MASP-2 inhibitors and methods of use

Abstract

The present disclosure relates to MASP-2 inhibitors and methods of use, and particularly provides compounds having MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.

Description

[0001] This application is a divisional application of the invention patent application filed on May 28, 2019, with application number 201980050586.3 and entitled "MASP-2 Inhibitor and Method of Use".

[0002] Cross-references to related applications

[0003] This application claims the benefits of U.S. Provisional Application Serial No. 62677472, filed May 29, 2018; U.S. Provisional Application Serial No. 62677538, filed May 29, 2018; U.S. Provisional Application Serial No. 62677495, filed May 29, 2018; and U.S. Provisional Application Serial No. 62677514, filed May 29, 2018. Each of the foregoing related applications is incorporated herein by reference in its entirety.

[0004] Statements about sequence lists

[0005] The sequence list relating to this application is provided in text format in lieu of a paper copy and is incorporated herein by reference. The text file containing the sequence list is named MP_1_0281_PCT_SequenceListing_20190528. The text file is 7KB, created on May 28, 2019, and submitted via EFS-Web at the time of this filing.

[0006] field

[0007] This disclosure generally relates to compositions and methods for use in the medical field. More specifically, this disclosure provides small molecule synthetic inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including small molecule inhibitors selective for MASP-2 relative to thrombin, compositions thereof, and methods for their preparation and use. background

[0008] The complement system plays a role in the inflammatory response and is activated by tissue damage or microbial infection. Complement activation must be tightly modulated to ensure selective targeting of invading microbes 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 typically triggered by a complex of host antibodies binding to foreign particles (i.e., antigens) and usually requires prior exposure to the antigen to generate a specific antibody response. Because activation of the classical pathway depends on the host's prior adaptive immune response, it is part of the adaptive immune system. In contrast, the lectin and alternative pathways are independent of adaptive immunity and are part of the innate immune system.

[0009] Mannan-binding lectin-associated serine protease-2 (MASP-2) has been shown to be required for the function of the lectin pathway, one of the major complement activation pathways (Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000; Ambrus et al., J Immunol. 170:1374-1382, 2003; Schwaeble et al., PNAS 108:7523-7528, 2011). Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, a key component of the acquired immune response to infection. As described in U.S. Patent No. 9,011,860 (assigned to Omeros Corporation) (which is incorporated herein by reference), a fully human monoclonal antibody targeting human MASP-2 has been produced. This antibody binds to human MASP-2 with high affinity and blocks complement activity in the lectin pathway, and is therefore intended for the treatment of various diseases and conditions related to the lectin complement pathway.

[0010] MASP-2-dependent complement activation has been suggested as contributing to the pathogenesis of many acute and chronic disease states. Therefore, there is a need for small molecule compounds suitable for administration to treat patients with MASP-2 complement pathway-related diseases and conditions.

[0011] A key protein in mammalian immunity is 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 major complement activation pathways (Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000; Ambrus et al., J Immunol. 170:1374-1382, 2003; Schwaeble et al., PNAS 108:7523-7528, 2011). Inhibition of MASP-2 appears not to interfere with antibody-dependent classical complement activation, a crucial component of the acquired immune response to infection. Inhibition of human MASP-2 to block complement activity via the lectin pathway could be used to treat various diseases and conditions related to the lectin complement pathway.

[0012] There is a need to identify therapeutic compounds and methods for small molecule inhibitors of MASP-2 because they are important for treating various diseases and conditions related to the lectin complement pathway, including those that cannot be adequately or effectively treated with macromolecular biological inhibitors.

[0013] Overview

[0014] This disclosure particularly provides compounds of formulas (I-1) and (I-2):

[0015]

[0016] Or its salts; where the variables are defined below.

[0017] This disclosure also provides pharmaceutical compositions comprising a compound of formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0018] Compounds of formula (I-1) or (I-2) can be used to treat MASP-2-related diseases and conditions, and to prepare medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (I-1) or (I-2) or a salt thereof.

[0019] This disclosure particularly provides compounds of formulas (IIA) and (IIB):

[0020]

[0021] Or its salts; wherein the variables are defined below. Various embodiments of compounds of formula (IIA) or (IIB) are also described.

[0022] This disclosure also provides pharmaceutical compositions comprising a compound of formula (IIA) or (IIB) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0023] Compounds of formula (IIA) or (IIB) can be used to treat MASP-2-related diseases and conditions, and to prepare medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (IIA) or (IIB) or a salt thereof.

[0024] This disclosure particularly provides compounds of formula (III):

[0025]

[0026] Or its salts; wherein the variables are defined below. Various embodiments of the compound of formula (III) are also described.

[0027] This disclosure also provides pharmaceutical compositions comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0028] The compounds of formula (III) can be used to treat MASP-2-related diseases and conditions, and to prepare medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (III) or a salt thereof.

[0029] This disclosure particularly provides compounds of formula (IV):

[0030]

[0031] Or its salts; wherein the variables are defined below. Various embodiments of the compound of formula (IV) are also described.

[0032] This disclosure also provides pharmaceutical compositions comprising a compound of formula (IV) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0033] Compounds of formula (IV) can be used as MASP-2 inhibitors. Compounds of formula (IV) can be used for treatment. Compounds of formula (IV) can be used to treat MASP-2-related diseases and conditions, and medicaments for treating MASP-2-related diseases and conditions are prepared. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (IV) or a salt thereof.

[0034] This disclosure particularly provides compounds of formula (VA) or (VB):

[0035]

[0036] Or its salts; wherein the variables are defined below. Various embodiments of the compound of formula (VA) or (VB) are also described.

[0037] This disclosure also provides pharmaceutical compositions comprising a compound of formula (VA) or (VB) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0038] Compounds of formulas (VA) and (VB) can be used as MASP-2 inhibitors. Compounds of formulas (VA) and (VB) can be used for treatment. Compounds of formulas (VA) and (VB) can be used to treat MASP-2-related diseases and conditions, and medicaments for treating MASP-2-related diseases and conditions are prepared. This disclosure also provides a method of treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (VA) or (VB) or a salt thereof.

[0039] This disclosure particularly provides compounds of formula (VIA) or (VIB):

[0040]

[0041] Or its salts; wherein the variables are defined below. Various embodiments of compounds of formula (VIA) or (VIB) are also described.

[0042] This disclosure also provides pharmaceutical compositions comprising a compound of formula (VIA) or (VIB) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0043] Compounds of formulas (VIA) and (VIB) can be used as MASP-2 inhibitors. Compounds of formulas (VIA) and (VIB) can be used for treatment. Compounds of formulas (VIA) and (VIB) can be used to treat MASP-2-related diseases and conditions, and medicaments for treating MASP-2-related diseases and conditions are prepared. This disclosure also provides a method of treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (VIA) or (VIB) or a salt thereof.

[0044] This disclosure particularly provides compounds of formula (VIIA) or (VIIB):

[0045]

[0046] Or its salts; wherein the variables are defined below. Various embodiments of compounds of formula (VIIA) or (VIIB) are also described.

[0047] This disclosure also provides pharmaceutical compositions comprising a compound of formula (VIIA) or (VIIB) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0048] Compounds of formulas (VIIA) and (VIIB) can be used as MASP-2 inhibitors. Compounds of formulas (VIIA) and (VIIB) can be used for treatment. Compounds of formulas (VIIA) and (VIIB) can be used to treat MASP-2-related diseases and conditions, and medicaments for treating MASP-2-related diseases and conditions are prepared. This disclosure also provides a method of treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (VIIA) or (VIIB) or a salt thereof.

[0049] This disclosure particularly provides small molecule compounds with MASP-2 inhibitory activity, especially small molecule compounds for therapeutic purposes. Small molecule compounds with MASP-2 inhibitory activity interact with the MASP-2 serine protease domain in the enzyme-inhibitor complex using a variety of intermolecular interactions. In some respects, small molecules are described using a set of empirically derived rules, characterized by complete specificity and by the number and type of intermolecular interactions within the MASP-2 binding site. Inhibitors follow one or more interaction rules.

[0050] In some respects, this disclosure provides small molecule compounds having MASP-2 inhibitory activity for therapeutic use, wherein said compounds have one or more of the following interactions (a) to (e), for example, 1, 2, 3, 4, or 5:

[0051] a) The compound is linked via an H-bond to one or more of PRO 606, ASP 627, SER 628, ARG 630, SER633, SER 654, GLY 656, SER 657, CYS 660 and GLN 665 in MASP-2;

[0052] b) The compound is bonded to one or more of ASP 627 and ARG 630 in MASP-2 via ionic or electrostatic interactions or hydrogen bonding;

[0053] c) The compound interacts in MASP-2 via water molecules with 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;

[0054] d) The compound interacts with one or more of PHE 529, TYR 607, and TRP 655 in MASP-2 via π-π interactions; and

[0055] e) The compound interacts with one or more of ALA 468, ALA 469, HIS 483, ASP526, 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, SER654, TRP 655, GLY656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, and TYR 669 in MASP-2 via van der Waals contacts.

[0056] In some embodiments, the compound is not an endogenous MASP-2 ligand.

[0057] In some embodiments, the compound is a synthetic small molecule MASP-2 inhibitor.

[0058] In some implementations, the compound selectively inhibits MASP-2 compared to thrombin.

[0059] Various embodiments of compounds defined by the interaction rules are described. This disclosure provides compositions comprising such compounds or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier or excipient. The compounds can be used as MASP-2 inhibitors. The compounds can be used for treatment. The compounds can be used to treat MASP-2-related diseases and conditions, and to prepare medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound defined by the interaction rules described herein.

[0060] This disclosure particularly provides compounds of formula (VIII):

[0061]

[0062] Or a salt thereof; wherein the elements of the formula may have values ​​as described below. Various embodiments of the compound of formula (VIII) are also described. This disclosure also provides pharmaceutical compositions comprising a compound of formula (VIII) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient. The compound of formula (VIII) can be used as a MASP-2 inhibitor. The compound of formula (VIII) can be used for treatment. The compound of formula (VIII) can be used to treat MASP-2-related diseases and conditions, and to prepare medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides a method of treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of the compound of formula (VIII) or a salt thereof.

[0063] This disclosure provides, in particular, pharmacophore models for describing small molecule compounds, including synthetic compounds that inhibit MASP-2 and compounds specifically defined with reference to such pharmacophore models.

[0064] In some embodiments, the compound active as a MASP-2 inhibitor may comprise one pharmacophore element or a combination of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 pharmacophore elements, preferably combinations of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 pharmacophore elements listed in Table 1. In some embodiments, the compound 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.

[0065] In some embodiments, a compound comprising a combination of pharmacophore elements is provided, said combination of pharmacophore elements including:

[0066] (a) S1 pharmacophore group, which contains CA1 and N1 pharmacophore elements or CA1 and C5 pharmacophore elements; and / or

[0067] (b) S2 pharmacophore group, which contains H4 and O2 pharmacophore elements; and / or

[0068] (c) S3 pharmacophore group, which contains C2 pharmacophore element and N2 or H3 pharmacophore element;

[0069] in:

[0070] C2 and C5 are hydrophobic groups;

[0071] CA1 is an aromatic ring;

[0072] H3 and H4 are hydrogen bond donors;

[0073] N1 and N2 are positively ionizable groups; and

[0074] O2 is a hydrogen bond acceptor;

[0075] C2, C5, CA1, H3, H4, N1, N2, and O2 have coordinates within the range given in Tables 3, 4, or 5 below.

[0076] In some embodiments, a compound comprising a combination of pharmacophore elements is provided, said combination of pharmacophore elements including:

[0077] (a) S1 pharmacophore group, which contains CA1 and N1 pharmacophore elements or CA1 and C5 pharmacophore elements;

[0078] (b) The S2 pharmacophore group, which contains H4 and O2 pharmacophore elements; and

[0079] (c) S3 pharmacophore group, which contains C2 pharmacophore elements and N2 or H3 pharmacophore elements.

[0080] Various embodiments of small molecule compounds defined by a pharmacophore model are described. This disclosure provides compositions comprising such compounds or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier or excipient. The compounds can be used as MASP-2 inhibitors. The compounds can be used for treatment. The compounds can be used to treat MASP-2-related diseases and conditions, and to prepare medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound defined by a pharmacophore model.

[0081] This disclosure also provides small molecule compounds with MASP-2 inhibitory activity, wherein said compounds interact with MASP-2 binding sites, and wherein said compounds are defined by reference to a “binding rule” or “rule set” derived using a virtual docking model of the MASP-2 enzyme co-crystal structure obtained crystallographically and the binding site within the MASP-2 enzyme. In some aspects, the amino acids and their respective atoms of the MASP-2 binding sites accessible to small molecule MASP-2 inhibitors are described. By using various compounds and their intermolecular interactions, a set of “binding rules” or “rule sets” can be designed to specifically describe MASP-2 inhibitors.

[0082] In some respects, small-molecule MASP-2 inhibitors are described by rule sets. Compounds with MASP-2 inhibitory activity employ a variety of intermolecular interactions with the MASP-2 binding site, such as enzyme-inhibitor complexes. In some respects, molecules are described by a complete description of the number and type of intermolecular interactions, achieved through computer simulations of the number and type of intermolecular interactions between atoms of the MASP-2 amino acid residues at the binding site and atoms of the inhibitor molecule. These rules are empirically derived using crystallographically obtained cocrystal structures of the MASP-2 enzyme and virtual docking models of the binding sites within the MASP-2 enzyme. In some cases, multiple MASP-2 enzyme-inhibitor models, 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, can be used to generate rule sets.

[0083] In some embodiments, this disclosure provides compounds having MASP-2 inhibitory activity, wherein the compounds interact with a binding site, the interaction being one or more of (a) to (e):

[0084] a) The compound interacts with one or more amino acid residues at the binding site of MASP-2 (SEQ ID NO:1) via an H-bond;

[0085] b) The compound interacts with the binding site of SEQ ID NO:1 via ionic or electrostatic interactions or hydrogen bonding;

[0086] c) The compound interacts with water molecules at the binding site of SEQ ID NO:1;

[0087] d) The compound interacts with one or more amino acid residues at the binding site of SEQ ID NO:1 via π-π interactions; and / or

[0088] e) The compound interacts with one or more amino acid residues at the binding site of SEQ ID NO:1 via van der Waals contact, wherein the compound is not an endogenous ligand or substrate.

[0089] In some respects, the compound has 1, 2, 3, 4 or 5 interactions (a)-(e).

[0090] In another embodiment, this disclosure provides a method for identifying small molecules capable of inhibiting MASP-2, the method comprising:

[0091] a) Using computer simulation docking to screen a library of small molecules to screen candidate small molecules, wherein the ability of said candidate small molecules to target and bind to MASP-2 at binding sites in the MASP-2 model is selectively identified; and

[0092] b) By one or more in vitro assays, test / evaluate the ability of the candidate reagents identified in step (a) to target and bind to the MASP-2 binding site, thereby identifying small molecules that can inhibit MASP-2.

[0093] In some respects, the candidate small molecules contain unique chemical scaffolds as identified in step (b), and their ability to inhibit MASP-2 has been optimized.

[0094] These and other aspects, objectives, and implementation schemes will become more apparent when reading the following detailed description and accompanying figures. Brief description of the attached diagram

[0095] Figure 1 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1129) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0096] Figure 2 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1034) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0097] Figure 3 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1024) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0098] Figure 4 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1059) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0099] Figure 5 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1088) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0100] Figure 6 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1036) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0101] Figure 7 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1081) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0102] Figure 8 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1063) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0103] Figure 9 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1065) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0104] Figure 10 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1030) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0105] Figure 11 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1037) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0106] Figure 12 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1118) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0107] Figure 13This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1090) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0108] Figure 14 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1007) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0109] Figure 15 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1021) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The non-bonded contact parameters between the hydrophobicity and any contact (such as van der Waals interactions) are calculated using a model derived from the co-structure of the corresponding crystalline MASP-2- compounds.

[0110] Figure 16 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1097) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0111] Figure 17 This is a schematic diagram of one embodiment of the atoms of the example inhibitory compound (1089) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The non-bonded contact parameters between the hydrophobicity and any contact (such as van der Waals interactions) are calculated using a model derived from the co-structure of the corresponding crystalline MASP-2- compounds.

[0112] Figure 18 This is a schematic diagram of one embodiment of the example inhibitory compound Maillard (Melagatran) and the atoms of the MASP-2 amino acid, as shown by hydrogen bond calculation parameters using LigPlot+ software. The maximum distance between the hydrogen bond donor and acceptor; and the maximum contact distance is The nonbonded contact parameters between the hydrophobic elements and any contact (e.g., van der Waals interactions) were calculated using a model derived from the costructure of the corresponding crystalline MASP-2- compounds.

[0113] Figure 19 This is a graph showing the binding of compound (14) to MASP-2, showing the hydrogen bonds calculated using LigPlot+ software.

[0114] Figure 20 This is a graph showing the binding of compound (54) to MASP-2, showing the hydrogen bonds calculated using LigPlot+ software.

