 247, wherein R33is(CR33AR33B)n33Cy3B.

252. The compound or salt thereof according to claim 251, wherein each R33Ais H.

253. The compound or salt thereof according to claim 251 or 252, wherein each R33Bis H.SUBSTITUTE SHEET (RULE 26)254. The compound or salt thereof of any one of claims 251 to 253, wherein n33 is 0.

255. The compound or salt thereof of any one of claims 251 to 253, wherein n33 is 1.

256. The compound or salt thereof of any one of claims 251 to 253, wherein n33 is 2.

257. The compound or salt thereof of any one of claims 251 to 253, wherein n33 is 3.

258. The compound or salt thereof of any one of claims 222 to 247, wherein R33isCH2Cy3B.

259. The compound or salt thereof of any one of claims 222 to 247, wherein R33is CH2CH2Cy3B.

260. The compound or salt thereof according to claim 259, wherein the compound is according to any of the following Formulae (III-2) to (III-4):(III-4)261. The compound or salt thereof according to claim 260, wherein the compound is according to any of the following Formulae (III-2a) to (III-2h):(III-2a) (III-2b)SUBSTITUTE SHEET (RULE 26)(III-2g) (III-2h)262. The compound or salt thereof according to claim 260, wherein the compound is according to any of the following Formulae (III-3a) to (III-3h):(III-3c) (III-3d)SUBSTITUTE SHEET (RULE 26)(III-3g) (III-3h)263. The compound or salt thereof according to claim 260, wherein the compound is according to any of the following Formulae (III-4a) to (III-4h):(III-4c) (III-4d)SUBSTITUTE SHEET (RULE 26)(III-4g) (III-4h)264. The compound or salt thereof of any one of claims 222 to 247, wherein R33isCH2CH2CH2Cy3B.

265. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bis unsubstituted Ce-io aryl.

266. The compound or salt thereof according to claim 265, wherein Cy3Bis unsubstituted phenyl.

267. The compound or salt thereof according to claim 266, wherein R33is CThCThPh.

268. The compound or salt thereof according to claim 266, wherein Cy3Bis unsubstituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

269. The compound or salt thereof according to claim 268, wherein R33is CH2CH2-l- naphthyl or CH2CH2-2-naphthyl.

270. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bunsubstituted 5-10 membered heteroaryl.

271. The compound or salt thereof according to claim 270, wherein Cy3Bis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo|6|thiophenylSUBSTITUTE SHEET (RULE 26)such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

272. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bunsubstituted C3-10 cycloalkyl.

273. The compound or salt thereof according to claim 272, wherein Cy3Bis unsubstituted cyclopentyl, cyclohexyl, or cycloheptyl.

274. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bunsubstituted 4-10 membered heterocycloalkyl.

275. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bis substituted C6-10 aryl.

276. The compound or salt thereof according to claim 275, wherein Cy3Bis substituted phenyl.

277. The compound or salt thereof according to claim 275, wherein Cy3Bis substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

278. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bsubstituted 5-10 membered heteroaryl.

279. The compound or salt thereof according to claim 278, wherein Cy3Bis substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo|6|thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo|6 |thiophenyl. or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

280. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bsubstituted C3-10 cycloalkyl.

281. The compound or salt thereof according to claim 280, wherein Cy3Bis substituted cyclopentyl, cyclohexyl, or cycloheptyl.

282. The compound or salt thereof of any one of claims 222 to 264, wherein Cy3Bsubstituted 4-10 membered heterocycloalkylSUBSTITUTE SHEET (RULE 26)283. The compound or salt thereof of any one of claims 275 to 282, wherein Cy3Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy3B, halogen, and Ci-6 haloalkyl;wherein each Rt 3Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming Rt 3Bis unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.284 The compound or salt thereof of any one of claims 222 to 283, wherein R33is selected from the following groups: phenyl; benzyl;, 2-phenylethyl; 2,3-dihydro-lH-inden-2- yl; 2-(2-methylphenyl)ethyl; 2-(3-methylphenyl)ethyl; 2-(4-methylphenyl)ethyl; 2- (2,4-dimethylphenyl)ethyl; 2-(2,5-dimethylphenyl)ethyl; 2-(3,5-dimethylphenyl)ethyl; 2-(2-ethylphenyl)ethyl; 2-(3-ethylphenyl)ethyl; 2-(4-ethylphenyl)ethyl; 2-(2,4- diethylphenyl)ethyl; 2-(2,5-dimethylphenyl)ethyl; 2-(3,5-dimethylphenyl)ethyl; 2-(2- trifluoromethylphenyl)ethyl; 2-(3-trifluoromethylphenyl)ethyl; 2-(4- trifluoromethylphenyl)ethyl; 2-(2-fluorophenyl)ethyl; 2-(3-fluorophenyl)ethyl; 2-(4- fluorophenyl)ethyl; 2-(2,4-difluorophenyl)ethyl; 2-(2,5-difluorophenyl)ethyl; 2-(3,5- difluorophenyl)ethyl; 2-(2-chlorophenyl)ethyl; 2-(3-chlorophenyl)ethyl; 2-(4- chlorophenyl)ethyl; 2-(2,4-dichlorophenyl)ethyl; 2-(2,5-dichlorophenyl)ethyl; 2-(3,5- dichlorophenyl)ethyl; 2-(2-methoxyphenyl)ethyl; 2-(3-methoxyphenyl)ethyl; 2-(4- methoxyphenyl)ethyl; 2-(2,4-dimethoxyphenyl)ethyl; 2-(2,5-dimethoxyphenyl)ethyl; 2-(3,5-dimethoxyphenyl)ethyl; 2-(cyclopentyl)ethyl; 2-(cyclohexyl)ethyl; 2- (cycloheptyl)ethyl; 2-(2-(aminomethyl)phenyl)ethyl; 2-(3- (aminomethyl)phenyl)ethyl; 2-(4-(aminomethyl)phenyl)ethyl; 2-(2- cyanophenyl)ethyl; 2-(3-cyanophenyl)ethyl; and 2-(4-cyanophenyl)ethyl; and groups of the following formulae:SUBSTITUTE SHEET (RULE 26)285. The compound or salt thereof of any one of claims 222 to 284, wherein R34ishydrogen.