[0115] Figure 21 This is a graph showing the binding of compound (1042) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0116] Figure 22 This is a graph showing the binding of compound (2018) to MASP-2, displaying hydrogen bonds calculated using LigPlot+ software.

[0117] Figure 23 This is a graph showing the binding of compound (1149) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0118] Figure 24 This is a graph showing the binding of compound (1031) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0119] Figure 25 This is a graph showing the binding of compound (1153) to MASP-2, displaying hydrogen bonds calculated using LigPlot+ software.

[0120] Figure 26 This is a graph showing the binding of compound (1025) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0121] Figure 27This is a graph showing the binding of compound (1012) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0122] Figure 28 This is a graph showing the binding of compound (1078) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0123] Figure 29 This is a graph showing the binding of compound (1145) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0124] Figure 30 This is a graph showing the binding of compound (1050) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0125] Figure 31 This is a graph showing the binding of compound (1253) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0126] Figure 32 This is a graph showing the binding of compound (1257) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0127] Figure 33 This is a graph showing the binding of compound (1297) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0128] Figure 34 This is a graph showing the binding of compound (1304) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0129] Figure 35 This is a graph showing the binding of compound (1306) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0130] Figure 36 This is a graph showing the binding of compound (1307) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0131] Figure 37 This is a graph showing the binding of compound (1328) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0132] Figure 38 This is a graph showing the binding of compound (1334) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0133] Figure 39This is a graph showing the binding of compound (1335) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0134] Figure 40 This is a graph showing the binding of compound (1338) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0135] Figure 41 This is a graph showing the binding of compound (1345) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0136] Figure 42 This is a graph showing the binding of compound (1351) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0137] Figure 43 This is a graph showing the binding of compound (1353) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0138] Figure 44 This is a graph showing the binding of compound (1360) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0139] Figure 45 This is a graph showing the binding of compound (1367) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0140] Figure 46 This is a graph showing the binding of compound (1368) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0141] Figure 47 This is a graph showing the binding of compound (1371) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0142] Figure 48 This is a graph showing the binding of compound (1372) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0143] Figure 49 This is a graph showing the binding of compound (1373) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0144] Figure 50 This is a graph showing the binding of compound (1492) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0145] Figure 51This is a graph showing the binding of compound (1399) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0146] Figure 52 This is a graph showing the binding of compound (1406) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0147] Figure 53 This is a graph showing the binding of compound (1411) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0148] Figure 54 This is a graph showing the binding of compound (1433) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0149] Figure 55 This is a graph showing the binding of compound (1435) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0150] Figure 56 This is a graph showing the binding of compound (1441) to MASP-2, displaying the hydrogen bonds calculated using LigPlot+ software.

[0151] Figure 57 This is a graph showing the binding of compound (1450) with MASP-2, displaying hydrogen bonds calculated using LigPlot+ software.

[0152] Figure 58 A diagram depicting the melatonin group bound to thrombin.

[0153] Figure 59 A superimposed diagram showing the melagatum that binds to thrombin and the MASP-2 selective compound (1065) that binds to MASP-2.

[0154] Figure 60 A diagram showing the compound (1065) that binds to the SP domain of MASP-2.

[0155] Figure 61 A graph showing the compound (1334) that binds to thrombin.

[0156] Figure 62 A diagram showing the compound (1334) that binds to the SP domain of MASP-2.

[0157] Figure 63 To show the superimposed diagram of compound (1334) that binds to MASP-2 and compound (1334) that binds to thrombin.

[0158] Figure 64 This is a diagram of the S3-S4 combination bag of example MASP-2.

[0159] Figure 65 This is a diagram of the S3-S4 binding bag of an example thrombin.

[0160] Figure 66 This is a diagram showing the MASP-2 combined sub-bag.

[0161] Figure 67 This describes the distances between pharmacophore elements in regions S1 and S2. Region S2 includes H4, O1, O2, and CA6. The area of ​​region S1 is composed of H2, O4, CA1, C3, C5, C7, and N1. The distances described in the text are displayed.

[0162] Figure 68 It is a diagram depicting the angles between the pharmacophore elements describing regions S1 and S2.

[0163] Figure 69 It is a diagram depicting the definition of the torsion angle used in the text.

[0164] Figure 70 It is a diagram depicting the definition of the torsion angle used in the text.

[0165] Figure 71 It is a diagram depicting the definition of the torsion angle used in the text.

[0166] Figure 72 It is a diagram depicting the distances between pharmacophore elements describing the S2, S4, and RM regions.

[0167] Figure 73 It is a diagram depicting the definition of angles used in the text.

[0168] Figure 74 It is a diagram depicting the definition of the torsion angle used in the text.

[0169] Figure 75 It is a diagram depicting the definition of the torsion angle used in the text.

[0170] Figure 76 This is a flowchart illustrating an implementation of the method described in this disclosure.

[0171] describe

[0172] I. Definition

[0173] Unless 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 pertains. While similar or equivalent methods and materials to those described herein may be used in the practice or testing of this invention, suitable methods and materials are described below. Furthermore, materials, methods, and examples are exemplary only and are not intended to be limiting.

[0174] Specific features and aspects of the invention, including method steps, have been mentioned in the foregoing overview, the description in this section, and the following claims. The disclosure of the invention in this specification includes all possible combinations of these specific features within the disclosed embodiments of the invention, at least to the extent that such combinations are not contradictory. For example, if aspects A, B, and C presenting embodiments are described, it should be understood that this also discloses specific embodiments including aspects A and B, aspects B and C, and aspects A and C, as well as embodiments having aspects A, B, and C.

[0175] a. General definition

[0176] The terms “a,” “an,” or “the” include not only aspects having one member but also aspects having more than one member. For example, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells, and reference to “the reagent” includes reference to one or more reagents known to those skilled in the art.

[0177] Given the nature or precision of the measurement, the terms “about” and “approximately” refer to an acceptable degree of error for the quantity being measured. Typical exemplary degrees of error are within 20 percent (%) of a given value or a range of given values; preferably, within 10%; and more preferably within 5%. Any reference to “about X” specifically refers to values ​​of at least X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Therefore, “about X” is intended to teach and provide written support for claims limiting, such as “0.98X”. Alternatively, in biological systems, the terms “about” and “approximately” may refer to values ​​within the order of magnitude of a given value, preferably within 5 times, and more preferably within 2 times. Unless otherwise stated, the numerical quantities given herein are approximate and are meant to be inferred when not explicitly stated otherwise. When “about” is applied to the beginning of a numerical range, it applies to both ends of that range. Therefore, “about 5% to 20%” is equivalent to “about 5% to about 20%”. When “about” is applied to the first value in a set of values, it applies to all values ​​in that set. Therefore, “about 7, 9 or 11 mg / kg” is equivalent to “about 7, about 9 or about 11 mg / kg”.

[0178] The term "MASP-2" refers to mannan-binding lectin-associated serine protease-2. The human MASP-2 protein has UniProt accession number 000187 (SEQ ID NO: 1). The serine protease domain ('B-chain' = mannan-binding lectin serine protease 2B chain, based on UniProtKB-000187 (MASP-2_HUMAN)) comprises residues 445-686 (or consists of residues 445-686).

[0179] The term "MASP-2-dependent complement activation" refers to the MASP-2-dependent activation of the lectin pathway under physiological conditions (i.e., in the presence of calcium). ++ The presence of lectin leads to the formation of C3 convertase C4b2a and, after the accumulation of C3 cleavage product C3b, the formation of C5 convertase C4b2a(C3b)n.

[0180] The term “MASP-2-dependent complement-related disease or condition” refers to a disease or condition associated with MASP-2-dependent complement activation.

[0181] The term “MASP-2 related disease or condition” refers to a disease or condition associated with the activation or activity of MASP-2, including MASP-2-dependent complement-related diseases or conditions, wherein inhibition of MASP-2 is therapeutically beneficial or expected to be therapeutically beneficial.

[0182] The term "lectin pathway" refers to complement activation that occurs through the specific binding of serum and non-serum carbohydrate-binding proteins, including mannan-binding lectin (MBL), CL-11, and fibrinogens (H-fibrinogen, M-fibrinogen, or L-fibrinogen).

[0183] The term "classical pathway" refers to complement activation, which is triggered by antibodies binding to exogenous particles and requires binding to the recognition molecule Clq.

[0184] The amino acid residue abbreviations are 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).

[0185] In the broadest sense, naturally occurring amino acids can be grouped based on the chemical properties of their side chains. "Hydrophobic" amino acids are His, Leu, Met, Phe, Trp, Tyr, Val, Ala, Cys, or Pro. "Hydrophilic" amino acids are Gly, Asn, Gln, Ser, Thr, Asp, Glu, Lys, Arg, or His. This grouping can be further subdivided as follows: "Uncharged hydrophilic" amino acids are Ser, Thr, Asn, or Gln. "Acidic" amino acids are Glu or Asp. "Basic" amino acids are Lys, Arg, or His.

[0186] The term “conservative amino acid substitution” is exemplified by substitutions between amino acids within the following groups: (1) glycine, alanine, valine, leucine and isoleucine, (2) phenylalanine, tyrosine and tryptophan, (3) serine and threonine, (4) aspartic acid and glutamic acid, (5) glutamine and asparagine, and (6) lysine, arginine and histidine.

[0187] The term "object" includes all mammals, including but not limited to humans, non-human primates, dogs, cats, horses, sheep, goats, cattle, rabbits, pigs, and rodents.

[0188] The terms "small molecule" and "small organic molecule" refer to small carbon-containing molecules with a molecular weight of about 2,500 Daltons or less. In some embodiments, the molecular weight of the small molecule is about 2,000 Daltons or less. In some embodiments, the molecular weight of the small molecule is about 1,500 Daltons or less. In some embodiments, the molecular weight of the small molecule is about 1,000 Daltons or less. In some embodiments, the molecular weight of the small molecule is about 750 Daltons or less. In some embodiments, the molecular weight of the small molecule is about 500 Daltons or less. In some embodiments, the molecular weight of the small molecule is about 50 Daltons or more. In some embodiments, the molecular weight of the small molecule is about 75 Daltons or more. In some embodiments, the molecular weight of the small molecule is about 100 Daltons or more. In some embodiments, the molecular weight of the small molecule is about 150 Daltons or more. In some embodiments, the molecular weight of the small molecule is about 250 Daltons or more. In some embodiments, the molecular weight of the small molecule can range from about 50 Daltons to about 500 Daltons, about 50 Daltons to about 750 Daltons, about 50 Daltons to about 1000 Daltons, about 50 Daltons to about 1500 Daltons, about 50 Daltons to about 2000 Daltons, or about 50 Daltons to about 2500 Daltons. When the term “compound” is used herein, it is expressly intended to include small molecule compounds as defined herein (including any embodiments thereof).

[0189] As used herein, the phrase “pharmaceutically acceptable” refers to compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0190] The terms "symptom," "disease," and "condition" are used interchangeably in relation to the condition. A symptom is a disorder or dysfunction that affects the normal functioning of the body. A disease is a pathological condition of an organ, part of the body, or system caused by various factors, such as infection, genetic defects, or environmental stress, characterized by a set of identifiable symptoms.

[0191] The term "effective amount" or "effective dose" refers to the amount sufficient to achieve the desired result, and will therefore depend on the ingredient and the desired result. Nevertheless, once the desired effect is determined, determining the effective amount is within the skill of those skilled in the art.

[0192] The term "subcutaneous application" refers to the application of a preparation under all layers of the skin of the target.

[0193] Unless otherwise stated, the term "histidine" explicitly includes L-histidine.

[0194] The term "isotonic" refers to a formulation that has a substantially the same osmotic pressure as human blood. Isotonic formulations typically have an osmotic pressure of about 250 to about 350 mOsmol / L. Isotonicity can be measured using, for example, vapor pressure or freezing point depression osmoremeters.

[0195] The term "hyperosmolar" refers to a formulation whose osmotic pressure is higher than that of a human body (i.e., greater than 350 mOsm / L).

[0196] The term "hydrogen bond" refers to a partial electrostatic attraction between a hydrogen (H) bonded to a more electronegative atom, such as nitrogen (N) or oxygen (O), and another adjacent atom with a lone pair of electrons. For example, when nitrogen is stated as a "hydrogen bond donor," it means that the hydrogen (H) bonded to nitrogen (N) is donated by nitrogen due to its electrostatic attraction to or acceptance by a neighboring atom with a lone pair of electrons (e.g., oxygen). Similarly, when oxygen is stated as a "hydrogen bond acceptor," it means that the hydrogen (H) bonded to a more electronegative atom (e.g., nitrogen (N)) is electrostatically attracted to or "accepted" by a neighboring atom with a lone pair of electrons (e.g., oxygen). Sometimes, the atom referred to as the hydrogen bond is used without explicitly stating the source and presence of the intermediate hydrogen atom. In the LigPlot+ software, using its algorithm, the maximum distance between the hydrogen bond donor and acceptor is... The application parameters predict the presence of hydrogen-bonded interactions anywhere, using the term "hydrogen-bonded." In reality, not all hydrogen bonds can be in the appropriate positions simultaneously; this is evident for atoms showing four putative hydrogen bonds, however, at any given time, only three hydrogen bonds are chemically possible. In general, although crystal structures such as the eutectic structures described herein do not directly show or detect hydrogen-bonded interactions, the software used to describe the eutectic does predict their presence. Therefore, throughout this disclosure, when H-bonds are present and described, it can be said that they are "predicted" to exist by the software.

[0197] The term ionic bonding refers to a chemical bond involving electrostatic attraction between ions with opposite charges, and is the primary interaction that occurs in ionic compounds.

[0198] The term "van der Waals" interaction refers to weak, short-range electrostatic attraction between uncharged molecules, caused by the interaction of permanent or transient electric dipole moments. As determined by the LigPlot+ software using a model derived from the co-structure of the corresponding crystalline MASP-2 compound, such interactions include those using a maximum contact distance of... The nonbonded contact parameters of the hydrophobic interaction between the hydrophobic element and any contact are calculated for all contacts.

[0199] The term “π-π interaction or π-π stacking” refers to the attractive non-covalent interaction between aromatic rings that are oriented approximately parallel or perpendicular to each other (e.g., in “edge-face” interactions) because they contain π bonds.

[0200] Typically, the active site of serine proteases such as MASP-2 is shaped like a cleft, where the peptide substrate or inhibitor binds. Schechter and Berger labeled the amino acid residues from the N-terminus to the C-terminus of the peptide substrate as follows: Pi, ..., P3, P2, P1, P1', P2', P3', ..., Pj) and their respective binding sites Si, ..., S3, S2, S1, S1', S2', S3', ..., Sj. Catalytic cleavage occurs between P1 and P1' (Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27 (1967)).

[0201] The term "binding site" refers to a region on a protein with which small molecules can interact, such as a region on the surface of MASP-2 that does not overlap with or only partially overlaps with the active site, but still reduces or inactivates the activity of the MASP-2 molecule.

[0202] The term "or" is alternative and should generally be interpreted non-exclusively. For example, a claim "composition comprising A or B" typically presents one aspect of a composition comprising both A and B. However, "or" should be interpreted as excluding those aspects that cannot be combined without contradiction (e.g., the composition has a pH of 9 to 10 or 7 to 8).

[0203] Group “A or B” is equivalent to “group selected from A and B”.

[0204] The linking term "comprising" or "including" is not closed. For example, "a composition comprising A" must include at least component A, but it may also include one or more other components (e.g., B; B and C; B, C and D; etc.). Therefore, the term "comprising" should generally be interpreted as not excluding additional ingredients. For example, a claim for "a composition comprising A" would cover compositions comprising A and B; A, B and C; A, B, C and D; A, B, C, D and E; etc.

[0205] The term "hyperosmolar" refers to a formulation whose osmotic pressure is higher than that of a human body (i.e., greater than 350 mOsm / KglHhO).

[0206] The term "reagent" refers to a compound or mixture of compounds that, when added to a composition, tend to have a specific effect on the properties of the composition. For example, a composition containing a thickener may be more viscous than a otherwise identical comparative composition that does not contain a thickener.

[0207] "Objects" include all mammals, including but not limited to humans, non-human primates, dogs, cats, horses, sheep, goats, cattle, rabbits, pigs, and rodents.

[0208] "Synthetic" compounds refer to compounds that are not naturally occurring and are synthesized by humans. Unless the context otherwise requires, references to compounds herein are to be understood as including references to synthetic compounds.

[0209] The term "treatment" includes the application or use of a composition (e.g., the composition described herein) in an amount, manner (e.g., administration schedule), and pattern (e.g., route of administration) to effectively improve a condition or its symptoms, or to prevent, delay, or slow the progression of a condition or its symptoms. These improvements may include, but are not limited to, reducing or improving one or more symptoms or conditions, reducing the severity of the disease, stabilizing (i.e., not worsening) a disease state, preventing the spread or diffusion of the disease, delaying or slowing the progression of the disease, improving or reducing a disease state, reducing disease recurrence, and achieving remission, whether partial or complete, and whether detectable or undetectable.