286. The compound or salt thereof of any one of claims 222 to 284, wherein R34is Ci-6 alkyl, such as methyl.

287. The compound or salt thereof of any one of claims 222 to 286, wherein R35is H.

288. The compound or salt thereof of any one of claims 222 to 286, wherein R35is Cy3C.

289. The compound or salt thereof of any one of claims 222 to 286, wherein R35isunsubstituted Ci-6 alkyl.

290. The compound or salt thereof of any one of claims 222 to 286, wherein R35issubstituted Ci-6 alkyl.

291. The compound or salt thereof according to claim 290, wherein the substituted Ci-6 alkyl forming R35is substituted by at least one substituent, wherein the substituents of R35are independently selected from: 1, 2, or 3 substituents selected from the group consisting of Cy3C, halogen, CN, OR831, SR831, C(0)Rb31, C(0)NRc31Rd31, C(0)0Ra31,31,292. The compound or salt thereof according to claim 290 or 291, wherein the substituted Ci-6 alkyl forming R35is substituted by at least one substituent, wherein the substituents include Cy3C.

293. The compound or salt thereof according to claim 292, wherein the substituted Ci-6 alkyl forming R35is substituted by one substituent, wherein the substituent is Cy3C.

294. The compound or salt thereof of any one of claims 290 to 293, wherein R35is (CH2)I-5Cy3C.SUBSTITUTE SHEET (RULE 26)295. The compound or salt thereof according to claim 294, wherein R35is CH2Cy3C.

296. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cis unsubstituted C6-10 aryl.

297. The compound or salt thereof according to claim 296, wherein Cy3Cis unsubstituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl.

298. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cis unsubstituted 5-10 membered heteroaryl.

299. The compound or salt thereof according to claim 298, wherein Cy3Cis unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo|6|thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo|6 |thiophenyl. or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

300. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cis unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

301. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cis unsubstituted 4-10 membered heterocycloalkyl.

302. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cis substituted C6-10 aryl.

303. The compound or salt thereof according to claim 302, wherein Cy3Cis substituted phenyl, or substituted naphthyl, such as substituted 1 -naphthyl or 2-naphthyl.

304. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Csubstituted 5-10 membered heteroaryl.

305. The compound or salt thereof according to claim 304, wherein Cy3Cis substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo|6|thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo|6 |thiophenyl. or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.SUBSTITUTE SHEET (RULE 26)306. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cis substituted C3-10 cycloalkyl such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

307. The compound or salt thereof of any one of claims 222 to 295, wherein Cy3Cissubstituted 4-10 membered heterocycloalkyl.

308. The compound or salt thereof of any one of claims 222 to 307, wherein R36is H.

309. The compound or salt thereof of any one of claims 222 to 307, wherein R36is C1-6 alkyl such as methyl.

310. The compound or salt thereof of any one of claims 222 to 309, wherein Ra31, Rb31, Rc31, Rd31, Ra32, Rb32, Rc32and Rd32are each independently selected from H and C1-6 alkyl.

311. The compound or salt thereof of any one of claims 222 to 310, wherein each Re31and each Re32is H.

312. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 222 to 311 and a pharmaceutically acceptable carrier or excipient.

313. A compound of Formula (IV):or a salt thereof, for use in treating a MASP-2-associated disease or disorder, wherein:Cy4Ais unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5- 10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy4Aconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy4Aare substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy4A, halogen, C1-6 haloalkyl, CN, ORa41, SRa41, C(0)Rb41,C(0)NRc41Rd41, C(0)0Ra41, 0C(0)Rb41, 0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41,SUBSTITUTE SHEET (RULE 26)NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41, C(=NRe41)NRc41Rd41, C(=NORa41)NRc41Rd41, C(=N0C(0)Rb41)NRc41Rd41, C(=NRe41)NRc41C(0)0Ra41, NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; each RCy4Ais independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10- membered heterocycloalkyl forming Rt 4Aconsist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming Rt 4Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa41, SRa41, C(0)Rb41,S(0)2NRc41Rd41and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming RC 4Ais independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa41, SRa41, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41, 0C(0)Rb41, 0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41, NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41, C(=NRe41)NRc41Rd41, NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2RM1, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;R41is H or C1-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the C1-6 alkyl forming R41is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, ORa41, SRa41, C(0)Rb41,S(0)2NRc41Rd41and oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R41is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa41, SRa41, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41, OC(0)Rb41,(0)0Ra41,SUBSTITUTE SHEET (RULE 26)R42is H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or Cy4B; wherein each of the Ci- 6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, forming R42is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy4B, halogen, CN, c41Rd41,than one of the substituents is Cy4B;Cy4Bis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, orunsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocycloalkyl forming Cy4Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl substituted C3-10 cycloalkyl, or 4-10 membered heterocycloalkyl forming Cy4Bis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy4B, halogen, Ci-6 haloalkyl, CN, ORa41, S11341, C(0)Rb41,S(0)Rb41, S(0)NRc41Rd41, S(0)2RM1, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;wherein each RC 4Bis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10- membered heterocycloalkyl forming RC 4Bconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, and wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming RC 4Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa41, SRa41, C(0)Rb41, C(0)NRc41Rd41, C(0)ORa41, 0C(0)Rb41, 0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41, NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41, C(=NRe41)NRc41Rd41,NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; and \each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming each RC 4Bis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected fromSUBSTITUTE SHEET (RULE 26)halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, ORa41, SRa41, C(0)RM1, C(0)NRc41Rd41, C(0)0Ra41, 0C(0)Rb41, 0C(0)NRc41Rd41, NRc41Rd41, NRc41C(0)Rb41, NRc41C(0)NRc41Rd41, NRc41C(0)0Ra41, C(=NRe41)NRc41Rd41, NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;or R41and R42, together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R41and R42are attached, form a 4-7 membered heterocycloalkyl ring; which is optionally further substituted by 1, 2, 3, 4 or 5 substituents each independently selected from RCy4B, halogen, C1-6 haloalkyl, CN,S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo;R43is H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or Cy4C; wherein each of the Ci- 6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R43is unsubstituted or substituted by 1,2, 3, 4 or 5 substituents each independently selected from: 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy4C, halogen, CN, ORa41, SRa41,S(0)2NRc41Rd41and oxo, provided that no more than one substituent of the Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R43is Cy4C;Cy4Cis unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- 10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, orunsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocycloalkyl forming Cy4Bconsist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl substituted C3-10 cycloalkyl, or 4-10 membered heterocycloalkyl forming Cy4Cis substituted with 1, 2, 3, 4 or 5 substituents each independently selected from RCy4C, halogen, Ci-6 haloalkyl, CN, ORa41, S11341, C(0)Rb41,SUBSTITUTE SHEET (RULE 26)C(=N0C(0)Rb41)NRc41Rd41, C(=NRe41)NRc41C(0)0Ra41, NRc41C(=NRe41)NRc41Rd41, S(0)RM1, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; each RCy4Cis independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10- membered heterocycloalkyl forming RC 4Cconsist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming Rt 4tis independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, ORa41, SRa41, C(0)Rb41,S(0)2NRc41Rd41and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl and 4-10 membered heterocycloalkyl forming each RCy4Aisindependently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, c41Rd41,-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming Ra41, Rb41, Rc41and Rd41are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, ORa42, SRa42, C(0)Rb42, C(0)NRc42Rd42, C(0)0Ra42, 0C(0)Rb42,(0)0Ra42,SUBSTITUTE SHEET (RULE 26)or Rc41and Rd41atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-6 alkyl, halo, CN, ORa42, SRa42, C(0)Rb42,S(0)2NRc42Rd42and oxo;Ra42, Rb42, Rc42and Rd42are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl- Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci- 3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming Ra42, Rb42, Rc42and Rd42are each optionally substituted with 1, 2 or 3 substituents independently selected from OH,CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;or Rc42and Rd42atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; andRe41and Re42are each, independently, H, CN or N02.

314. The compound or salt thereof according to claim 313, wherein Cy4Ais unsubstituted or substituted aryl.

315. The compound or salt thereof according to claim 314, wherein Cy4Ais unsubstituted or substituted phenyl.

316. The compound or salt thereof according to claim 315, wherein Cy4Ais substituted phenyl.SUBSTITUTE SHEET (RULE 26)317. The compound or salt thereof of any one of claims 313 to 316, wherein Cy4Ais substituted with at least one ORa41or at least one C(=NRe41)NRc41Rd41,C(=NORa41)NRc41Rd41, C(=N0C(0)Rb41)NRc41Rd41, or C(=NRe41)NRc41C(0)0Ra41.

318. The compound or salt thereof of any one of claims 313 to 317, wherein Cy4Ais substituted with at least one ORa41and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

319. The compound or salt thereof of any one of claims 313 to 318, wherein Cy4Aissubstituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

320. The compound or salt thereof of any one of claims 313 to 319, wherein Cy4Aissubstituted with at least one C(=NRe41)NRc41Rd41, C(=NORa41)NRc41Rd41,C(=N0C(0)Rb41)NRc41Rd41, C(=NRe41)NRc41C(0)0Ra41, preferably in the 4-position.

321. The compound or salt thereof according to claim 320, wherein Cy4Ais substituted with at least one C(=NRe41)NRc41Rd41, such as C(=NH)NH2, preferably in the 4- position.

322. The compound or salt thereof according to claim 316, wherein Cy4Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)323. The compound or salt thereof according to claim 322, wherein, in the formula defining Cy4A, Ra41is Ci-6 alkyl, such as methyl, RM1is Ci-6 alkyl, such as methyl, RM1is Ci-6 haloalkyl, such as trifluoromethyl, and Rc41is alkyl such as methyl.324 The compound or salt thereof according to claim 313, wherein Cy4Ais unsubstituted or substituted heteroaryl.SUBSTITUTE SHEET (RULE 26)325. The compound or salt thereof according to claim 324, wherein Cy4Ais unsubstituted or substituted pyridin-3-yl, lH-pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol- 6-yl.

326. The compound or salt thereof according to claim 324 or 325, wherein Cy4Ais of any one of the following formulae:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)327. The compound or salt thereof according to claim 326, wherein each R4Ain the formula defining Cy4Ais independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl.

328. The compound or salt thereof according to claim 326 or 327, wherein each Rt 4Aattached to nitrogen in the formula defining Cy4Ais Ci-6 alkyl, such as methyl or ethyl.

329. The compound or salt thereof of any one of claims 313 to 328, wherein R41is H.

330. The compound or salt thereof of any one of claims 313 to 328, wherein R41is Ci-6 alkyl.

331. The compound or salt thereof according to claim 330, wherein R41is methyl.

332. The compound or salt thereof of any one of claims 313 to 331, wherein R42is H.SUBSTITUTE SHEET (RULE 26)333. The compound or salt thereof of any one of claims 313 to 331, wherein R42is unsubstituted Ci-6 alkyl, such as methyl.

334. The compound or salt thereof of any one of claims 313 to 331, wherein R42is Cy4B.

335. The compound or salt thereof of any one of claims 313 to 331, wherein R42issubstituted Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.

336. The compound or salt thereof according to claim 335, wherein R42is substituted Ci-6 alkyl.

337. The compound or salt thereof according to claim 335, wherein R42is substituted Ci-6 alkyl, wherein the Ci-6 alkyl forming R42is substituted by 1, 2, or 3 substituents selected from the group consisting of Cy4B, halogen, CN, ORa41, SRa41, C(0)Rb41,NRc41C(=NRe41)NRc41Rd41, S(0)Rb41, S(0)NRc41Rd41, S(0)2Rb41, NRc41S(0)2Rb41, S(0)2NRc41Rd41and oxo; provided that no more than one of the substituents is Cy4B.

338. The compound or salt thereof according to claim 336 or 337, wherein the substituted Ci-6 alkyl forming R42is substituted by at least one substituent, wherein the substituents include Cy4B.

339. The compound or salt thereof according to claim 338, wherein the substituted Ci-6 alkyl forming R35is substituted by one substituent, wherein the substituent is Cy4B.