[0210] "Treatment" also includes preventative treatment. In some embodiments, the treatment method includes administering a therapeutically effective amount of the active agent to the subject. The administration steps may consist of a single administration or may include 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 the active agent, the activity of the composition used for treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. Changes in dose may result from and become apparent from standard diagnostic assays known in the art. In one aspect, prolonged administration may be required. For example, administering the composition to the subject in an amount sufficient to treat the subject and continuing for a period of time.

[0211] As used herein, the terms “ambient temperature” and “room temperature” are understood in the art and generally refer to temperature, such as reaction temperature, which is approximately the temperature of the room where the reaction takes place, for example, a temperature of about 20°C to about 30°C.

[0212] b. Chemical definition

[0213] In different places in this specification, certain features of the compounds are disclosed by group or scope. In particular, such disclosure is intended to include each and each individual sub-combination of the members of these groups and scopes. For example, the terms “C1-6 alkyl” and “C1-C6 alkyl” are explicitly intended to disclose individually (but not limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0214] At various points in this specification, variations defining the divalent linking group are described. In particular, each linking substituent is intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R”). n -Including-NR(CR'R”) n - and -(CR'R”) nNR - and is intended to disclose each form separately. When the structure requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group, and the Markush group definition for that variable lists "alkyl" or "aryl", then "alkyl" or "aryl" should be understood to represent a linking alkylene or arylene, respectively.

[0215] The term "substituted" refers to an atom or group of atoms that formally replaces hydrogen as a "substituent" attached to another group. Unless otherwise stated, the term "substituted" refers to any level of substitution, such as mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. 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, such as oxo, can replace two hydrogen atoms.

[0216] Term "C" n-m "and "C n -C m ", where n and m are integers, representing a group containing n to m carbon atoms. Examples include C 1-4 C 1-6 The term is intended to explicitly disclose each member within that scope, namely C. n C n+1 C n+2 …C m-2 C m-1 C m For example, C 1-6 The intention is to disclose C1, C2, C3, C4, C5, and C6. "C" n-m The meaning of "C" is the same as "C". n -C m "same.

[0217] The term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be straight-chain or branched. The term "C" n-m "alkyl" and "C" n -C m "Alkyl" refers to an alkyl group having n to m carbon atoms. For example, C1-C 12This indicates that the group may have 1 to 12 (including terminal values) carbon atoms. Unless otherwise specified, it is an alkyl group with about 1 to about 20 carbon atoms. An alkyl group formally corresponds to an alkane in which one of the CH bonds is replaced by the alkyl group at the junction with the rest of the compound. In some embodiments, the alkyl group comprises 1-6 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms. Examples of alkyl moiety include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, 1,1-dimethylpropyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms in the chain. "Substituted alkyl" is an alkyl group substituted with one or more substituents.

[0218] The term "alkenyl," used 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 carbon-carbon double bonds. Formally, an alkenyl group corresponds to an alkene in which one of the CH bonds is replaced by the alkenyl group at the junction with the rest of the compound. The term "C..." n-m "Alkenyl" and "C" n -C m "Alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2-6, 2-4, or 2-3 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0219] The term "alkynyl" used 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 carbon-carbon triple bonds. Formally, an alkynyl group corresponds to an alkyne in which one of the CH bonds is replaced by the alkyl group at the junction with the rest of the compound. The term "C..." n-m "Alkyne" and "C" n -C m "Alynyl" refers to an alkynyl group having n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2-6, 2-4, or 2-3 carbon atoms.

[0220] The term "alkylene" used alone or in combination with other terms refers to a divalent alkyl linking group. Alkylene formally corresponds to an alkane in which two CH bonds are replaced by the alkylene group at the junction with the rest of the compound. The term "C n-m"Alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc. In some embodiments, "C n-m "alkylene" can represent n to m m m m methylene (CH2) groups, -(CH2) n-m - chains, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, etc.

[0221] The term "alkoxy" used alone or in combination with other terms refers to a group of the formula -O-alkyl, wherein the alkyl group is as defined above. The term "C" n-m "Alkoxy" refers to an alkoxy group whose alkyl group has n to m carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. In some embodiments, the alkyl group has 1-6, 1-4, or 1-3 carbon atoms.

[0222] The term "alkoxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an alkoxy group. The term "C"... n-m Alkoxy-C p-q "alkyl" refers to an alkyl group formed by C n-m alkoxy-substituted C p-q Alkyl group. In some embodiments, the hydroxyalkyl group has one alkoxy group. In some embodiments, the alkoxyalkyl group has one or two alkoxy groups, each on a different carbon atom. Examples may include, but are not limited to, methoxymethyl, ethoxymethyl, 3-ethoxyethyl, and 1-methoxyethyl.

[0223] The term "amino" refers to a group with the formula -NH2.

[0224] The term "carbamoyl" refers to a group with the formula –C(O)NH2.

[0225] The term "carbonyl" used alone or in combination with other terms refers to the -C(=O)- group, which can also be written as C(O).

[0226] The term "cyano" or "nitrile" refers to a group with the formula -C≡N, which can also be written as -CN.

[0227] The term "halogenated" or "halogen" used alone or in combination with other terms refers to fluorine, chlorine, bromine, and iodine. In some embodiments, "halogenated" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halogenation is F.

[0228] The term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. The term "C"... n-m "Halogenated alkyl" refers to a C14-alkyl group having n to m carbon atoms and at least one to a maximum of {2(n to m) + 1} halogen atoms. n-m Alkyl groups, wherein the halogen atoms may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1-6 or 1-4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0229] The term "haloalkoxy" used alone or in combination with other terms refers to a group of the formula -O-haloalkyl, wherein the haloalkyl is as defined above. The term "C" n-m "Haloalkoxy" refers to a haloalkoxy group in which the haloalkyl group has n to m carbon atoms. Examples of haloalkoxy groups include trifluoromethoxy groups. In some embodiments, the haloalkoxy group has 1-6, 1-4, or 1-3 carbon atoms.

[0230] The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups. The term "C"... n-m "Hydroxyalkyl" refers to a C14-hydroxyalkyl group having n to m carbon atoms and at least one hydroxyl group. n-m Alkyl group. In some embodiments, the hydroxyalkyl group has one alcohol group. In some aspects, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In some aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0231] The term "oxo" refers to an oxygen atom as a divalent substituent, which, when attached to a carbon atom, forms a carbonyl group, or when attached to a heteroatom, forms a sulfoxide or sulfone group, or an N-oxide group.

[0232] The term "sulfido" refers to a sulfur atom as a divalent substituent, which, when attached to carbon, forms a thiocarbonyl group (C=S).

[0233] The term "n-membered" (n-ary), where n is an integer, typically describes the number of cyclic atoms in a subset where the number of cyclic atoms is n. The term "nm-membered" (nm-ary), where n and m are integers, describes the range where the number of cyclic atoms is n to m. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl ring.

[0234] The term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings that exhibit aromatic properties (i.e., have (4n+2) delocalized π(pi) electrons, where n is an integer).

[0235] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m "Aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthraceneyl, phenanthryl, indanyl, indenyl, and tetraphenyl. In some embodiments, the aryl group has 6 to about 20 carbon atoms, 6 to about 18 carbon atoms, 6 to about 15 carbon atoms, or 6 to about 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0236] The terms "arylalkyl" or "arylalkyl" or "alkylaryl" used alone or in combination with other terms refer to a group of the formula -alkylene-aryl, and specifically to an alkyl group as defined herein, wherein at least one hydrogen atom has been replaced by an aryl group as defined herein. In some embodiments, the arylalkyl group is C10-32 ... 6-10 Aryl-C 1-3 Alkyl group. In some embodiments, the arylalkyl group is C10. 6-10 Aryl-C 1-4 Alkyl group. In some embodiments, the arylalkyl group is C10. 6-10 Aryl-C 1-3 Alkyl group. In some embodiments, the aryl alkyl group is phenyl-C 1-3 Alkyl groups. Examples include, but are not limited to, benzyl, 1-phenylethyl, 4-methylbenzyl, and 1,1-dimethyl-1-phenylmethyl. In some embodiments, the aryl alkyl group is benzyl.

[0237] The term "heteroaryl" or "heteroaromatic group," used 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. "n-membered heteroaryl" or "n-membered heteroaromatic group," where n is an integer, refers to a heteroaryl having n cyclic atoms. "nm-membered heteroaryl" or "nm-membered heteroaromatic group," where n and m are integers, refers to a heteroaryl having n to m cyclic atoms. The number of carbon atoms in the ring is less than the number of heteroatoms. Therefore, in some embodiments, an n-membered heteroaryl may have n-1, n-2, n-3, or n-4 cyclic carbon atoms, and an nm-membered heteroaryl may have n-1, n-2, n-3, or n-4 cyclic carbon atoms to m-1, m-2, m-3, or m-4 cyclic carbon atoms. In some embodiments, an nm-membered heteroaryl may have 1 to m-1 cyclic 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 cyclic N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl group has 5-10 ring atoms, including a carbon atom and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a five- or six-membered heteroaryl ring. In other embodiments, the heteroaryl group is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrrole, pyrazole, azole, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, quinoline, isoquinoline, naphthidine (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthidine), indole, azaindole, benzothiophene, benzofuran, benzoisoxazole, benzimidazole, imidazo[1,2-b]thiazole, purine, furazine, triazole, tetrazolium, 1,2,4-thiadiazole, quinazoline, phthalazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazole, etc.

[0238] 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 heteroaryl rings include thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0239] 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 heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0240] The term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of the formula -alkylene-heteroaryl. The term "n-membered heteroarylalkyl," where n is an integer, refers to a heteroarylalkyl group where the heteroaryl group is n-membered. The term "nm-membered-C" p-q "-alkyl" (where n, m, p, and q are integers) refers to a heteroarylalkyl group, wherein the heteroaryl group is n to m-membered and the alkyl group has p to q carbon atoms. In some embodiments, the heteroarylalkyl group is a 5-10-membered heteroaryl-C group. 1-3 Alkyl or C 1-9 heteroaryl-C 1-3 Alkyl groups, wherein the heteroaryl moiety is monocyclic or bicyclic and has 1, 2, 3, 4, or 5 independent heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl alkyl group is C10. 1-9 heteroaryl-C 1-4 Alkyl groups, wherein the heteroaryl moiety is monocyclic or bicyclic and has 1, 2, 3, or 4 independent heteroatom ring members selected from nitrogen, sulfur, and oxygen. Examples include pyridylmethyl, such as 2-pyridylmethyl, 3-pyridylmethyl, or 4-pyridylmethyl.

[0241] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic, saturated, monocyclic, bicyclic, or polycyclic hydrocarbon ring system. This term includes cyclic alkyl and alkenyl groups. The term "C n-m "Cycloalkyl" refers to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups can have 3, 4, 5, 6, or 7 cyclic carbons (C1, C2, C3, C4, C5, C6, C7, C8, C9 ... 3-7 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 C16-3 ... 3-6Monocyclic cycloalkyl groups. The cycloforming carbon atom of a cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylidene groups. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes a portion having one or more aromatic rings fused (i.e., sharing a common bond) to the cycloalkyl ring, such as benzo or thiophene derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be linked by any cycloforming atom, including the cycloforming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinyl, norcamyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0242] The term "cycloalkylalkyl" used alone or in combination with other terms refers to a group of the formula -alkylene-cycloalkyl. Term C n-m cycloalkyl-C p-q Alkyl, where n, m, p, and q are integers, refers to a cycloalkyl group having n to m carbon atoms linked to an alkyl group having p to q carbon atoms. In some embodiments, the cycloalkyl group is C10 ... 3-7 cycloalkyl-C 1-3 Alkyl groups, wherein the cycloalkyl moiety is monocyclic or bicyclic. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentanemethyl, and cyclohexylmethyl.

[0243] The term "heterocyclic alkyl" used alone or in combination with other terms refers to a non-aromatic ring or cyclic system that optionally contains one or more alkenyl groups as part of a ring structure having at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. "n-membered heterocyclic alkyl," where n is an integer, refers to a heteroaryl group having n ring-forming atoms. "nm-membered heterocyclic alkyl," where n and m are integers, refers to a heterocyclic alkyl group having n to m ring-forming atoms. The number of carbon atoms in the ring is less than the number of heteroatoms. Thus, in some embodiments, an n-membered heterocyclic alkyl group may have n-1, n-2, n-3, or n-4 ring carbon atoms, and an nm-membered heterocyclic alkyl group may have n-1, n-2, n-3, or n-4 to m-1, m-2, m-3, or m-4 ring carbon atoms. In some embodiments, an nm-membered heterocyclic alkyl group may have 1 to m-1 ring carbon atoms. In some embodiments, the heterocyclic alkyl group has 4-12 ring members, 4-10 ring members, 4-7 ring members, or 4-6 ring members. The heterocyclic alkyl group includes monocyclic 4-, 5-, 6-, and 7-membered heterocyclic alkyl groups. The heterocyclic alkyl group can comprise monocyclic or bicyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocyclic alkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be oxidized to form an oxo group or sulfide group or other oxidized bond (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocyclic alkyl group can be linked by the cyclic carbon atom or the cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0-3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0-2 double bonds. The definition of heterocyclic alkyl also includes aromatic rings having one or more fused (i.e., sharing a common bond) to the heterocyclic alkyl ring, such as piperidine, morpholine, and azathioline. Benzoyl or thiophene derivatives, etc. Heterocyclic alkyl groups containing fused aromatic rings can be linked by any cyclic atom, including the cyclic atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include aziridine, aziridine heptane, dihydrobenzofuran, dihydrofuran, dihydropyran, morpholine, 3-oxa-9-azaspiro[5.5]undecane, 1-oxa-8-azaspiro[4.5]decane, piperidine, piperazine, pyran, pyrrolidine, quinine ring, tetrahydrofuran, tetrahydropyran, 1,2,3,4-tetrahydroquinoline, tropane, and thiomorpholine.

[0244] As used herein, the term "heterocyclic alkyl alkyl" alone or in combination with other terms refers to a group of the formula -alkylene-heterocyclic alkyl. The term "n-membered heterocyclic alkyl alkyl," where n is an integer, refers to a heteroarylalkyl alkyl, wherein the heterocyclic alkyl group is n-membered. The term "nm-membered-C" p-q"-alkyl", where n, m, p, and q are integers, refers to a heterocyclic alkyl group, wherein the heterocyclic alkyl group is n to m-membered and has p to q carbon atoms. In some embodiments, the heterocyclic alkyl group is a 4-10-membered heterocyclic alkyl group. 1-3 Alkyl or C 1-9 Heterocyclic alkyl-C 1-3 Alkyl group, wherein the heterocyclic alkyl portion is monocyclic or bicyclic and has 1, 2, 3, 4, or 5 independent heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocyclic alkyl group is C10. 2-9 Heterocyclic alkyl-C 1-4 Alkyl or C 2-9 Heterocyclic alkyl-C 1-3 Alkyl groups, wherein the heterocyclic alkyl portion is monocyclic or bicyclic and has 1, 2, 3 or 4 independent heteroatom ring members selected from nitrogen, sulfur and oxygen.

[0245] In some contexts, a definition or embodiment may refer to a specific ring (e.g., an aziridine ring, a pyridine ring, etc.). Unless otherwise stated, these rings may be attached to any ring member, provided that the valence of the atoms does not exceed the valence. For example, an aziridine ring may be attached at any position on the ring, while an aziridine-3-yl ring may be attached at the 3-position.

[0246] When any two groups or two instances of the same substituent are "independently selected" from a list of options, the groups can be the same or different. For example, if R a and R b Individually selected from the group consisting of alkyl, fluorine, amino, and hydroxyalkyl groups, they have two Rs. a Group and two R b The molecule of the group can have all alkyl groups (e.g., four different alkyl groups). Or, the first R a It can be an alkyl group, the second R a It could be fluorine, the first R b It can be hydroxyalkyl, and the second R b It can be an amino group (or any other substituent from that group). Alternatively, R a And the first R b Both can be fluorine, but the second R... b It can be an alkyl group (i.e., some substituent pairs can be the same, while others can be different). Unless otherwise specified, if two or more groups with the same definition exist, but the definition provides 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 R... a The group is present in the compound, and R a The definition of R a If it can be A, B, or C, then it should be understood that each R present in the compound...a The groups are independently selected from A, B, and C, such that R exists in the compound. a The functional groups can be the same or different.

[0247] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are desirable. Compounds containing asymmetrically substituted carbon atoms described herein can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are contemplated in this invention. Cis and trans geometric isomers of the compounds of this invention are described and can be isolated as mixtures of isomers or as separate isomers.

[0248] The resolution of racemic mixtures of compounds can be carried out by any of the many methods known in the art. One method involves fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid in D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional recrystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0249] Resolution of racemic mixtures can also be performed by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0250] In some embodiments, the compounds of the present invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one chiral center, each chiral center in the compound may be independently (R) or (S), unless otherwise stated.

[0251] The compounds described herein may also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton-shift tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-shift tautomers include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or spatially locked into one form through appropriate substitution. This disclosure is intended to include all such tautomers of the said compounds.

[0252] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0253] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structure described.