340. The compound or salt thereof according to any claim 339, wherein R42is (CH2)I- sCy4B.

341. The compound or salt thereof according to claim 340, wherein R42is CThCy4®342. The compound or salt thereof of any one of claims 313 to 341, wherein Cy4Bis unsubstituted Ce-io aryl such as unsubstituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl, Cy4Bis unsubstituted 5-10 membered heteroaryl, such as unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo|6 |thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo|6 |thiophenyl. or unsubstitutedSUBSTITUTE SHEET (RULE 26)indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl, Cy4Bis unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy4Bis unsubstituted 4-10 membered heterocycloalkyl.

343. The compound or salt thereof of any one of claims 313 to 341, wherein Cy4Bissubstituted C6-10 aryl such as substituted phenyl or naphthyl, such as 1 -naphthyl or 2- naphthyl, Cy4Bis substituted 5-10 membered heteroaryl, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2- yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl, Cy4Bis substituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy4Bis substituted 4-10 membered heterocycloalkyl.

344. The compound or salt thereof of any one of claims 313 to 328, wherein R41and R42, together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R41and R42are attached, form a 4-7 membered heterocycloalkyl ring; which is optionally further substituted by 1, 2, 3, 4 or 5 substituents eachindependently selected from RCy4B, halogen, C1-6 haloalkyl, CN, ORa41, SRa41,S(0)2NRc41Rd41and oxo.

345. The compound or salt thereof according to claim 344, wherein R41and R42, together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R41and R42are attached, form a 5 or 6 membered heterocycloalkyl ring.

346. The compound or salt thereof according to claim 345, wherein the compound isaccording to any of the following Formulae (IV-1), (IV-2), (IV-la), (IV-lb), (IV-2a), or (IV-2b),SUBSTITUTE SHEET (RULE 26)(IV-2a) (IV-2b)347. The compound or salt thereof of any one of claims 313 to 346, wherein R43is Cy4C.

348. The compound or salt thereof of any one of claims 313 to 346, wherein R43isunsubstituted Ci-6 alkyl.

349. The compound or salt thereof of any one of claims 313 to 346, wherein R43issubstituted Ci-6 alkyl.

350. The compound or salt thereof according to claim 349, wherein the substituted Ci-6 alkyl forming R43is substituted by at least one substituent independently selected from: 1, 2, or 3 substituents selected from the group consisting of Cy4C, halogen, CN, c41Rd41,351. The compound or salt thereof according to claim 349 or 350, wherein the substituted Ci-6 alkyl forming R43is substituted by at least one substituent, wherein the substituents include Cy4C.SUBSTITUTE SHEET (RULE 26)352. The compound or salt thereof according to claim 351, wherein the substituted Ci-6 alkyl forming R43is substituted by one substituent, wherein the substituent is Cy4C.

353. The compound or salt thereof of any one of claims 349 to 352, wherein R43is (CH2)I-5Cy4C.

354. The compound or salt thereof according to claim 353, wherein R43is CFl2Cy4C355. The compound or salt thereof according to claim 353, wherein R43is CThCThCy40356. The compound or salt thereof according to claim 351, wherein R43is CF2Cy4CorCF2CH2Cy4C.

357. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cisunsubstituted C6-10 aryl, such as phenyl, 1 -naphthyl or 2-naphthyl.

358. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cisunsubstituted 5-10 membered heteroaryl, such as unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo|6|thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo|6|thiophenyl. or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

359. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cisunsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

360. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cisunsubstituted 4-10 membered heterocycloalkyl.

361. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cissubstituted C6-10 aryl, such as substituted phenyl, substituted 1 -naphthyl or substituted 2-naphthyl.

362. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cissubstituted 5-10 membered heteroaryl, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8- quinolyl, substituted benzo|6 |thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7-5UB5TITUTE SHEET (RULE 26)benzo|6|thiophenyl. or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

363. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cissubstituted C3-10 cycloalkyl such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

364. The compound or salt thereof of any one of claims 313 to 356, wherein Cy4Cissubstituted 4-10 membered heterocycloalkyl.

365. The compound or salt thereof of any one of claims 313 to 364, wherein the compound is according to any of the following Formulae (IV-3)-(IV-7), (IV-3a), (IV-3b), (IV- 5a), (IV-5b), (IV-7a), or (IV-7b):(IV-3a) (IV-3b)SUBSTITUTE SHEET (RULE 26)(IV-7a) (IV-7b)366. The compound or salt thereof of any one of claims 313 to 365, wherein Ra41, Rb41, RC4I, pd41 _ R I42_ pb4 py42an(Rd42are each independently selected from H and Ci-6alkyl.

367. The compound or salt thereof of any one of claims 313 to 366, wherein each Re41and each Re42is H.

368. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 313 to 367 and a pharmaceutically acceptable carrier or excipient.

369. A MASP-2 inhibitory compound for therapeutic use in the treatment of a MASP-2- associated disease or disorder, wherein the compound is of the Formula (VA) or (VB):or a salt thereof;wherein:SUBSTITUTE SHEET (RULE 26)A1is a member selected from the group consisting of -(C=NH)-, -(C=NORa)--[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting of-Nfh. -NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is-NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2 or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci- C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;A2is a member selected from the group consisting of C3-C6 heteroaryl, G, aryl, and C2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of-NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is Ce aryl, Y2is selected from the group consisting of aminomethyl, hydroxy, and halo, and A2is substituted with m additional R1groups;when A2is C2-C6 alkyl, Y2is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;L is -(0)P-(C(R2a)(R2b))q-,SUBSTITUTE SHEET (RULE 26)each R2aor R2bis a member independently selected from the group consisting of hydrogen and fluoro;p is an integer from 0 to 1 ;q is an integer from 1 to 2;R3is a member selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-Ce fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R3and R4join to form an azetidine, pyrrolidine, or piperidine ring;R4is a member selected from the group consisting of hydrogen and C1-C6 alkyl; or, alternatively, R4and R3join to form an azetidine, pyrrolidine, or piperidine ring;R5is a member selected from the group consisting of C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents; or, alternatively, R5and R6join to form a heterocyclic ring with from 0 to 3 R13substituents;R6is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R6and R5join to form a heterocyclic ring with from 0 to 3 R13substituents; and each R13is a member independently selected from the group consisting of Ci- C6 alkyl, C6-C10 aryl, (C6-C10 aryl)Ci-C6 alkyl, carboxy(Ci-C6 alkyloxy), heteroaryl, (C6-C10 heteroaryl)Ci-C6 alkyl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring.

370. A MASP-2 inhibitory compound for therapeutic use in the treatment of a MASP-2- associated disease or disorder, wherein the compound is of the Formula (VA) or (VB):SUBSTITUTE SHEET (RULE 26)or a salt thereof;wherein:A1is a member selected from the group consisting of -(C=NH)-,-(C=NORa)--[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting of-Nfh. - NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is -NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2 or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci- C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;A2is a member selected from the group consisting of C3-C6 heteroaryl, G, aryl, and C2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of-NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is Ce aryl, Y2is selected from the group consisting of aminomethyl, hydroxy, and halo, and A2is substituted with m additional R1groups;5UB5TITUTE SHEET (RULE 26)when A2is C2-C6 alkyl, Y2is selected from the group consisting of- NH(C=NH)NH2,-NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;L is -(0)P-(C(R2a)(R2b))q-,each R2aor R2bis a member independently selected from the group consisting of hydrogen and fluoro;p is an integer from 0 to 1 ;q is an integer from 1 to 2;R3is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R3and R4join to form an azetidine, pyrrolidine, or piperidine ring;R4is a member selected from the group consisting of hydrogen and C1-C6 alkyl; or, alternatively, R4and R3join to form an azetidine, pyrrolidine, or piperidine ring;R5is a member selected from the group consisting of C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents; or, alternatively, R5and R6join to form a heterocyclic ring with from 0 to 3 R13substituents;R6is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R13substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R6and R5join to form a heterocyclic ring with from 0 to 3 R13substituents; and each R13is a member independently selected from the group consisting of Ci- C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring;with the proviso that the compound is not melagatran.

371. The compound or salt thereof of claim 369 or 370, wherein the compound is ofFormula V A.SUBSTITUTE SHEET (RULE 26)372. The compound or salt thereof of any one of claims 369 to 371, wherein the compound is selected from the group consisting of compounds of Formulae (VC) to (VF):and salts thereof; wherein:R7is a member selected from the group consisting of hydrogen, hydroxyl, and Ci-Ce alkyl;R8is a member selected from the group consisting of hydrogen and C1-C6 alkyl; andeach m and n is an independently selected integer from 0 to 2.

373. The compound or salt thereof of any one of claims 369 to 372, wherein R7ishydrogen.

374. The compound or salt thereof of any one of claims 369 to 373, wherein R8ishydrogen.

375. The compound or salt thereof of claim 371, wherein A1is -(C=NH)-.

376. The compound or salt thereof of claim 371, wherein A1is fused heteroaryl.

377. The compound or salt thereof of claim 375 or 376, wherein Y1is-NFk.

378. The compound or salt thereof of claim 369 or 370, wherein the compound is ofFormula VB.

379. The compound or salt thereof of claim 378, wherein A2is Ce aryl.

380. The compound or salt thereof of claim 378 or 379, wherein Y2is 3-chloro.SUBSTITUTE SHEET (RULE 26)381. The compound or salt thereof of claim 378, wherein A2is C2-C6 alkyl.

382. The compound or salt thereof of claim 378 to 381, wherein Y2is -NH(C=NH)NH2.

383. The compound or salt thereof of any one of claims 369 to 382, wherein the compound has an R3stereochemistry of384. The compound or salt thereof of any one of claims 369 to 383, wherein R3is amember selected from the group consisting of hydrogen or methyl.

385. The compound or salt thereof of claim 384, wherein R3is methyl.

386. The compound or salt thereof of any one of claims 369 to 385, wherein R4is amember selected from the group consisting of hydrogen or methyl.

387. The compound or salt thereof of claim 386, wherein R4is hydrogen.

388. The compound or salt thereof of any one of claims 369 to 383, wherein R3and R4join to form an azetidine, pyrrolidine, or piperidine ring.

389. The compound or salt thereof of claim 388, wherein R3and R4join to form apyrrolidine ring.

390. The compound or salt thereof of claim 388, wherein R3and R4join to form apiperidine ring.

391. The compound or salt thereof of any one of claims 369 to 390, wherein R5is amember selected from the group consisting of 2,3-dihydro- li / -inden-2-yl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenethyl, and phenpropyl with from 0 to 5 R13substituents.

392. The compound or salt thereof of claim 391, wherein R5is a member selected from the group consisting of phenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4- fluorophenethyl, 3-methylphenethyl, 3-chlorophenethyl, 3-fluorophenethyl, 2- methylphenethyl, 2-chlorophenethyl, 2-fluorophenethyl, phenpropyl, 4-SUBSTITUTE SHEET (RULE 26)methylphenpropyl, 4-chlorophenpropyl, 4-fluorophenpropyl, 3-methylphenpropyl, 3- chlorophenpropyl, 3-fluorophenpropyl, 2-methylphenpropyl, 2-chlorophenpropyl, and 2-fluorophenpropyl.

393. The compound or salt thereof of any one of claims 369 to 392, wherein R6is amember selected from the group consisting of amino(Ci-C8 alkyl).and C7-C 12 arylalkyl with from 0 to 3 R13substituents,394. The compound or salt thereof of any one of claims 369 to 393, wherein R6is amember selected from the group consisting of hydrogen and carboxy methyl.

395. The compound or salt thereof of any one of claims 369 to 391, wherein R6and R5join to form a pyrrolidine, octahydro- 1 / / -indole. 3-phenylpyrrolidine, piperidine, 1, 2,3,4- tetrahydroisoquinoline, 2,5-dihydro-lH-pyrrole, or l,2,3,6-tetrahydropyridine ring.