[0254] The compounds described herein may include acidic and / or basic groups and are capable of forming salts. It should be understood that this disclosure is intended to include all salts of compounds capable of forming salts, whether or not the possible presence of salts is explicitly described, including acidic and basic salts of the compounds. Furthermore, when a compound is described as a salt, it should be understood that the disclosure of the compound is intended to include all forms of the compound, including free bases or free acids, and their alternative salt forms. The term "salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting the present acidic or basic portion into its salt form. Examples of salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. The term "its salt" may be applied to any of the aforementioned members of the relevant Markush group. For example, the group consisting of A, B, C, and their salts includes, within its scope, embodiments of a salt of A, embodiments of a salt of B, and embodiments of a salt of C.

[0255] Salts of the compounds disclosed herein include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers, for example, a non-toxic salt of a parent compound formed from a non-toxic inorganic or organic acid. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, these salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as ethers, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. For a list of suitable salts, see Remington's Pharmaceutical Sciences, 17th edition (Mack Publishing Company, Easton, 1985), p. 1418; Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley, 2002). In some embodiments, the compounds described herein comprise N-oxide forms. Further information regarding 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.

[0256] Compounds and their salts, 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 and their salts described herein can exist in a variety of forms and can, for example, take the form of solvates, including hydrates. Compounds can be in any solid form, such as polymorphs or solvates, and therefore, unless otherwise expressly stated, references to compounds and their salts should be understood to include any solid form of the compound.

[0257] In some embodiments, the compounds described herein or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions enriching the compounds of the invention. Substantialtive isolation may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of the invention or their salts.

[0258] c. Abbreviation

[0259] The following abbreviations may be used in this document, unless otherwise specified, and have the following meanings: μ (micro); ℃ (degrees Celsius); Ac (acetyl); ACN (acetonitrile); anhyd (anhydrous); aq (aqueous or aqueous); atm (atmospheric pressure); Bn (benzyl); Boc (tert-butoxycarbonyl); Bu (butyl); calcd (calculated); Cbz (benzyloxycarbonyl); chrom. (chromatography); CPME (cyclopentylmethyl ether); CH2Cl2 (dichloromethane); concd (concentrated); conc (concentration); DCC (N,N'-bicyclo) Hexylcarbodiimide); DIAD (diisopropyl azodicarboxylate); DIEA (N,N-diisopropylethylamine); DMAP (4-(N,N-dimethylamino)pyridine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride); equiv (equivalent); ES (electrospray); Et (ethyl); Et2O (diethyl ether); g (gram); h (hour); HATU (N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine- 1-Methylene]-N-methylmethylammonium hexafluorophosphate (N-oxide); HBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)ureonium hexafluorophosphate); HPLC (High Performance Liquid Chromatography); HOBt (1-hydroxybenzotriazole hydrate); L (liter); m (milliliter); m- (meta-position); M (molar); MeCN (acetonitrile); min (minute); mL (milliliter); mol (molal; molecular weight); Ms (methanesulfonyl); MS (mass spectrometry); MW (molecular weight) (Quantity); NBS (N-bromosuccinimide); NCS (N-chlorosuccinimide); NIS (N-iodosuccinimide); NHS (N-hydroxysuccinimide); NMM (4-methylmorpholine); NMR (nuclear magnetic resonance); o- (ortho); obsd (measured value); 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 (triphenylmethyl). Other abbreviations may also be used and have meanings that will be understood by those skilled in the art.

[0260] II.Compounds

[0261] A. Compounds of Formula I-1

[0262] In some respects, this disclosure provides compounds of formula (I-1):

[0263]

[0264] Or its salt, wherein:

[0265] Cy 1A C is unsubstituted or substituted 6-10 aryl or unsubstituted or substituted 5-10 heteroaryl groups; wherein Cy is formed 1A The 5-10 membered heteroaryl ring atom is composed of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein Cy forms 1A The replaced C 6-10 The aryl or substituted 5-10 heteroaryl group is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy1A Halogen, C 1-6 Halogenated alkyl, CN, OR a11 S Ra11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 C(=NOR) a11 )NR c11 R d11 C(=NOC(O)R) b11 )NR c11 R d11 C(=NR) e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NRc11 R d11 And oxygenation;

[0266] Each R Cy1A Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy1A The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, 3 or 4 heteroatoms selected from O, N and S; wherein R forms Cy1A Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation, and the formation of R in it Cy1A Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0267] R 11 For H or C 1-6 Alkyl, C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 Alkyl groups, wherein R is formed 11 C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from halogens, CN, OR. a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation, and the formation of R in it 11 C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NRe11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0268] R 12 For H or C 1-6 Alkyl; or

[0269] R 11 and R 12 Together with the groups they are attached to, they form 4-6 membered heterocyclic alkyl rings;

[0270] A 11 For CR 13 R 15 Or N;

[0271] Each R 13 Independent for Cy 1B 、(CR 13A R 13B ) n3 Cy 1B (C) 1-6 (alkylene) Cy 1B (C) 2-6 (Cy) 1B (C) 2-6 (Nyneylyl)Cy 1B or OCY 1B , where R 13 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is either unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, each of which is independently selected from halogens, CN, OR. a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0272] Each R 14 Independently selected from H and C 1-6 alkyl;

[0273] R 15 Selected from H, R 13 C 1-6 Alkyl groups and OH groups;

[0274] A pair of R atoms connected to adjacent carbon atoms 14 Groups or a pair of R atoms attached to adjacent carbon atoms 14 and R 15 The group can be independent of R. 14 Other occurrences were replaced by bonds connecting adjacent carbon atoms, the adjacent carbon atoms to the pair of R atoms. 14 Group or a pair of R 14 and R 15 The groups are linked together, thereby connecting the adjacent carbon atoms through a double bond; or

[0275] A pair of R atoms bonded to the same carbon atom 14 Groups or a pair of R atoms attached to the same carbon atom 13 and R 15 The group can be independent of R. 14 Other occurrences, related to the connection of the pair of R 14 Group or a pair of R 13 and R 15 The carbon atoms of the group together form a spiro-fused C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl rings, wherein the ring atoms of the formed 4-10 membered heterocyclic alkyl rings consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the formed spiro-fused C 3-10The cycloalkyl or 4-10 membered heterocyclic alkyl ring is optionally further substituted by one, two, or three substituents, said substituents being independently selected from halogens, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, haloalkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 and oxygenation; or

[0276] A pair of R atoms connected to adjacent carbon atoms 14 Groups or a pair of R atoms attached to adjacent carbon atoms 14 and R 15 The group can be independent of R. 14 Other occurrences, related to the connection of the pair of R 14 Group or a pair of R 14 and R 15 Adjacent carbon atoms of the group together form fused C atoms. 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl rings, wherein the ring atoms of the formed 4-10 membered heterocyclic alkyl rings consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the formed fused C 3-10The cycloalkyl or 4-10 membered heterocyclic alkyl ring is optionally further substituted by one, two, or three substituents, said substituents being independently selected from halogens, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, haloalkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 and oxygenation; or

[0277] A set of four R atoms connected to two adjacent carbon atoms 14 A group or a set of two R groups attached to two adjacent carbon atoms 14 An R 13 And an R 15 The group can be independent of R. 14 Other occurrences, related to the connection of the set of four R 14 Group or a set of two R 14 An R 13 And an R 15 Two adjacent carbon atoms of the group together form a fused C 6-10 Aryl or 5-10 quinone heteroaryl, C 3-10Cycloalkyl or 4-10 membered heterocyclic alkyl rings, wherein the ring atoms of the formed 5-10 membered heteroaryl or 4-10 membered heterocyclic alkyl rings consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, and wherein the fused C atoms formed therein... 6-10 Aryl or 5-10 quinone heteroaryl, C 3-10 The cycloalkyl or 4-10 membered heterocyclic alkyl ring is optionally further substituted by one, two, or three substituents, said substituents being independently selected from halogens, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, haloalkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0278] n1 is 1 or 2;

[0279] n2 is 0, 1, or 2;

[0280] The condition is that the sum of n1 and n2 is 1, 2, or 3;

[0281] The condition is that if n1 is 1 or n2 is 0, then A 11 For CR 13 R 15 ;

[0282] n3 is 0, 1, or 2;

[0283] Each R 13A Independently H or C 1-6 alkyl;

[0284] Each R 13B Independently H or C 1-6 Alkyl; or

[0285] Or R attached to the same carbon atom 13A and R 13B Independent of any other R 13A and R 13B These groups can combine to form –(CH2). 2-5 - thereby forming a 3-6 membered cycloalkyl ring;

[0286] Cy 1B C is unsubstituted or substituted 6-10 aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy forms 1B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; and

[0287] Cy is formed 1B The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy1B Halogen, C 1-6 Halogenated alkyl, CN, OR a11 S Ra11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NRc11 R d11 C(=NOR) a11 )NR c11 R d11 C(=NOC(O)R) b11 )NR c11 R d11 C(=NR) e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0288] Among them, each R Cy1B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy1B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein R forms Cy1B Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NRc11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation; and the formation of R in it Cy1B Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11S(O)2NR c11 R d11 And oxygenation;

[0289] R 16 For H, Cy 1C C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, in which R is formed 16 C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is either unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from Cy. 1C Halogen, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation, provided there is no more than one R. 16 The substituent is Cy 1C ;

[0290] Cy 1C C is unsubstituted or substituted 6-10 aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy forms 1C The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; and

[0291] Cy is formed 1C The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy1C Halogen, C 1-6 Halogenated alkyl, CN, OR a11 S Ra11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 C(=NOR) a11 )NR c11 R d11 C(=NOC(O)R) b11 )NR c11 R d11 C(=NR) e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0292] Among them, each R Cy1C Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy1C The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein R forms Cy1C Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation; and the formation of R in it Cy1C Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a11 SR a11 C(O)R b11 C(O)NR c11 R d11 C(O)OR a11 OC(O)R b11 OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 C(=NR) e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 S(O)R b11 S(O)NR c11 R d11 S(O)2R b11 NR c11 S(O)2R b11 S(O)2NR c11 R d11 And oxygenation;

[0293] R a11 R b11 R c11 and R d11 Each is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a11 R b11 Rc11 and R d11 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents, said substituents being independently selected from C10. 1-6 Alkyl, halogen, CN, OR a12 SR a12 C(O)R b12 C(O)NR c12 R d12 C(O)OR a12 OC(O)R b12 OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 C(=NR) e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 S(O)R b12 S(O)NR c12 R d12 S(O)2R b12 NR c12 S(O)2R b12 S(O)2NR c12 R d12 And oxygenation;

[0294] Or R connected to the same N atom c11 and R d11Together with the N atom attached to either of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl or a 5-membered heteroaryl group, each optionally substituted with one, two, or three substituents, said substituents being independently selected from C. 1-6 Alkyl, halogen, CN, OR a12 SR a12 C(O)R b12 C(O)NR c12 R d12 C(O)OR a12 OC(O)R b12 OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 C(=NR) e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 S(O)R b12 S(O)NR c12 R d12 S(O)2R b12 NR c12 S(O)2R b12 S(O)2NR c12 R d12 And oxygenation;

[0295] R a12 R b12 R c12 and R d12 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a12 R b12 Rc12 and R d12 The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and oxo groups;

[0296] Or R connected to the same N atom c12 and R d12 Together with the N atom attached to either of them, they form 4-, 5-, 6-, or 7-membered heterocyclic alkyl or 5-membered heteroaryl groups, each of which is unsubstituted or substituted by 1, 2, or 3 substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and oxo; and

[0297] R e11 and Re 12 Each can be independently H, CN, or NO2.

[0298] In some embodiments, the compound has the formula (I-2):

[0299]

[0300] In some implementations, Cy 1A It is an unsubstituted or substituted aryl group.

[0301] In some implementations, Cy 1A It is an unsubstituted or substituted phenyl group.

[0302] In some implementations, Cy 1AIt is a substituted phenyl group.

[0303] In some implementations, Cy 1A By at least one OR a11 Or at least one C (=NR) e11 )NR c11 R d11 C(=NOR) a11 )NR c11 R d11 C(=NOC(O)R) b11 )NR c11 R d11 Or C(=NR) e11 )NR c11 C(O)OR a11 replace.

[0304] In some implementations, Cy 1A By at least one OR a11 and selected from at least one of C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0305] In some implementations, Cy 1A With at least one OH and with at least one selected from C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0306] In some implementations, Cy 1A By at least one C (=NR) e11 )NR c11 R d11 C(=NOR) a11 )NR c11 R d11 C(=NOC(O)R) b11 )NR c11 R d11 C(=NR) e11 )NR c11 C(O)OR a11 The replacement is preferably at position 4.

[0307] In some implementations, Cy 1A By at least one C (=NR) e11 )NR c11 R d11 The replacement is preferably at position 4.

[0308] In some implementations, Cy 1A It is replaced by at least one C(=NH)NH2, preferably at the 4-position.

[0309] In some implementations, Cy 1A For any of the following formulas:

[0310]

[0311]

[0312] In some implementations, in defining Cy 1A In the formula, each R Cy1A Independently for C 1-6 Alkyl groups, such as methyl groups, or halogens, such as Cl or Br, or amino groups.

[0313] In some implementations, Cy 1A For any of the following formulas:

[0314]

[0315] In some implementations, in defining Cy 1A In the formula, R a11 C 1-6 Alkyl, such as methyl, R b11 C 1-6 Alkyl, such as methyl, R b11 C 1-6 Halogenated alkyl groups, such as trifluoromethyl, and R c11 It is an alkyl group, such as methyl.

[0316] In some implementations, Cy 1A It is an unsubstituted or substituted heteroaryl group.

[0317] In some implementations, Cy 1A It is unsubstituted or substituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl or 1H-benzo[d]imidazol-6-yl.

[0318] In some implementations, Cy 1A For any of the following formulas:

[0319]

[0320]

[0321]

[0322]

[0323]

[0324] In some implementations, in defining Cy 1AThe R in the formula Cy1A Independently for C 1-6 Alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.

[0325] In some implementations, in defining Cy 1A The R values ​​connected to nitrogen in the formula Cy1A C 1-6 Alkyl groups, such as methyl or ethyl.

[0326] In some implementation schemes, R 11 C 1-6 alkyl.

[0327] In some implementation schemes, R 11 It is a methyl group.

[0328] In some implementation schemes, R 11 For H.

[0329] In some implementation schemes, R 12 For H.

[0330] In some implementation schemes, R 12 C 1-6 Alkyl, such as methyl or ethyl, preferably methyl.

[0331] In some implementation schemes, R 11 and R 12 Together with the groups to which they are attached, they form 4-6 membered heterocyclic alkyl rings.

[0332] In some implementations, n1 is 1.

[0333] In some implementations, n1 is 2.

[0334] In some implementations, n2 is 0.

[0335] In some implementations, n2 is 1.

[0336] In some implementations, n2 is 2.

[0337] In some embodiments, the compound is according to any of the following formulas (I-1a) to (I-1f) and (I-2a) to (I-2r):

[0338]

[0339]

[0340] In some embodiments, the compound is according to any of the following formulas: (I-1g) to (I-1o) and (I-2aa) to (I-2az):

[0341]

[0342]

[0343]

[0344]

[0345] In some embodiments, the compound is according to any of the following formulas (I-3) to (I-9):

[0346]

[0347] In some embodiments, the compound is according to any of the following formulas (I-3a) to (I-3k):

[0348] In some embodiments, the compound is according to any of the following formulas (I-4a) to (I-4bf):

[0349]

[0350]

[0351]

[0352]

[0353]

[0354] In some embodiments, the compound is according to any of the following formulas (I-5a) to (I-5u):

[0355]

[0356]

[0357]

[0358] In some embodiments, the compound is according to any of the following formulas (I-6a) to (I-6cw):

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368] In some embodiments, the compound is according to any of the following formulas (I-7a) to (I-7co):

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] In some embodiments, the compound is according to any of the following formulas (I-8a) to (I-8z):

[0379]

[0380]

[0381]

[0382] In some embodiments, the compound is according to any of the following formulas (I-9a) to (I-9z):

[0383]

[0384]

[0385]

[0386] In some implementation schemes, R13 For Cy 1B .

[0387] In some implementation schemes, R 13 For (C) 1-6 (alkylene) Cy 1B (C) 2-6 (Cy) 1B or (C) 2-6 (Nyneylyl)Cy 1B In some implementations, R 13 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is unsubstituted.

[0388] In some implementation schemes, R 13 For (CR) 13A R 13B ) n3 Cy 1B .

[0389] In some implementation schemes, each R 13A For H.

[0390] In some implementation schemes, each R 13B For H.

[0391] In some implementations, n3 is 0.

[0392] In some implementations, n3 is 1.

[0393] In some implementations, n3 is 2.

[0394] In some implementation schemes, R 13 (CH2) 0-2 Cy 1B .

[0395] In some implementation schemes, R 13 CH2Cy 1B .

[0396] In some implementation schemes, R 13 CH2CH2Cy 1B .

[0397] In some implementation schemes, R 13 For OCY 1B .

[0398] In some implementations, Cy 1B For unreplaced C 6-10 Aryl.

[0399] In some implementations, Cy 1B It is an unsubstituted phenyl group.

[0400] In some implementations, Cy 1B It is an unsubstituted naphthyl group, such as 1-naphthyl or 2-naphthyl.

[0401] In some implementations, Cy 1B It is an unsubstituted 5-10 heteroaryl group.

[0402] In some implementations, Cy 1B It is an unsubstituted pyridinyl group, such as unsubstituted 2-, 3- or 4-pyridinyl or an unsubstituted quinolinyl group, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl.

[0403] In some implementations, Cy 1B For unreplaced C 6-10 Aryl.

[0404] In some implementations, Cy 1B It is a substituted phenyl group.

[0405] In some implementations, Cy 1B It is a biphenyl (i.e., a phenyl substituted with a phenyl group), such as 2-, 3-, or 4-biphenyl.

[0406] In some implementations, Cy 1B The naphthyl group is substituted, such as 1-naphthyl or 2-naphthyl.

[0407] In some implementations, Cy 1B It replaces 5-10 heteroaryl groups.

[0408] In some implementations, Cy 1B The substituted pyridyl group, such as substituted 2-, 3- or 4-pyridyl, or the substituted quinolinyl group, such as substituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl.

[0409] In some implementations, Cy 1B It is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy1B halogens and C 1-6 Halogenated alkyl groups; wherein each R Cy1B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 6-10 Aryl or 5-10 heteroaryl groups, wherein R is formed Cy1B Each C 6-10The aryl or 5-10 heteroaryl group is unsubstituted or substituted by 1, 2, or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups and haloalkyl groups.

[0410] In some implementation schemes, R 13 Groups selected from the following formulas:

[0411]

[0412]

[0413]

[0414]

[0415]

[0416] In some implementation schemes, in the representation of R 13 R in the formula Cy1B C 1-6 Alkyl groups, such as methyl or ethyl, preferably methyl, or halogens, such as fluorine or chlorine, preferably fluorine.

[0417] In some implementation schemes, in the representation of R 13 R in the formula Cy1B C 1-6 Alkyl, such as methyl or ethyl, preferably methyl.

[0418] In some implementation schemes, in the representation of R 13 R in the formula Cy1B It is a halogen, such as fluorine or chlorine, with fluorine being preferred.

[0419] In some implementations, no more than one R 14 It's not hydrogen.

[0420] In some implementations, no more than one R 14 Not hydrogen and an R 14 C 1-6 Alkyl groups, such as methyl groups.

[0421] In some implementation schemes, each R 14 It is hydrogen.

[0422] In some implementation schemes, A 11 Let N be the number of elements in the array.

[0423] In some implementation schemes, R 15 It is hydrogen.

[0424] In some implementation schemes, R15 C 1-6 Alkyl groups, such as methyl groups.

[0425] In some implementation schemes, R 15 It is a hydroxyl group.

[0426] In some implementation schemes, R 16 It is hydrogen.

[0427] In some implementation schemes, R 16 C is unsubstituted or substituted 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0428] In some implementation schemes, R 16 For unreplaced C 1-6 Alkyl groups, such as methyl groups.

[0429] In some implementation schemes, R 16 To replace C 1-6 alkyl.

[0430] In some implementations, R is formed 16 The replacement of C 1-6 The alkyl group is substituted by 1, 2, 3, 4 or 5, for example 1, 2 or 3, or preferably 1 substituent, said substituent being selected from halogens, CN, C(O)NR. c11 R d11 and C(O)OR a11 .

[0431] In some implementation schemes, R 16 (CH2) 1-6 C(O)OR a11 .

[0432] In some implementations, R is defined 16 R a11 For H or C 1-6 Alkyl groups, such as methyl groups.

[0433] In some implementations, R is defined 16 R a11 For H.

[0434] In some implementation schemes, R a11 R b11 R c11 and R d11 R a12 R b12 R c12 and R d12 Each is independently selected from H and C. 1-6 alkyl.

[0435] In some implementation schemes, each R e11 and each R e12 For H.

[0436] In some embodiments, the compound of formula (I-1) and its embodiments may be in salt form, such as a pharmaceutically acceptable salt.

[0437] The compounds of formula (I-1) and embodiments thereof are available for use as inhibitors of MASP-2 and for therapeutic purposes. The compounds of formula (I-1) and embodiments thereof are available for treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (I-1) or an embodiment thereof, optionally in salt form.

[0438] In some embodiments, a compound of formula (I-1) or an embodiment thereof is provided as 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.

[0439] In some aspects, the compound is one or more compounds selected from those of formula (I-1) described in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some aspects, one or more variables of the compound of formula (I) are defined (e.g., Cy). 1A ;R Cy1A ;R 11 ;R 12 A 11 ;R 13 ;R 14 ;R 15 ;n1;n2;n3;R 13A ;R 13B Cy 1B ;R 16 ;R 16A ;R 16B Cy 1C ;R Cy1C ;R a11 R b11 R c11 ;R d11 ;R e11 R a12 R b12 R c12 ;R d12 and R e11The substituents are selected from the compounds of formula (I-1) in the examples, including the compounds listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[0440] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0441] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[0442] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is typically converted to its biologically active form (e.g., ester to acid form, carbamate to amino or hydroxyl form; hydroxymididine to amididine) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Amididine-group prodrugs include amidoximes, O-alkylmidoximes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0443] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0444] B. Compounds of formulas IIA and IIB

[0445] In some respects, this disclosure provides compounds of formulas (IIA) and (IIB):

[0446]

[0447] Or its salt, wherein:

[0448] Cy 2A C is unsubstituted or substituted 6-10 aryl or unsubstituted or substituted 5-10 heteroaryl groups; wherein Cy is formed 2A The 5-10 membered heteroaryl ring atom is composed of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein Cy forms 2A The replaced C 6-10 The aryl or substituted 5-10 heteroaryl group is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy2A Halogen, C 1-6 Halogenated alkyl, CN, OR a21 S Ra21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NR c21 R d21C(=NOR) a21 )NR c21 R d21 C(=NOC(O)R) b21 )NR c21 R d21 C(=NR) e21 )NR c21 C(O)OR a21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation;

[0449] Each R Cy2A Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy2A The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, 3 or 4 heteroatoms selected from O, N and S; wherein R forms Cy2A Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a21 SR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation, and the formation of R in it Cy2A Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a21 SR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21And oxygenation;

[0450] R 21 For H or C 1-6 Alkyl, C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 Alkyl groups, wherein R is formed 21 C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from halogens, CN, OR. a21 SR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation, and the formation of R in it 21 C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a21 SR a21 C(O)R b21 C(O)NRc21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation;

[0451] R 22 For H or C 1-6 Alkyl; or

[0452] R 21 and R 22 Together with the groups they are attached to, they form 4-6 membered heterocyclic alkyl rings;

[0453] A 23 For N or NR 23 ;

[0454] A 24 For CR 24 N or NR 24 ;

[0455] A 26 For CR 26 Or S;

[0456] The condition is

[0457] A in option (IIA) 23 A 24 and A 26 Makes A 23 A 24 and A 26The ring is a heteroaryl ring, and the symbol is... Indicates the aromatic ring (normalized) bond;

[0458] R 23 For H or C 1-6 alkyl;

[0459] R 24 For H; C 1-6 Alkyl or phenyl;

[0460] R 25 For Cy 2B 、(CR 25A R 25B ) n25 Cy 2B (C) 1-6 (alkylene) Cy 2B (C) 2-6 (Cy) 2B or (C) 2-6 (Nyneylyl)Cy 2B , where R 25 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is either unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, each of which is independently selected from halogens, CN, OR. a21 SR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NRc21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation;

[0461] R 26 For H or C 1-6 alkyl;

[0462] Each R 25A For H or C 1-6 alkyl;

[0463] Each R 25B For H or C 1-6 alkyl;

[0464] n25 is 0, 1, or 2;

[0465] Cy 2B C is unsubstituted or substituted 6-10 aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy forms 2B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; and

[0466] Cy is formed 2B The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy2B Halogen, C 1-6 Halogenated alkyl, CN, OR a21 S Ra21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O)R b21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NRc21 R d21 C(=NOR) a21 )NR c21 R d21 C(=NOC(O)R) b21 )NR c21 R d21 C(=NR) e21 )NR c21 C(O)OR a21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation;

[0467] Among them, each R Cy2B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy2B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein R forms Cy2B Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a21 SR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O) Rb21 NR c21 C(O)NR c21 R d21 NRc21 C(O)OR a21 C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21 S(O)2NR c21 R d21 And oxygenation; and the formation of R in it Cy2B Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a21 SR a21 C(O)R b21 C(O)NR c21 R d21 C(O)OR a21 OC(O)R b21 OC(O)NR c21 R d21 NR c21 R d21 NR c21 C(O) Rb21 NR c21 C(O)NR c21 R d21 NR c21 C(O)OR a21 C(=NR) e21 )NR c21 R d21 NR c21 C(=NR e21 )NR c21 R d21 S(O)R b21 S(O)NR c21 R d21 S(O)2R b21 NR c21 S(O)2R b21S(O)2NR c21 R d21 And oxygenation;

[0468] R a21 R b21 R c21 and R d21 Each is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a21 R b21 R c21 and R d21 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents, said substituents being independently selected from C10. 1-6 Alkyl, halogen, CN, OR a22 SR a22 C(O)R b22 C(O)NR c22 R d22 C(O)OR a22 OC(O)R b22 OC(O)NR c22 R d22 NR c22 R d22 NR c22 C(O)R b22 NR c22 C(O)NR c22 R d22 NR c22 C(O)ORa22 C(=NR) e22 )NR c22 R d22 NR c22 C(=NR e22 )NR c22 R d22 S(O)R b22 S(O)NR c22 R d22 S(O)2R b22 NR c22 S(O)2R b22 S(O)2NR c22 R d22 And oxygenation;

[0469] Or R connected to the same N atom c21 and R d21 Together with the N atom attached to either of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl or a 5-membered heteroaryl group, each optionally substituted by one, two, or three substituents, said substituents being independently selected from C. 1-6 Alkyl, halogen, CN, OR a22 SR a22 C(O)R b22 C(O)NR c22 R d22 C(O)OR a22 OC(O)R b22 OC(O)NR c22 R d22 NR c22 R d22 NR c22 C(O)R b22 NR c22 C(O)NR c22 R d22 NR c22 C(O)OR a22 C(=NR) e22 )NR c22 R d22 NR c22 C(=NR e22 )NR c22 R d22 S(O)R b22 S(O)NR c22 R d22 S(O)2R b22 NR c22 S(O)2R b22 S(O)2NR c22 R d22 And oxygenation;

[0470] R a22 R b22 R c22 and R d22 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a22 R b22 R c22 and R d22 The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and oxo groups;

[0471] Or R connected to the same N atom c22 and R d22 Together with the N atom attached to either of them, they form 4-, 5-, 6-, or 7-membered heterocyclic alkyl or 5-membered heteroaryl groups, each of which is unsubstituted or substituted by 1, 2, or 3 substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6Halogenated alkoxy and oxo; and

[0472] R e21 and Re 22 Each can be independently H, CN, or NO2.

[0473] In some implementations, Cy 2A It is an unsubstituted or substituted aryl group.

[0474] In some implementations, Cy 2A It is an unsubstituted or substituted phenyl group.

[0475] In some implementations, Cy 2A It is a substituted phenyl group.

[0476] In some implementations, Cy 2A By at least one OR a21 Or at least one C (=NR) e21 )NR c21 R d21 C(=NOR) a21 )NR c21 R d21 C(=NOC(O)R) b21 )NR c21 R d21 Or C(=NR) e21 )NR c21 C(O)OR a21 replace.

[0477] In some implementations, Cy 2A By at least one OR a21 and selected from at least one of C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0478] In some implementations, Cy 2A With at least one OH and with at least one selected from C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0479] In some implementations, Cy 2A By at least one C (=NR) e21 )NR c21 R d21 C(=NOR) a21 )NR c21 R d21 C(=NOC(O)R) b21 )NR c21 R d21 C(=NR)e21 )NR c21 C(O)OR a21 The replacement is preferably at position 4.

[0480] In some implementations, Cy 2A By at least one C (=NR) e21 )NR c21 R d21 The replacement is preferably at position 4.

[0481] In some implementations, Cy 2A It is replaced by at least one C(=NH)NH2, preferably at the 4-position.

[0482] In some implementations, Cy 2A For any of the following formulas:

[0483]

[0484]

[0485] In some implementations, in defining Cy 2A In the formula, each R Cy2A Independently for C 1-6 Alkyl groups, such as methyl groups, or halogens, such as Cl or Br, or amino groups.

[0486] In some implementations, Cy 2A For any of the following formulas:

[0487]

[0488] In some implementation schemes, R a21 C 1-6 Alkyl and R b21 C 1-6 alkyl.

[0489] In some implementations, Cy 2A It is an unsubstituted or substituted heteroaryl group, such as pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl or 1H-benzo[d]imidazol-6-yl.

[0490] In some implementations, Cy 2A For any of the following formulas:

[0491]

[0492]

[0493]

[0494]

[0495]

[0496] In some implementations, in defining Cy 2A The R in the formula Cy2A Independently for C 1-6 Alkyl groups, such as methyl or ethyl, preferably methyl, or halogens such as F, Cl or Br, preferably Cl.

[0497] In some implementations, in defining Cy 2A The R values ​​connected to nitrogen in the formula Cy2A C 1-6 Alkyl groups, such as methyl or ethyl.

[0498] In some implementation schemes, R 21 C 1-6 alkyl.

[0499] In some implementation schemes, R 21 It is a methyl group.

[0500] In some implementation schemes, R 21 For H.

[0501] In some implementation schemes, R 22 For H.

[0502] In some implementation schemes, R 22 C 1-6 alkyl.

[0503] In some implementation schemes, R 22 It is a methyl group.

[0504] In some implementation schemes, R 21 and R 22 Together with the groups to which they are attached, they form 4-6 membered heterocyclic alkyl rings.

[0505] In some embodiments, the compound has formula (IIA).

[0506] In some embodiments, the compound is according to any of the following formulas (IIA-1a) or (IIA-1b):

[0507]

[0508] In some embodiments, the compound is according to any of the following formulas (IIA-2) to (IIA-5):

[0509]

[0510] In some embodiments, the compound is according to any of the following formulas (IIA-2a) to (IIA-5b):

[0511]

[0512]

[0513] In some embodiments, the compound has formula (IIB).

[0514] In some embodiments, the compound is according to any of the following formulas (IIB-1a) or (IIB-1b):

[0515]

[0516] In some implementation schemes, R 23 For H.

[0517] In some implementation schemes, R 23 C 1-6 alkyl.

[0518] In some implementation schemes, R 24 For H.

[0519] In some implementation schemes, R 24 C 1-6 alkyl.

[0520] In some implementation schemes, R 24 It is a phenyl group.

[0521] In some implementation schemes, R 25 For Cy 2B .

[0522] In some implementation schemes, R 25 For (C) 1-6 (alkylene) Cy 2B (C) 2-6 (Cy) 2B or (C) 2-6 (Nyneylyl)Cy 2B , where R 25 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is either unsubstituted or substituted.

[0523] In some implementation schemes, R 25 For (C) 1-6 (alkylene) Cy 2B (C) 2-6 (Cy) 2B or (C) 2-6(Nyneylyl)Cy 2B , where R 25 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is unsubstituted.

[0524] In some implementation schemes, R 25 For (CR) 25A R 25B ) n25 Cy 2B .

[0525] In some implementation schemes, each R 25A For H.

[0526] In some implementation schemes, each R 25B For H.

[0527] In some implementations, n25 is 0.

[0528] In some implementations, n25 is 1.

[0529] In some implementations, n25 is 2.

[0530] In some implementation schemes, R 25 CH2Cy 2B .

[0531] In some implementation schemes, R 25 CH2CH2Cy 2B .

[0532] In some implementations, Cy 2B For unreplaced C 6-10 Aryl.

[0533] In some implementations, Cy 2B It is an unsubstituted phenyl group.

[0534] In some implementations, Cy 2B It is an unsubstituted naphthyl group, such as 1-naphthyl or 2-naphthyl.

[0535] In some implementations, Cy 2B Unsubstituted 5-10 heteroaryl compounds.

[0536] In some implementations, Cy 2B It is an unsubstituted pyridinyl group, such as unsubstituted 2-, 3- or 4-pyridinyl or an unsubstituted quinolinyl group, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl.

[0537] In some implementations, Cy2B To replace C 6-10 Aryl.

[0538] In some implementations, Cy 2B It is a substituted phenyl group.

[0539] In some implementations, Cy 2B It is a biphenyl (i.e., a phenyl substituted with a phenyl group), such as 2-, 3-, or 4-biphenyl.

[0540] In some implementations, Cy 2B The naphthyl group is substituted, such as 1-naphthyl or 2-naphthyl.

[0541] In some implementations, Cy 2B It replaces 5-10 heteroaryl groups.

[0542] In some implementations, Cy 2B The substituted pyridyl group, such as substituted 2-, 3- or 4-pyridyl, or the substituted quinolinyl group, such as substituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl.