396. The compound or salt thereof of any one of claims 369 to 395, wherein R1is hydroxyl or C1-C6 alkoxy.

397. The compound or salt thereof of any one of claims 369 to 396, wherein n is 0.

398. The compound or salt thereof of any one of claims 369 to 397, wherein p is 0.

399. The compound or salt thereof of any one of claims 369 to 398, wherein q is 1.

400. The compound or salt thereof of any one of claims 369 to 399, wherein each R2aorR2bis hydrogen.

401. The compound or salt thereof of claim 400, where L is methylene.

402. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 369 to 401 and a pharmaceutically acceptable carrier or excipient.

403. A MASP-2 inhibitory compound for therapeutic use in the treatment of MASP-2- associated diseases or disorders, wherein the compound is of the Formula (VIA) or (VIB):SUBSTITUTE SHEET (RULE 26)or a salt thereof; wherein:A1is a member selected from the group consisting of -(C=NH)-, -(C=NORa)--[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting 0G-NH2. - NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is -NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2 or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci- C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;A2is a member selected from the group consisting of C3-C6 heteroaryl and C2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of-NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;SUBSTITUTE SHEET (RULE 26)when A2is C2-C6 alkyl, Y2is selected from the group consisting of- NH(C=NH)NH2,-NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;X and X2are each a member selected from the group consisting of NR8, CH, and CR10;each R8is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl;each R10is a member independently selected from the group consisting of Ci- C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R13substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R10groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents;r is an integer from 0 to 4; andeach R13is a member independently selected from the group consisting of Ci- C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring.

404. The compound or salt thereof of claim 403, wherein the compound is selected from the group consisting of compounds of formulae:and salts thereof; wherein:each R7is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; andm is an integer from 0 to 2.

405. The compound or salt thereof of claim 403 or 404, wherein R7is hydrogen.SUBSTITUTE SHEET (RULE 26)406. The compound or salt thereof of any one of claims 403 to 405, wherein (i) the compound is VIA or a salt thereof, and m is 0; or (ii) the compound is VIB or a salt thereof, and r is 0.

407. The compound or salt thereof of any one of claims 403 to 406, wherein X is NR8.

408. The compound or salt thereof of claim 407, wherein R8is hydrogen.

409. The compound or salt thereof of any one of claims 403 to 408, wherein X2is CH orCR10.

410. The compound or salt thereof of any one of claims 403 to 409, wherein R10is amember independently selected from the group consisting of C1-C6 alkyl, G, aryl with from 0 to 3 R13substituents, C1-C6 alkoxy, and C2-C9 alkoxyalkyl.

411. The compound or salt thereof of any one of claims 403 to 410, wherein two R10groups join to form a fused Ce aryl ring with from 0 to 3 R13substituents.

412. The compound or salt thereof of any one of claims 403 to 411, wherein R1is hydroxyl or C1-C6 alkoxy.

413. The compound or salt thereof of any one of claims 403 to 412, wherein p is 0.

414. The compound or salt thereof of any one of claims 403 to 413, wherein q is 1.

415. The compound or salt thereof of any one of claims 403 to 414, wherein each R2aorR2bis hydrogen.

416. The compound or salt thereof of any one of claims 403 to 415, where L is methylene.

417. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 403 to 416 and a pharmaceutically acceptable carrier or excipient.

418. A MASP-2 inhibitory compound for therapeutic use in the treatment of MASP-2- associated diseases or disorders, wherein the compound is of the formula:SUBSTITUTE SHEET (RULE 26)or a salt thereof;wherein:A1is a member selected from the group consisting of -(C=NH)-,-(C=NORa)- , -[C=N0(C=0)Ra]-, -[C=N[0(C=0)ZRb]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;when A1is -(C=NH)-, Y1is selected from the group consisting of-NH2, - NH(C=0)Ra, and - NH(C=0)ZRb;when A1is -(C=NORa)-, -[C=N0(C=0)Ra]-, or -{C=N[0(C=0)ZRb]}-, Y1is -NH2;when A1is fused heterocyclyl or heteroaryl, Y1is -NH2 or halo, and A1is substituted with m additional R1groups;each Raand Rbis independently selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein Rahas m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci- C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, Raand Rbjoin to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;each Z is independently selected from the group consisting of O and S;A2is a member selected from the group consisting of C3-C6 heteroaryl and C2-C6 alkyl;when A2is C3-C6 heteroaryl, Y2is selected from the group consisting of-NH2,- CH2NH2, chloro, -(C=NH)NH2, -(C=NH)NH(C=0)Ra,5UB5TITUTE SHEET (RULE 26)-(C=NH)NH(C=0)ZRb, -(C=NORa)NH2, -[C=N0(C=0)Ra]NH2, and-{C=N[0(C=0)ZRb]}NH2; and A2is substituted with m additional R1groups;when A2is C2-C6alkyl, Y2is selected from the group consisting of- NH(C=NH)NH2,-NH(C=NH)NH(C=0)Ra, and -NH(C=NH)NH(C=0)ZRb;each R1is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;each m and n is an independently selected integer from 0 to 3;L is -(0)P-(C(R2a)(R2b))q-,each R2aor R2bis a member independently selected from the group consisting of hydrogen and fluoro;p is an integer from 0 to 1 ;q is an integer from 1 to 2;R3is a member selected from the group consisting of hydrogen, C1-C6 alkyl, and carboxy(Ci-C6 alkyl);each R11is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, halo, and(R14)(R14)N(CO)-; or, alternatively, two R11groups join to form a fused G, aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R13substituents;r is an integer from 0 to 4; andeach Z is a member independently selected from the group consisting of O andNR8;each R8is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl;each R12is a member independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C7-C14 arylalkyl with from 0 to 3 R13substituents;each R13is a member independently selected from the group consisting of Ci- C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, G-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R13groups join to form a fused G, aryl, heteroaryl, or C5-C7 cycloalkyl ring; andeach R14is a member independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C7-C14 arylalkyl, and heteroaryl(Ci-C6 alkyl); or, alternatively, two R13groups join to form a fused heterocyclyl ring.SUBSTITUTE SHEET (RULE 26)419. The compound or salt thereof of claim 418, wherein the compound is of Formula (VIIC):or a salt thereof;wherein each R7is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl.