[0543] In some implementations, Cy 2B It is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy2B halogens and C 1-6 Halogenated alkyl groups; wherein each R Cy2B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 6-10 Aryl or 5-10 heteroaryl groups, wherein R is formed Cy2B Each C 6-10 The aryl or 5-10 heteroaryl group is unsubstituted or substituted by 1, 2, or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups and haloalkyl groups.

[0544] In some implementation schemes, R 25 Groups selected from the following formulas:

[0545]

[0546]

[0547]

[0548]

[0549]

[0550] In some implementation schemes, in the representation of R 25 R in the formula Cy2B C 1-6 Alkyl groups, such as methyl or ethyl, preferably methyl, or halogens, such as fluorine or chlorine, preferably fluorine.

[0551] In some implementation schemes, in the representation of R 25 R in the formula Cy2B C 1-6 Alkyl, such as methyl or ethyl, preferably methyl.

[0552] In some implementation schemes, in the representation of R 25 R in the formula Cy2B It is a halogen, such as fluorine or chlorine, with fluorine being preferred.

[0553] In some implementation schemes, R a21 R b21 R c21 R d21 R a22 R b22 R c22 R d22 Each is independently selected from H and C. 1-6 alkyl.

[0554] In some implementation schemes, each R e21 and each R e22 For H.

[0555] The compounds of formulas (IIA) and (IIB) and their embodiments may be used as inhibitors of MASP-2 and for therapeutic purposes.

[0556] In some embodiments, the compounds of formulas (IIA) and (IIB) and their embodiments may be in salt form, such as pharmaceutically acceptable salts.

[0557] Compounds of formulas (IIA) and (IIB) and embodiments thereof are available for use as inhibitors of MASP-2 and for therapeutic purposes. Compounds of formulas (IIA) and (IIB) and embodiments thereof are available for treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (IIA) or (IIB) or an embodiment thereof, optionally in salt form.

[0558] In some embodiments, a compound of formula (IIA) or (IIB) or an embodiment thereof is provided as 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.

[0559] In some aspects, the compound is one or more compounds selected from those of formulas (IIA) and (IIB) described in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some aspects, one or more variables (e.g., Cy) of the compounds of formulas (IIA) and (IIB) are defined. 2A R Cy2A Cy 2B R Cy2B A 23 A 24 A 26 R 21 R 22 R 23 R 24 R 25 R 26 n25, R a21 R b21 R c21 R d21 R e21 R a22 R b22 R c22 R d22 and R e22 The substituents are selected from the compounds of formulas (IIA) and (IIB) in the examples, including the compounds listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[0560] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomer or diastereomer excess), and racemic mixtures of enantiomers or diastereomers.

[0561] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[0562] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is normally converted to its biologically active form (e.g., ester to acid form; carbamate to amino or hydroxyl form; hydroxymididine to amididine form) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; and Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Amididine-group prodrugs include amidothimes, O-alkyl amidothimes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0563] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0564] Compounds of Formula III

[0565] In some respects, this disclosure provides compounds of formula (III).

[0566]

[0567] Or its salts, used to treat MASP-2-related diseases or conditions, wherein:

[0568] Cy 3A C is unsubstituted or substituted 6-10aryl or unsubstituted or substituted 5-10 heteroaryl groups; wherein Cy is formed 3A The 5-10 membered heteroaryl ring atom is composed of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein Cy forms 3A The replaced C 6-10 The aryl or substituted 5-10 heteroaryl group is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy3A Halogen, C 1-6 Halogenated alkyl, CN, OR a31 S Ra31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 C(=NOR) a31 )NR c31 R d31 C(=NOC(O)R) b31 )NR c31 R d31 C(=NR) e31 )NR c31 C(O)OR a31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0569] Each R Cy3A Selected independently from C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy3A The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, 3 or 4 heteroatoms selected from O, N and S; wherein R forms Cy3A Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation, and the formation of R in it Cy3A Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, ORa31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0570] R 31 For H or C 1-6 Alkyl, C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 Alkyl groups, wherein R is formed 31 C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from halogens, CN, OR. a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NRc31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation, and the formation of R in it 31 C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NRc31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0571] R 32 For H or C 1-6 Alkyl; or

[0572] R 31 and R 32 Together with the groups they are attached to, they form 4-6 membered heterocyclic alkyl rings;

[0573] R 33 For Cy 3B 、(CR 33A R 33B ) n33 Cy 3B (C) 1-6 (alkylene) Cy 3B (C) 2-6 (Cy) 3B or (C) 2-6 (Nyneylyl)Cy 3B , where R 35 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is either unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, each of which is independently selected from halogens, CN, OR. a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NRc31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0574] Each R 33A Independently H or C 1-6 alkyl;

[0575] Each R 33B Independently H or C 1-6 Alkyl; or

[0576] Or R attached to the same carbon atom 33A and R 33B Independent of any other R 33A and R 33B These groups can combine to form –(CH2). 2-5 - thereby forming a 3-6 membered cycloalkyl ring;

[0577] n33 can be 0, 1, 2, or 3;

[0578] Cy 3B C is unsubstituted or substituted 6-10 aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy forms 3B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; and

[0579] Cy is formed 3B The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy3B Halogen, C 1-6 Halogenated alkyl, CN, OR a31 S Ra31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NRc31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 C(=NOR) a31 )NR c31 R d31 C(=NOC(O)R) b31 )NR c31 R d31 C(=NR) e31 )NR c31 C(O)OR a31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0580] Among them, each R Cy3B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy3B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein R forms Cy3B Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31R d31 NR c31 R d31 NR c31 C(O) Rb31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation; and the formation of R in it Cy3B Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O) Rb31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NRc31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0581] R 34 Selected from H and C 1-6 alkyl;

[0582] R 35 Selected from H, unsubstituted or substituted C 1-6 Alkyl and Cy 3C R is formed 35 The replaced C 1-6 The alkyl group is substituted with 1, 2, 3, 4, or 5 substituents selected from Cy. 3C Halogen, CN, OR a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation; the condition is that there is no more than one R. 35 The substituent is Cy3C ;

[0583] Cy 3C C is unsubstituted or substituted 6-10 aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy forms 3C The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; and

[0584] Cy is formed 3C The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy3C Halogen, C 1-6 Halogenated alkyl, CN, OR a31 S Ra31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 C(=NOR) a31 )NR c31 R d31 C(=NOC(O)R) b31 )NR c31 R d31 C(=NR) e31 )NR c31 C(O)OR a31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NRc31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0585] Among them, each R Cy3C Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy3C The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein R forms Cy3C Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O) Rb31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 Rd31 And oxygenation; and the formation of R in it Cy3C Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O) Rb31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation;

[0586] R 36 Selected from H and C 1-6 alkyl;

[0587] R a31 R b31 R c31 and R d31 Each is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a31 R b31 R c31 and R d31 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents, said substituents being independently selected from C10. 1-6 Alkyl, halogen, CN, OR a32 SR a32 C(O)R b32 C(O)NR c32 R d32 C(O)OR a32 OC(O)R b32 OC(O)NR c32 R d32 NR c32 R d32 NR c32 C(O)R b32 NR c32 C(O)NR c32 R d32 NR c32 C(O)OR a32 C(=NR) e32 )NR c32 R d32 NR c32 C(=NR e32 )NR c32 R d32 S(O)R b32 S(O)NR c32 R d32 S(O)2R b32 NR c32S(O)2R b32 S(O)2NR c32 R d32 And oxygenation;

[0588] Or R connected to the same N atom c31 and R d31 Together with the N atom attached to either of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl or a 5-membered heteroaryl group, each optionally substituted with one, two, or three substituents, said substituents being independently selected from C. 1-6 Alkyl, halogen, CN, OR a32 SR a32 C(O)R b32 C(O)NR c32 R d32 C(O)OR a32 OC(O)R b32 OC(O)NR c32 R d32 NR c32 R d32 NR c32 C(O)R b32 NR c32 C(O)NR c32 R d32 NR c32 C(O)OR a32 C(=NR) e32 )NR c32 R d32 NR c32 C(=NR e32 )NR c32 R d32 S(O)R b32 S(O)NR c32 R d32 S(O)2R b32 NR c32 S(O)2R b32 S(O)2NR c32 R d32 And oxygenation;

[0589] R a32 R b32 R c32 and R d32 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a32 R b32 R c32 and R d32 The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and oxo groups;

[0590] Or R connected to the same N atom c32 and R d32 Together with the N atom attached to either of them, they form 4-, 5-, 6-, or 7-membered heterocyclic alkyl or 5-membered heteroaryl groups, each of which is unsubstituted or substituted by 1, 2, or 3 substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and oxo; and

[0591] R e31 and Re 32 Each can be H, CN, or NO2 independently.

[0592] In some implementations, Cy 3A It is an unsubstituted or substituted aryl group.

[0593] In some implementations, Cy 3A It is an unsubstituted or substituted phenyl group.

[0594] In some implementations, Cy 3A It is a substituted phenyl group.

[0595] In some implementations, Cy 3A By at least one OR a31 Or at least one C (=NR) e31 )NR c31 R d31 C(=NOR) a31 )NR c31 R d31 C(=NOC(O)R) b31 )NR c31 R d31 Or C(=NR) e31 )NR c31 C(O)OR a31 replace.

[0596] In some implementations, Cy 3A By at least one OR a31 and selected from at least one of C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0597] In some implementations, Cy 3A With at least one OH and with at least one selected from C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0598] In some implementations, Cy 3A By at least one C (=NR) e31 )NR c31 R d31 C(=NOR) a31 )NR c31 R d31 C(=NOC(O)R) b31 )NR c31 R d31 C(=NR) e31 )NR c31 C(O)OR a31 The replacement is preferably at position 4.

[0599] In some implementations, Cy 3A By at least one C (=NR) e31 )NR c31 R d31 The replacement is preferably at position 4.

[0600] In some implementations, Cy 3AIt is replaced by at least one C(=NH)NH2, preferably at the 4-position.

[0601] In some implementations, Cy 3A For any of the following formulas:

[0602]

[0603] In some implementations, Cy 3A For any of the following formulas:

[0604]

[0605] In some implementations, in defining Cy 3A In the formula, R a31 C 1-6 Alkyl, such as methyl; R b31 C 1-6 Alkyl, such as methyl, or R b31 C 1-6 Halogenated alkyl groups, such as trifluoromethyl, and R c31 It is an alkyl group, such as methyl.

[0606] In some implementations, Cy 3A It is an unsubstituted or substituted heteroaryl group.

[0607] In some implementations, Cy 3A It is unsubstituted or substituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl or 1H-benzo[d]imidazol-6-yl.

[0608] In some implementations, Cy 3A For any of the following formulas:

[0609]

[0610]

[0611]

[0612]

[0613]

[0614] In some implementations, in defining Cy 3A The R in the formula Cy3A Independently for C 1-6 Alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.

[0615] In some implementations, in defining Cy3A The R values ​​connected to nitrogen in the formula Cy3A C 1-6 Alkyl groups, such as methyl or ethyl.

[0616] In some implementation schemes, R 31 C 1-6 alkyl.

[0617] In some implementation schemes, R 31 It is a methyl group.

[0618] In some implementation schemes, R 31 For H.

[0619] In some implementation schemes, R 32 For H.

[0620] In some implementation schemes, R 32 C 1-6 alkyl.

[0621] In some implementation schemes, R 32 It is a methyl group.

[0622] In some implementation schemes, R 31 and R 32 Together with the groups to which they are attached, they form 4-6 membered heterocyclic alkyl rings.

[0623] In some embodiments, the compound is according to any of the following formulas (III-1a) to (III-1h):

[0624]

[0625]

[0626] In some implementation schemes, R 33 For Cy 3B .

[0627] In some implementation schemes, R 33 For (C) 1-6 (alkylene) Cy 3B (C) 2-6 (Cy) 3B or (C) 2-6 (Nyneylyl)Cy 3B , where R 35 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is unsubstituted.

[0628] In some implementation schemes, R 33 For (C) 1-6(alkylene) Cy 3B (C) 2-6 (Cy) 3B or (C) 2-6 (Nyneylyl)Cy 3B , where R 35 C 1-6 Alkylene, C 2-6 imide or C 2-6 The ynyl group is substituted by 1, 2, 3, 4, or 5 substituents, each of which is independently selected from halogens, CN, OR. a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation.

[0629] In some implementation schemes, R 33 For Cy 3B 、(CR 33A R 33B ) n33 Cy 3B .

[0630] In some implementation schemes, each R 33A For H.

[0631] In some implementation schemes, each R 33B For H.

[0632] In some implementations, n33 is 0.

[0633] In some implementations, n33 is 1.

[0634] In some implementations, n33 is 2.

[0635] In some implementations, n33 is 3.

[0636] In some implementation schemes, R 33 CH2Cy 3B .

[0637] In some implementation schemes, R 33 CH2CH2Cy 3B .

[0638] In some embodiments, the compound is according to any of the following formulas (III-2) to (III-4):

[0639]

[0640] In some embodiments, the compound is according to any of the following formulas (III-2a) to (III-2h):

[0641]

[0642] In some embodiments, the compound is according to any of the following formulas (III-3a) to (III-3h):

[0643]

[0644] In some embodiments, the compound is according to any of the following formulas (III-4a) to (III-4h):

[0645]

[0646]

[0647] In some implementation schemes, R 33 CH2CH2CH2Cy 3B .

[0648] In some implementations, Cy 3B For unreplaced C 6-10 Aryl.

[0649] In some implementations, Cy 3B It is an unsubstituted phenyl group.

[0650] In some implementation schemes, R33 It is CH2CH2Ph.

[0651] In some implementations, Cy 3B It is an unsubstituted naphthyl group, such as 1-naphthyl or 2-naphthyl.

[0652] In some implementation schemes, R 33 It is CH2CH2-1-naphthyl or CH2CH2-2-naphthyl.

[0653] In some implementations, Cy 3B It is an unsubstituted 5-10 heteroaryl group.

[0654] In some implementations, Cy 3B It is an unsubstituted pyridyl group, such as unsubstituted 2-, 3- or 4-pyridyl; an unsubstituted quinolinyl group, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; an unsubstituted benzo[b]thiophenyl group, such as unsubstituted 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thiophenyl; or an unsubstituted indole group, such as unsubstituted indole-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

[0655] In some implementations, Cy 3B For unreplaced C 3-10 Cycloalkyl.

[0656] In some implementations, Cy 3B It is an unsubstituted cyclopentyl, cyclohexyl, or cycloheptyl group.

[0657] In some implementations, Cy 3B It is an unsubstituted 4-10 membered heterocyclic alkyl group.

[0658] In some implementations, Cy 3B To replace C 6-10 Aryl.

[0659] In some implementations, Cy 3B It is a substituted phenyl group.

[0660] In some implementations, Cy 3B The naphthyl group is substituted, such as 1-naphthyl or 2-naphthyl.

[0661] In some implementations, Cy 3B It replaces 5-10 heteroaryl groups.

[0662] In some implementations, Cy 3BThe substituted pyridyl group, such as substituted 2-, 3- or 4-pyridyl; the substituted quinolinyl group, such as substituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; the substituted benzo[b]thiophene group, such as substituted 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thiophene; or the substituted indole group, such as substituted indole-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

[0663] In some implementations, Cy 3B To replace C 3-10 Cycloalkyl.

[0664] In some implementations, Cy 3B The substituted cyclopentyl, cyclohexyl, or cycloheptyl groups are used.

[0665] In some implementations, Cy 3B It is a substituted 4-10 membered heterocyclic alkyl group.

[0666] In some implementations, Cy 3B It is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy3B halogens and C 1-6 Halogenated alkyl groups; wherein each R Cy3B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group and C 6-10 Aryl or 5-10 heteroaryl groups, wherein R is formed Cy3B Each C 6-10 The aryl or 5-10 heteroaryl group is unsubstituted or substituted by 1, 2, or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups and haloalkyl groups.

[0667] In some implementation schemes, R 33Selected from the following groups: phenyl; benzyl; 2-phenylethyl; 2,3-dihydro-1H-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 formula:

[0668]

[0669] In some implementation schemes, R 34 It is hydrogen.

[0670] In some implementation schemes, R 34 C 1-6 Alkyl groups, such as methyl groups.

[0671] In some implementation schemes, R 35 For H.

[0672] In some implementation schemes, R 35 For Cy 3C .

[0673] In some implementation schemes, R 35 For unreplaced C 1-6 alkyl.

[0674] In some implementation schemes, R 35 To replace C 1-6 alkyl.

[0675] In some implementations, R is formed 35 The replacement of C 1-6 The alkyl group is substituted with at least one substituent, wherein R 35 The substituents are independently selected from: 1, 2, or 3 substituents selected from the following: Cy 3C Halogen, CN, OR a31 SR a31 C(O)R b31 C(O)NR c31 R d31 C(O)OR a31 OC(O)R b31 OC(O)NR c31 R d31 NR c31 R d31 NR c31 C(O)R b31 NR c31 C(O)NR c31 R d31 NR c31 C(O)OR a31 C(=NR) e31 )NR c31 R d31 NR c31 C(=NR e31 )NR c31 R d31 S(O)R b31 S(O)NR c31 R d31 S(O)2R b31 NR c31 S(O)2R b31 S(O)2NR c31 R d31 And oxygenation.

[0676] In some implementations, R is formed 35 The replacement of C 1-6 The alkyl group is substituted with at least one substituent, wherein the substituent includes Cy. 3C .

[0677] In some implementations, R is formed 35 The replacement of C 1-6 The alkyl group is replaced by a substituent, wherein the substituent is Cy. 3C .

[0678] In some implementation schemes, R 35 (CH2) 1-5 Cy 3C .

[0679] In some implementation schemes, R 35 CH2Cy 3C .

[0680] In some implementations, Cy 3C For unreplaced C 6-10 Aryl.

[0681] In some implementations, Cy 3C It is an unsubstituted phenyl or naphthyl group, such as 1-naphthyl or 2-naphthyl.

[0682] In some implementations, Cy 3C It is an unsubstituted 5-10 heteroaryl group.

[0683] In some implementations, Cy 3C It is an unsubstituted pyridyl group, such as unsubstituted 2-, 3- or 4-pyridyl; an unsubstituted quinolinyl group, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; an unsubstituted benzo[b]thiophenyl group, such as unsubstituted 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thiophenyl; or an unsubstituted indole group, such as unsubstituted indole-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

[0684] In some implementations, Cy 3C For unreplaced C 3-10 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0685] In some implementations, Cy 3C It is an unsubstituted 4-10 membered heterocyclic alkyl group.

[0686] In some implementations, Cy 3C To replace C 6-10 Aryl.

[0687] In some implementations, Cy 3C It is a substituted phenyl group, or a substituted naphthyl group, such as a substituted 1-naphthyl or 2-naphthyl group.

[0688] In some implementations, Cy 3C It replaces 5-10 heteroaryl groups.

[0689] In some implementations, Cy 3CThe substituted pyridyl group, such as substituted 2-, 3- or 4-pyridyl; the substituted quinolinyl group, such as substituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; the substituted benzo[b]thiophene group, such as substituted 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thiophene; or the substituted indole group, such as substituted indole-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

[0690] In some implementations, Cy 3C To replace C 3-10 Cycloalkyl, such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0691] In some implementations, Cy 3C It is a substituted 4-10 membered heterocyclic alkyl group.

[0692] In some implementation schemes, R 36 For H.

[0693] In some implementation schemes, R 36 C 1-6 Alkyl groups, such as methyl groups.

[0694] In some implementation schemes, R a31 R b31 R c31 R d31 R a32 R b32 R c32 and R d32 Each is independently selected from H and C. 1-6 alkyl.

[0695] In some implementation schemes, each R e31 and each R e32 For H.

[0696] The compounds of formula (III) and their embodiments can be used as inhibitors of MASP-2 and for therapeutic purposes.

[0697] In some embodiments, the compound of formula (III) and its embodiments may be in salt form, such as a pharmaceutically acceptable salt.

[0698] Compounds of formula (III) and embodiments thereof are available for use as inhibitors of MASP-2 and for therapeutic purposes. Compounds of formula (III) and embodiments thereof are available for treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (III) or an embodiment thereof, optionally in salt form.

[0699] In some embodiments, a compound of formula (III) or an embodiment thereof is provided as 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.

[0700] In some respects, the compound is one or more compounds selected from those of formula (III) described in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some respects, one or more variables of the compounds of formula (III) are defined (e.g., Cy). 3A R Cy3A Cy 3B R Cy3B Cy 3C R Cy3C R 31 R 32 R 33 R 33A R 33B R 34 R 35 R 36 n33, R a31 R b31 R c31 R d31 R e31 R a32 R b32 R c32 R d32 and R e32 The substituents are selected from the compounds of formula (III) in the examples, including the compounds listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[0701] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0702] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[0703] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is normally converted to its biologically active form (e.g., ester to acid form; carbamate to amino or hydroxyl form; hydroxymididine to amididine form) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Amididine-group prodrugs include amididine oximes, O-alkyl amididine oximes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0704] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0705] Compounds of formula IV, D.

[0706] In some respects, this disclosure provides compounds of formula (IV).

[0707]

[0708] Or its salts, used to treat MASP-2-related diseases or conditions, wherein:

[0709] Cy 4A C is unsubstituted or substituted 6-10 aryl or unsubstituted or substituted 5-10 heteroaryl groups; wherein Cy is formed 4A The 5-10 membered heteroaryl ring atom is composed of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S; wherein Cy forms 4A The replaced C 6-10 The aryl or substituted 5-10 heteroaryl group is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy4A Halogen, C 1-6 Halogenated alkyl, CN, OR a41 S Ra41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 Rd41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 C(=NR) e41 )NR c41 C(O)OR a41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation;

[0710] Each R Cy4A Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy4A The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, 3 or 4 heteroatoms selected from O, N and S; wherein R forms Cy4A Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation, and the formation of R in it Cy4A Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NRc41 R d41 And oxygenation;

[0711] R 41 For H or C 1-6 Alkyl, C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 Alkyl groups, wherein R is formed 41 C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from halogens, CN, OR. a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation, and the formation of R in it 41 C 6-10 Aryl-C 1-6 Alkyl or 5-10 heteroaryl-C 1-6 The alkyl group is unsubstituted or substituted with one, two, or three substituents, which are independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a41 SR a41C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation;

[0712] R 42 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or Cy 4B ; where R is formed 42 Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is either unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from Cy. 4B Halogen, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NRc41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation; the condition is that no more than one substituent is Cy. 4B ;

[0713] Cy 4B C is unsubstituted or substituted 6-10 aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy is formed 4B The 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocyclic alkyl ring atoms consist of a carbon atom and 1, 2 or 3 heteroatoms selected from O, N and S; and Cy is formed therein. 4B The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy4B Halogen, C 1-6 Halogenated alkyl, CN, OR a41 S Ra41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NRc41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 C(=NR) e41 )NR c41 C(O)OR a41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation;

[0714] Among them, each R Cy4B Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy4B The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2 or 3 heteroatoms selected from O, N and S, and R is formed therein. Cy4B Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation; and the formation of various R Cy4B Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation;

[0715] Or R 41 and R 42 The atoms they are connected to and the connection R 41 and R 42 The nitrogen atoms of the linked atoms together form a 4-7 membered heterocyclic alkyl ring; it is optionally further substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy4B Halogen, C 1-6 Halogenated alkyl, CN, OR a41 S Ra41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 C(=NR) e41 )NR c41 C(O)OR a41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 Rd41 And oxygenation;

[0716] R 43 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or Cy 4C ; where R is formed 43 Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is unsubstituted or substituted by 1, 2, 3, 4, or 5 substituents, each of which is independently selected from 0, 1, 2, 3, 4, or 5 substituents, and the substituents are selected from Cy. 4C Halogen, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation, the condition is the formation of R 43 C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 No more than one substituent of the alkynyl group is Cy 4C ;

[0717] Cy 4C C is unsubstituted or substituted 6-10aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocyclic alkyl; wherein Cy is formed 4B The 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocyclic alkyl ring atoms consist of a carbon atom and 1, 2 or 3 heteroatoms selected from O, N and S; and Cy is formed therein. 4C The replaced C 6-10 aryl, substituted 5-10 heteroaryl, substituted C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl group is substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy4C Halogen, C 1-6 Halogenated alkyl, CN, OR a41 S Ra41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 C(=NR) e41 )NR c41 C(O)OR a41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 Rd41 And oxygenation;

[0718] Each R Cy4C Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic alkyl groups, wherein R is formed Cy4C The ring atoms of the 5-10-membered heteroaryl or 4-10-membered heterocyclic alkyl group consist of a carbon atom and 1, 2, or 3 heteroatoms selected from O, N, and S, wherein R forms Cy4C Each C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is independently unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from halogens, CN, OR. a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation; and the formation of various Rs therein Cy4A Each C 6-10 Aryl, 5-10 heteroaryl, C 3-10The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation;

[0719] R a41 R b41 R c41 and R d41 Each is independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C1-3 Alkyl groups, wherein R is formed a41 R b41 R c41 and R d41 The C mentioned 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10-membered heteroaryl, 4-10-membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents, said substituents being independently selected from C10. 1-6 Alkyl, halogen, CN, OR a42 SR a42 C(O)R b42 C(O)NR c42 R d42 C(O)OR a42 OC(O)R b42 OC(O)NR c42 R d42 NR c42 R d42 NR c42 C(O)R b42 NR c42 C(O)NR c42 R d42 NR c42 C(O)OR a42 C(=NR) e42 )NR c42 R d42 NR c42 C(=NR e42 )NR c42 R d42 S(O)R b42 S(O)NR c42 R d42 S(O)2R b42 NR c42 S(O)2R b42 S(O)2NR c42 R d42 And oxygenation;

[0720] Or R connected to the same N atom c41 and R d41Together with the N atom attached to either of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl or a 5-membered heteroaryl group, each optionally substituted with one, two, or three substituents, said substituents being independently selected from C. 1-6 Alkyl, halogen, CN, OR a42 SR a42 C(O)R b42 C(O)NR c42 R d42 C(O)OR a42 OC(O)R b42 OC(O)NR c42 R d42 NR c42 R d42 NR c42 C(O)R b42 NR c42 C(O)NR c42 R d42 NR c42 C(O)OR a42 C(=NR) e42 )NR c42 R d42 NR c42 C(=NR e42 )NR c42 R d42 S(O)R b42 S(O)NR c42 R d42 S(O)2R b42 NR c42 S(O)2R b42 S(O)2NR c42 R d42 And oxygenation;

[0721] R a42 R b42 R c42 and R d42 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Alkyl groups, wherein R is formed a42 R b42 Rc42 and R d42 The C mentioned 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6-membered heteroaryl-C 1-3 Alkyl, C 3-7 cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocyclic alkyl-C 1-3 Each alkyl group is optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C) 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and oxo groups;

[0722] Or R connected to the same N atom c42 and R d42 Together with the N atom attached to either of them, they form a 4-, 5-, 6-, or 7-membered heterocyclic alkyl or a 5-membered heteroaryl group, each of which is unsubstituted or substituted by one, two, or three substituents, said substituents being independently selected from OH, CN, amino, NH(C 1-6 alkyl), N(C) 1-6 Alkyl group 2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and oxo; and

[0723] R e41 and Re 42 Each can be H, CN, or NO2 independently.

[0724] In some implementations, Cy 4A It is an unsubstituted or substituted aryl group.

[0725] In some implementations, Cy 4A It is an unsubstituted or substituted phenyl group.

[0726] In some implementations, Cy 4A It is a substituted phenyl group.

[0727] In some implementations, Cy 4A By at least one OR a41 Or at least one C (=NR)e41 )NR c41 R d41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 Or C(=NR) e41 )NR c41 C(O)OR a41 replace.

[0728] In some implementations, Cy 4A By at least one OR a41 and selected from at least one of C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0729] In some implementations, Cy 4A With at least one OH and with at least one selected from C 1-6 Alkyl, C 1-6 Additional substituents of haloalkyl groups and halogens.

[0730] In some implementations, Cy 4A By at least one C (=NR) e41 )NR c41 R d41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 C(=NR) e41 )NR c41 C(O)OR a41 The replacement is preferably at position 4.

[0731] In some implementations, Cy 4A By at least one C (=NR) e41 )NR c41 R d41 For example, C(=NH)NH2 substitution, preferably at the 4-position.

[0732] In some implementations, Cy 4A For any of the following formulas:

[0733]

[0734]

[0735] In some implementations, in defining Cy 4A In the formula, R a41 C 1-6 Alkyl, such as methyl, R b41 C 1-6 Alkyl, such as methyl, R b41 C 1-6 Halogenated alkyl groups, such as trifluoromethyl, and R c41 It is an alkyl group, such as methyl.

[0736] In some implementations, Cy 4A It is an unsubstituted or substituted heteroaryl group.

[0737] In some implementations, Cy 4A It is unsubstituted or substituted pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl or 1H-benzo[d]imidazol-6-yl.

[0738] In some implementations, Cy 4A For any of the following formulas:

[0739]

[0740]

[0741]

[0742]

[0743]

[0744] In some implementations, in defining Cy 4A The R in the formula Cy4A Independently for C 1-6 Alkyl groups, such as methyl or ethyl, preferably methyl, or halogens such as F, Cl or Br, preferably Cl.

[0745] In some implementations, in defining Cy 4A The R values ​​connected to nitrogen in the formula Cy4A C 1-6 Alkyl groups, such as methyl or ethyl.

[0746] In some implementation schemes, R 41 C 1-6 alkyl.

[0747] In some implementation schemes, R 41 For H.

[0748] In some implementation schemes, R 41 It is a methyl group.

[0749] In some implementation schemes, R 42 For H.

[0750] In some implementation schemes, R 42 For unreplaced C 1-6 Alkyl groups, such as methyl groups.

[0751] In some implementation schemes, R 42 For Cy 4B .

[0752] In some implementation schemes, R 42 To replace C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0753] In some implementation schemes, R 42 To replace C 1-6 alkyl.

[0754] In some implementation schemes, R 42 To replace C 1-6 Alkyl groups, wherein R is formed 42 C 1-6 The alkyl group is substituted with one, two, or three substituents selected from Cy. 4B Halogen, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NRc41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation; the condition is that no more than one substituent is Cy. 4B .

[0755] In some implementations, R is formed 42 The replacement of C 1-6 The alkyl group is substituted with at least one substituent, wherein the substituent includes Cy. 4B .

[0756] In some implementations, R is formed 35 The replacement of C 1-6 The alkyl group is substituted with at least one substituent, wherein the substituent is Cy. 4B .

[0757] In some implementation schemes, R 42 (CH2) 1-5 Cy 4B .

[0758] In some implementation schemes, R 42 CH2Cy 4B .

[0759] In some implementations, Cy 4B For unreplaced C 6-10 Aryl groups, such as unsubstituted phenyl or naphthyl groups, such as 1-naphthyl or 2-naphthyl groups, Cy 4B Unsubstituted 5-10-membered heteroaryl groups, such as unsubstituted pyridyl groups, such as unsubstituted 2-, 3-, or 4-pyridyl groups; unsubstituted quinolinyl groups, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl groups; unsubstituted benzo[b]thiophene groups, such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene groups; or unsubstituted indole groups, such as unsubstituted indole-2-yl, -3-yl, -4-yl, -5-yl, -6-yl, or -7-yl groups. 4B For unreplaced C 3-10 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy 4B It is an unsubstituted 4-10 membered heterocyclic alkyl group.

[0760] In some implementations, Cy 4B To replace C 6-10 Aryl groups, such as substituted phenyl or naphthyl groups, such as 1-naphthyl or 2-naphthyl groups, Cy 4BThe substituted 5-10-membered heteroaryl group, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl; substituted quinolinyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; substituted benzo[b]thiophene, such as substituted 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene; or substituted indole, such as substituted indole-2-yl, -3-yl, -4-yl, -5-yl, -6-yl, or -7-yl, Cy 4B To replace C 3-10 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy 4B It is a substituted 4-10 membered heterocyclic alkyl group.

[0761] In some implementation schemes, R 41 and R 42 The atoms they are connected to and the connection R 41 and R 42 The nitrogen atoms of the linked atoms together form a 4-7 membered heterocyclic alkyl ring; it is optionally further substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R. Cy4B Halogen, C 1-6 Halogenated alkyl, CN, OR a41 S Ra41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 C(=NOR) a41 )NR c41 R d41 C(=NOC(O)R) b41 )NR c41 R d41 C(=NR) e41 )NR c41 C(O)OR a41 NR c41 C(=NRe41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation.

[0762] In some implementation schemes, R 41 and R 42 The atoms they are connected to and the connection R 41 and R 42 The nitrogen atoms of the connected atoms together form a 5- or 6-membered heterocyclic alkyl ring.

[0763] In some embodiments, the compound is according to any of the following formulas: (IV-1), (IV-2), (IV-1a), (IV-1b), (IV-2a), or (IV-2b).

[0764]

[0765]

[0766] In some implementation schemes, R 43 For Cy 4C .

[0767] In some implementation schemes, R 43 For unreplaced C 1-6 alkyl.

[0768] In some implementation schemes, R 43 To replace C 1-6 alkyl.

[0769] In some implementations, R is formed 43 The replacement of C 1-6 The alkyl group is substituted by at least one substituent, said substituent being independently selected from: 1, 2, or 3 substituents, said substituent being selected from Cy. 4C Halogen, CN, OR a41 SR a41 C(O)R b41 C(O)NR c41 R d41 C(O)OR a41 OC(O)R b41 OC(O)NR c41 R d41 NR c41R d41 NR c41 C(O)R b41 NR c41 C(O)NR c41 R d41 NR c41 C(O)OR a41 C(=NR) e41 )NR c41 R d41 NR c41 C(=NR e41 )NR c41 R d41 S(O)R b41 S(O)NR c41 R d41 S(O)2R b41 NR c41 S(O)2R b41 S(O)2NR c41 R d41 And oxygenation.