420. The compound or salt thereof of claim 418 or 419, wherein R7is hydrogen.

421. The compound or salt thereof of any one of claims 418 to 420, wherein R3is amember selected from the group consisting of hydrogen or methyl.

422. The compound or salt thereof of claim 421, wherein R3is methyl.

423. The compound or salt thereof of any one of claims 418 to 422, wherein Z is O.

424. The compound or salt thereof of any one of claims 418 to 423, wherein R11is(R14)(R14)N(CO)-.

425. The compound or salt thereof of claim 424, wherein R11is (R14)(H)N(CO)-.

426. The compound or salt thereof of claim 425, wherein R14is C1-C6 alkyl, C3-C7cycloalkyl, or C4-C8 cycloalkylalkyl.

427. The compound or salt thereof of any one of claims 418 to 426, wherein R12ishydrogen or C7-C14 arylalkyl.

428. The compound or salt thereof of any one of claims 418 to 427, wherein R1is hydroxyl or C1-C6 alkoxy.

429. The compound or salt thereof of any one of claims 418 to 428, wherein p is 0.

430. The compound or salt thereof of any one of claims 418 to 429, wherein q is 1.SUBSTITUTE SHEET (RULE 26)431. The compound or salt thereof of any one of claims 418 to 430, wherein each R2aor R2bis hydrogen.

432. The compound or salt thereof of any one of claims 418 to 431, where L is methylene.

433. A pharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof of any one of claims 418 to 432 and a pharmaceutically acceptable carrier or excipient.

434. A small molecule compound with MASP-2 inhibitory activity for use in therapy for the treatment of a MASP-2-associated disease or disorder, wherein the compound interacts with a binding site, the interactions being one or more of (a) to (e):a) the compound interacts via H-bonds with one or more amino acid residues in the binding site of MASP-2 (SEQ ID NO: 1);b) the compound interacts via ionic or electrostatic interactions or hydrogen bonding in the binding site of SEQ ID NO: 1;c) the compound interacts via a water molecule in a binding site of SEQ IDNO: 1;d) the compound interacts via p-p interactions with one or more amino acid residues in the binding site of SEQ ID NO: 1; and / ore) the compound interacts via van der Waals contacts to one or more amino acid residues in the binding site of SEQ ID NO: 1, wherein the compound is not an endogenous MASP-2 ligand.

435. The compound of claim 434, wherein the compound has 1, 2, 3, 4, or 5 of theinteractions (a)-(e).

436. The compound of claim 434 or 435, wherein the compound binds via 1-10 H-bonds to one or more amino acid residues in the binding site of SEQ ID NO: 1.

437. The compound of any one of claims 434 to 436, wherein the compound binds via a water molecule in the binding site of SEQ ID NO: 1.

438. The compound of any one of claims 434 to 437, wherein the compound binds via 1-20 water molecule(s) in the binding site of SEQ ID NO: 1.SUBSTITUTE SHEET (RULE 26)439. The compound of any one of claims 434 to 438, wherein the compound binds via 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 water molecule(s) in the binding site of SEQ ID NO: 1.

440. The compound of any one of claims 434 to 439, wherein the compound interacts via van der Waals contacts in the binding site to one or more amino acid residues of SEQ ID NO: 1.

441. The compound of any one of claims 434 to 440, wherein the compound has amolecular weight of about 300 g / mol to about 600 g / mol.

442. A method for identifying a small molecule capable of inhibiting MASP-2, comprising the steps of:a) screening small molecule libraries using in silico docking for candidate small molecules that are selectively identified for their ability to target and bind to MASP-2 surface residues at a binding site of a MASP-2 model; andb) testing / evaluating the candidate agents identified in step (a) through one or more in vitro assays for their ability to target and bind to MASP-2 surface residues to thereby identify the small molecule capable of inhibiting MASP-2.

443. The method of claim 442, wherein candidate small molecules comprise uniquechemical scaffolds as identified in step (b), and are optimized for their ability to inhibit MASP-2.

444. The method of claim 442 or 443, wherein the binding site is identified using a MASP- 2 model.

445. The method of any one of claims 442 to 444, wherein the MASP-2 protein model is computationally derived from crystallographic data.

446. The method of claim 445, wherein the MASP-2 protein model is verified via RMSD (root mean square deviation) and superimposition on the respective crystal structures.

447. The method of any one of claims 442 to 446, wherein in silico docking comprises computational docking of small molecules onto surface exposed residues of a binding site of a MASP-2 model.SUBSTITUTE SHEET (RULE 26)448. The method of any one of claims 442 to 447, wherein the docked ligand orientations are sampled, scored and binned and, and assigned a distance cutoff to match ligand atoms to MASP-2 surface exposed atoms.

449. A compound which is a small molecule candidate agent identified by a method, the method comprising:a) screening small molecule libraries using in silico docking for candidate small molecules that are selectively identified for their ability to target and bind to MASP-2 surface residues at a binding site of a MASP-2 model; andb) testing / evaluating the candidate agents identified in step (a) through one or more in vitro assays for their ability to target and bind to MASP-2 surface residues to thereby identify the small molecule capable of inhibiting MASP-2.

450. The compound of claim 449, wherein the compound has a molecular weight of about 300 g / mol to about 600 g / mol.

451. The compound of claim 449 or 450, wherein the compound has a lower Ki for MASP- 2 compared to thrombin.

452. A method for treating a MASP-2-associated disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of a small molecule MASP-2 inhibitor that binds to the catalytic, substrate-binding region of MASP-2.

453. A method for treating a MASP-2-associated disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of a small molecule MASP-2 inhibitor that binds to a binding site comprising the Sl, S2 and S3 regions, and optionally, further comprises the S4 and RM regions, of the MASP-2.

454. A method for treating a MASP-2-associated disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of a small molecule MASP-2 inhibitor that binds to a binding site comprising the amino acids ALA 468, ALA 469, HIS 483, ASP 526, ALA 527, GLY 528, PHE 529, LEU 575, TYR 602, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, GLY 631, ASP 632, SER 633, GLY 634, GLY 635, VAL 653, SER 654, TRP 655, GLY 656, SER 657, MET 658, ASN 659, CYS 660, GLU 662, GLN 665,SUBSTITUTE SHEET (RULE 26)TYR 666, GLY 667, VAL 668, and TYR 669, subset of any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 of the amino acids ALA 468, ALA 469, HIS 483, ASP 526, ALA 527, GLY 528, PHE 529, LEU 575, TYR 602, PRO 606, TYR 607, PRO 608, SER 611, ASP 627, SER 628, CYS 629, ARG 630, GLY 631, ASP 632, SER 633, GLY 634, GLY 635, VAL 653, SER 654, TRP 655, GLY 656, SER 657, MET 658, ASN 659, CYS 660, GLU 662, GLN 665, TYR 666, GLY 667, VAL 668, and / or TYR 669.

455. A method for treating a MASP-2-associated disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of a small molecule MASP-2 inhibitor or a pharmaceutical composition thereof according to any one of claims 1 to 441.

456. The method of any one of claims 452 to 455, wherein the compound is administered in an amount sufficient to inhibit MASP-2 dependent complement activation in the subject.

457. The method of any one of claims 452 to 456, wherein the subject has been diagnosed as being in need of treatment for a lectin complement-associated disease or disorder.

458. The method of any one of claims 452 to 457, wherein disease or disorder is athrombotic microangiopathy (TMA), a renal condition, an inflammatory reaction resulting from tissue or organ transplantation, an ischemia reperfusion injury, a complication associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ophthalmic disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno- occlusive disease or diffuse alveolar hemorrhage.

459. The method of any one of claims 452 to 457, wherein the disease or disorder is a thrombotic microangiopathy (TMA) thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman Syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic syndrome (aHUS), non-F actor H-dependent atypical hemolytic syndrome, aHUS secondary to an infection, plasma therapy -resistant aHUS, a TMA secondary to cancer, a TMA secondary to chemotherapy, a TMA secondary to transplantation, or a TMA associated with hematopoietic stem cell transplant.SUBSTITUTE SHEET (RULE 26)460. The method of any one of claims 452 to 457, wherein the disease or disorder is graft- versus-host disease.

461. The method of any one of claims 452 to 457, wherein the disease or disorder isdiffuse alveolar hemorrhage (DAH).

462. The method of any one of claims 452 to 457, wherein the disease or disorder is veno- occlusive disease (VOD).

463. The method of any one of claims 452 to 457, wherein the disease or disorder is a renal condition.

464. The method of claim 463, wherein the renal condition is mesangioproliferativeglomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post infectious glomerulonephritis (poststreptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schonlein purpura nephritis or IgA nephropathy.

465. The method of any one of claims 452 to 457, wherein the disease or disorder is renal fibrosis and / or proteinuria.

466. The method of any one of claims 452 to 457, wherein the disease or disorder is an inflammatory reaction resulting from tissue or solid organ transplantation.

467. The method of any one of claims 452 to 457, wherein the disease or disorder is an ischemia reperfusion injury (I / R).

468. The method of any one of claims 452 to 457, wherein the disease or disorder is a complication associated with non-obese diabetes and / or complications associated with Type-l or Type-2 (adult onset) diabetes.

469. The method of any one of claims 452 to 457, wherein the disease or disorder is a cardiovascular disease or disorder.

470. The method of any one of claims 452 to 457, wherein the disease or disorder is an inflammatory gastrointestinal disorder.SUBSTITUTE SHEET (RULE 26)471. The method of any one of claims 452 to 457, wherein the disease or disorder is a pulmonary disorder.

472. The method of any one of claims 452 to 457, wherein the disease or disorder is an extracorporeal exposure-triggered inflammatory reaction and the method comprises treating a subject undergoing an extracorporeal circulation procedure.

473. The method of any one of claims 452 to 457, wherein the disease or disorder is an inflammatory or non-inflammatory arthritis or other musculoskeletal disorder.

474. The method of any one of claims 452 to 457, wherein the disease or disorder is a skin disorder.

475. The method of any one of claims 452 to 457, wherein the disease or disorder isperipheral nervous system (PNS) and / or central nervous system (CNS) disorder or injury.

476. The method of any one of claims 452 to 457, wherein the disease or disorder is sepsis or a condition resulting from sepsis.

477. The method of any one of claims 452 to 457, wherein the disease or disorder is a urogenital disorder.

478. The method of any one of claims 452 to 457, wherein the disease or disorder is an inflammatory reaction in a subject being treated with chemotherapeutics and / or radiation therapy.

479. The method of any one of claims 452 to 457, wherein the disease or disorder is an angiogenesis-dependent cancer.

480. The method of any one of claims 452 to 457, wherein the disease or disorder is an angiogenesis-dependent benign tumor.

481. The method of any one of claims 452 to 457, wherein the disease or disorder is an endocrine disorder.

482. The method of any one of claims 452 to 457, wherein the disease or disorder is an ophthalmic disease or disorder.SUBSTITUTE SHEET (RULE 26)483. The method of any one of claims 452 to 457, wherein the disease or disorder is an ocular angiogenic disease or condition.

484. The method of any one of claims 452 to 457, wherein the disease or disorder isdisseminated intravascular coagulation (DIC) or another complement mediated coagulation disorder.

485. The method of any one of claims 452 to 457, wherein the disease or disorder is acute radiation syndrome, dense deposit disease, Degos Disease, CatastrophicAntiphospholipid Syndrome (CAPS), Behcet's disease, cryoglobulinemia; paroxysmal nocturnal hemoglobinuria ("PNH") or cold agglutinin disease.

486. The method of any one of claims 452 to 457, wherein the disease or disorder isatypical hemolytic uremic syndrome (aHUS).

487. The method of any one of claims 452 to 457, wherein the disease or disorder ishematopoietic stem cell transplant-associated TMA.

488. The method of any one of claims 452 to 457, wherein the disease or disorder isimmunoglobulin A nephropathy (IgAN)489. The method of any one of claims 452 to 457, wherein the disease or disorder is lupus nephritis (LN).SUBSTITUTE SHEET (RULE 26)