[0770] In some implementations, R is formed 43 The replacement of C 1-6 The alkyl group is substituted with at least one substituent, wherein the substituent includes Cy. 4C .

[0771] In some implementations, R is formed 43 The replacement of C 1-6 The alkyl group is replaced by a substituent, wherein the substituent is Cy. 4C .

[0772] In some implementation schemes, R 43 (CH2) 1-5 Cy 4C .

[0773] In some implementation schemes, R 43 CH2Cy 4C .

[0774] In some implementation schemes, R 43 CH2CH2Cy 4C .

[0775] In some implementation schemes, R 43 For CF2Cy 4C or CF2CH2Cy 4C .

[0776] In some implementations, Cy 4C For unreplaced C 6-10Aryl groups, such as phenyl, 1-naphthyl, or 2-naphthyl.

[0777] In some implementations, Cy 4C It is an unsubstituted 5-10-membered heteroaryl group, such as an unsubstituted pyridyl group, such as an unsubstituted 2-, 3- or 4-pyridyl group; an unsubstituted quinolinyl group, such as an unsubstituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl group; an unsubstituted benzo[b]thiophenyl group, such as an unsubstituted 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thiophenyl group; or an unsubstituted indole group, such as an unsubstituted indole-2-, -3-, -4-, -5-, -6- or -7-.

[0778] In some implementations, Cy 4C For unreplaced C 3-10 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0779] In some implementations, Cy 4C It is an unsubstituted 4-10 membered heterocyclic alkyl group.

[0780] In some implementations, Cy 4C To replace C 6-10 Aryl groups, such as substituted phenyl, substituted 1-naphthyl, or substituted 2-naphthyl.

[0781] In some implementations, Cy 4C The substituted 5- to 10-membered heteroaryl group, such as substituted pyridyl, such as substituted 2-, 3- or 4-pyridyl, substituted quinolinyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, substituted benzo[b]thiophene, such as substituted 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thiophene, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

[0782] In some implementations, Cy 4C To replace C 3-10 Cycloalkyl groups, such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0783] In some implementations, Cy 4C It is a substituted 4-10 membered heterocyclic alkyl group.

[0784] In some embodiments, the compound is according to any of the following formulas: (IV-3)-(IV-7), (IV-3a), (IV-3b), (IV-5a), (IV-5b), (IV-7a), or (IV-7b):

[0785]

[0786] In some implementation schemes, R a41 R b41 R c41 R d41 R a42 R b42 R c42 and R d42 Each is independently selected from H and C. 1-6 alkyl.

[0787] In some implementation schemes, each R e41 and each R e42 For H.

[0788] In some implementations, the compound of formula (IV) and its implementations may be in salt form, such as a pharmaceutically acceptable salt.

[0789] Compounds of formula (IV) and embodiments thereof are available for use as inhibitors of MASP-2 and for therapeutic purposes. Compounds of formula (IV) and embodiments thereof are available for use in treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (IV) or an embodiment thereof, optionally in salt form.

[0790] In some embodiments, a compound of formula (IV) or an embodiment thereof is provided as 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.

[0791] In some aspects, the compound is one or more compounds selected from those of formula (IV) described in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some aspects, one or more variables of the compound of formula (IV) are defined (e.g., Cy). 4A R Cy4A Cy 4B R Cy4B Cy 4C R Cy4C R 41 R 42 R 43 R a41 R b41 R c41 R d41 R e41 R a42 R b42R c42 R d42 and R e42 The substituents are selected from the compounds of formula (IV) in the examples, including the compounds listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[0792] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0793] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[0794] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is normally converted into its biologically active form (e.g., ester to acid form; carbamate to amino or hydroxyl form; hydroxymididine to amididine form) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Prodrugs with amididine groups include amidothimes, O-alkyl amidothimes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0795] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0796] Compounds of formulas E, VA, VB, VIA, VIB, VIIA, and VIIB

[0797] 1. Another chemical definition

[0798] The following definitions apply herein to this part (II)(E) and the claims relating to compounds of formulas (VA), (VB), (VIA), (VIB), (VIIA) and (VIIB) disclosed herein.

[0799] The term "alkoxy" refers to a straight-chain or branched saturated or unsaturated hydrocarbon (e.g., EtO-) containing at least one oxygen atom in an ether group. The chain may contain a specified number of carbon atoms. For example, "C1-C..." 12 "Alkoxy" indicates a group that can have 1 to 12 (including terminal) carbon atoms and at least one oxygen atom. C1-C 12 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.

[0800] The term "alkyl" includes aliphatic hydrocarbon chains that can be straight-chain or branched. The chain can contain a specified number of carbon atoms. For example, C1-C 12 This indicates that the group may have 1 to 12 carbon atoms (including terminal values). Unless otherwise specified, an alkyl group has about 1 to about 20 carbon atoms. In one aspect, an alkyl group has 1 to about 12 carbon atoms in the chain. In another aspect, an alkyl group (“lower alkyl”) has 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, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, cyclopentyl, or cyclohexyl. In one aspect, an alkyl group may exclude methyl (e.g., 2 to 6 carbon atoms in the chain).

[0801] As used herein, the term "aryl" includes cyclic aromatic carbocyclic systems containing 6 to 18 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthraceneyl, tetraphenyl, biphenyl, and phenanthryl.

[0802] The terms “arylalkyl” and “aralkyl” are used interchangeably to include alkyl as defined herein, wherein at least one hydrogen substituent has been replaced by an aryl group as defined herein. Examples include, but are not limited to, benzyl, 1-phenylethyl, 4-methylbenzyl, and 1,1,-dimethyl-1-phenylmethyl.

[0803] As used herein, the term "cycloalkyl" includes cyclic hydrocarbon groups that may contain a specified number of carbon atoms. For example, C3-C 12 This indicates that the group may have 3 to 12 carbon atoms (including terminal values). Unless otherwise specified, cycloalkyl groups comprise about 3 to about 20 carbon atoms. In one aspect, the cycloalkyl group has 3 to about 12 carbon atoms. In another aspect, the cycloalkyl group has 3 to about 7 carbon atoms. Examples may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.

[0804] As used herein, “halogenated” or “halogen” includes fluorine, chlorine, bromine, or iodine. In one aspect, “halogenated” includes fluorine or chlorine (preferably chlorine).

[0805] The term "heteroaryl" includes monocyclic and bicyclic aryl groups having about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms). The heteroatom used in the term heteroaryl refers to oxygen, sulfur, and nitrogen. The nitrogen atom of a heteroaryl group is optionally oxidized to the corresponding N-oxide. Examples include, but are not limited to, pyrazinyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrroleyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, indoleyl, azaindoleyl, benzimidazolyl, benzothiopheneyl, quinolinyl, imidazolyl, thiophenepyridinyl, quinazolinyl, thiophenepyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, benzoazaindoleyl, 1,2,4-triazinyl, and benzothiazolyl.

[0806] As used herein, "heterocyclic group" includes non-aromatic saturated monocyclic or polycyclic ring systems having about 4 to about 10 ring atoms (e.g., 5 to about 8 ring atoms, or 5 to about 6 ring atoms), wherein one or more atoms in said ring system are one or more elements other than carbon, such as nitrogen, oxygen, or sulfur. Heterocyclic groups optionally contain at least one sp... 2- Hybridized atoms (e.g., introducing a carbonyl group, an inner-ring olefin, or an outer-ring olefin). In some embodiments, the nitrogen or sulfur atom of the heterocyclic group is optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Examples of monocyclic heterocyclic groups include, but are not limited to, piperidinyl, pyrrolyl, piperazine, morpholinyl, thiomorpholinyl, thiazolyl, 1,3-dioxacyclopentyl, 1,4-dioxacyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothioranyl.

[0807] As used herein, the term "hydroxyalkyl" includes an alkyl group in which at least one hydrogen substituent has been replaced by an alcohol (-OH) group. In some aspects, a hydroxyalkyl group has one alcohol group. In some aspects, a hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In some aspects, a hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0808] The term "hyperosmolar" refers to a formulation whose osmotic pressure is higher than that of a human (i.e., greater than 350 mOsm / KglHhO).

[0809] When any two substituents, or examples of any two identical substituents, are "independently selected" from a list of selectable groups, the groups can be the same or different. For example, if R a and R b Individually selected from the group consisting of alkyl, fluorine, amino, and hydroxyalkyl groups, they have two Rs. a Group and two R b The molecule may have all alkyl groups (e.g., four different alkyl groups). Alternatively, the first R... a It can be an alkyl group, the second R a It could be fluorine, the first R b It can be hydroxyalkyl and a second R b It can be an amino group (or any other substituent selected from this group). Alternatively, R a And the first R b Both can be fluorine, but the second R... b It can be an alkyl group (i.e., some pairs of substituents can be the same, while other pairs can be different).

[0810] As used herein, the term "salt" refers to an acid or base salt of a compound, such as ZNA or another 2-(acylamino)imidazole. Exemplary examples of pharmaceutically acceptable salts are cationic salts, such as alkali metal and alkaline earth metal (e.g., sodium, lithium, potassium, calcium, and magnesium) salts, ammonium (ammonium, trimethylammonium, diethylammonium, and tri-(hydroxymethyl)-methyl-ammonium) salts, inorganic acid (hydrochloric acid, hydrobromic acid, phosphate, etc.) salts, organic carboxylic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, organic sulfonic acid (methanesulfonic acid) salts, and quaternary ammonium (methyl iodine, ethyl iodine, etc.) salts. Further 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.

[0811] The term "its salt" may be applied to any of the aforementioned members of the relevant Markush group. For example, a group consisting of A, B, C and their salts includes, within its scope, an implementation of a salt of A, an implementation of a salt of B, and an implementation of a salt of C.

[0812] 2. Compounds of formulas VA and VB

[0813] In some respects, this disclosure provides compounds having the formula (VA) or (VB):

[0814]

[0815] or its salt; wherein:

[0816] A 1 For members selected from the following: –(C=NH)–, –(C=NOR)– a )–、–[C=NO(C=O)R a ]–、–[C=N[O(C=O)ZR b ]}–, fused 5- or 6-membered heterocyclic groups and fused 5- or 6-membered heteroaryl groups;

[0817] When A 1 When Y is –(C=NH)–, 1 Selected from –NH2, –NH(C=O)R a and –NH(C=O)ZR b ;

[0818] When A 1 –(C=NOR) a )–、–[C=NO(C=O)R a ]–or–{C=N[O(C=O)ZR b When Y 1 For –NH2;

[0819] When A 1 When Y is a fused heterocyclic or heteroaryl group, 1 For –NH2 or halogen, and A 1 by m other R 1 Group substitution;

[0820] Each R a and R b Independently selected from C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl and C7-C 12 arylalkyl; wherein R a It has m substituents selected from the following: C1-C6 alkyl, hydroxy, hydroxy(C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or R a and R b The combination forms a heterocyclic ring having m substituents selected from the following: C1-C6 alkyl, hydroxyl, C1-C6 alkoxy and halogen;

[0821] Each Z is independently selected from O and S;

[0822] A 2 It is selected from the following members: C3-C6 heteroaryl, C6 aryl, and C2-C6 alkyl;

[0823] When A 2 When Y is a C3-C6 heteroaryl group, 2 Selected from –NH2, -CH2NH2, chlorine, –(C=NH)NH2, –(C=NH)NH(C=O)R a –(C=NH)NH(C=O)ZR b –(C=NOR) a )NH2、–[C=NO(C=O)R a ]NH2 and –{C=N[O(C=O)ZR b NH2; and A 2 by m other R 1 Group substitution;

[0824] When A 2 When it is C6 aryl, Y 2 Selected from aminomethyl, hydroxyl, and halogen, and A 2 by m other R 1 Group substitution;

[0825] When A 2 When Y is a C2-C6 alkyl group, 2Selected from –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a and –NH(C=NH)NH(C=O)ZR b ;

[0826] Each R 1 It is independently selected from the following members: C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino and halogen;

[0827] m and n are each independently selected from integers from 0 to 3;

[0828] L is –(O) p –(C(R 2a (R) 2b )) q –,

[0829] Each R 2a Or R 2b It is a member independently selected from hydrogen and fluorine;

[0830] p is an integer between 0 and 1;

[0831] q is an integer from 1 to 2;

[0832] R 3 It is selected from the following members: hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxyl (C1-C6 alkyl); or R 3 and R 4 They combine to form nitrogen-containing heterocyclic butanes, pyrrolidines, or piperidine rings;

[0833] R 4 It is selected from the following members: hydrogen and C1-C6 alkyl; or R 4 and R 3 They combine to form nitrogen-containing heterocyclic butanes, pyrrolidines, or piperidine rings;

[0834] R 5 It is selected from the following members: C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and having 0 to 3 Rs. 13 C7-C of substituents 12 arylalkyl or heteroarylalkyl; or R 5 and R 6 Combined to form 0 to 3 R 13 Heterocyclic compounds with substituents;

[0835] R 6 It is selected from the following members: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxyl (C1-C6 alkyl), having 0 to 3 R groups. 13 C7-C of substituents 12Arylalkyl or heteroarylalkyl, amino (C1-C8 alkyl) and amide (C1-C8 alkyl); or R 6 and R 5 Combined to form 0 to 3 R 13 Heterocyclic compounds with substituents; and

[0836] Each R 13 Individually selected from the following members: C1-C6 alkyl, C6-C 10 Aryl, (C6-C 10 Aryl (C1-C6 alkyl), carboxyl (C1-C6 alkyloxy), heteroaryl, (C6-C 10 (Heteroaryl) C1-C6 alkyl, heterocyclic, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amide, C1-C6 alkylamino and halogen; or two R 13 Groups combine to form fused C6-C 10 Aryl, C6-C 10 Heteroaryl or C5-C7 cycloalkyl ring.

[0837] In some respects, this disclosure provides compounds having the formula (VA) or (VB):

[0838]

[0839] or its salt; wherein:

[0840] A 1 For members selected from the following groups: –(C=NH)–, –(C=NOR)– a )–、

[0841] –[C=NO(C=O)R a ]–、–[C=N[O(C=O)ZR b ]}–, fused 5- or 6-membered heterocyclic groups, and fused 5- or 6-membered heteroaryl groups;

[0842] When A 1 When Y is –(C=NH)–, 1 Selected from the following groups: –NH2, –NH(C=O)R a and –NH(C=O)ZR b ;

[0843] When A 1 –(C=NOR) a )–、–[C=NO(C=O)R a ]–or–{C=N[O(C=O)ZR b When Y 1 For –NH2;

[0844] When A 1 When Y is a fused heterocyclic or heteroaryl group, 1 For –NH2 or halogen, and A 1 by m other R 1 Group substitution;

[0845] Each R a and R b Independently selected from the group consisting of: C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl and C7-C 12 arylalkyl; wherein R a Having m substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, hydroxy(C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino and halogen; or R a and R b The combination forms a heterocyclic ring having m substituents selected from the group consisting of: C1-C6 alkyl, hydroxyl, C1-C6 alkoxy and halogen;

[0846] Each Z is independently selected from the following groups: O and S;

[0847] A 2 It is selected from members of the group consisting of: C3-C6 heteroaryl, C6 aryl, and C2-C6 alkyl;

[0848] When A 2 When Y is a C3-C6 heteroaryl group, 2 Selected from the following groups: –NH2,

[0849] –CH2NH2, chlorine, –(C=NH)NH2, –(C=NH)NH(C=O)R a –(C=NH)NH(C=O)ZR b –(C=NOR) a )NH2、–[C=NO(C=O)R a ]NH2 and –{C=N[O(C=O)ZR b NH2; and A 2 by m other R 1 Group substitution;

[0850] When A 2 When it is C6 aryl, Y 2 Selected from the group consisting of: aminomethyl, hydroxyl, and halogen, and A 2 by m other R 1 Group substitution;

[0851] When A 2 When Y is a C2-C6 alkyl group, 2 Selected from the following groups: –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a and –NH(C=NH)NH(C=O)ZR b ;

[0852] Each R 1 It is independently selected from members of the group consisting of: C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino and halogen;

[0853] m and n are each independently selected from integers from 0 to 3;

[0854] L is –(O) p –(C(R 2a (R) 2b )) q –,

[0855] Each R 2a Or R 2b It is selected independently from members of the group consisting of hydrogen and fluorine;

[0856] p is an integer between 0 and 1;

[0857] q is an integer from 1 to 2;

[0858] R 3 For members selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxyl (C1-C6 alkyl); or R 3 and R 4 They combine to form nitrogen-containing heterocyclic butanes, pyrrolidines, or piperidine rings;

[0859] R 4 For members selected from the group consisting of: hydrogen and C1-C6 alkyl; or R 4 and R 3 They combine to form nitrogen-containing heterocyclic butanes, pyrrolidines, or piperidine rings;

[0860] R 5 Members selected from the group consisting of: C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and having 0 to 3 R groups. 13 C7-C of substituents 12 arylalkyl or heteroarylalkyl; or R 5 and R 6 Combined to form 0 to 3 R 13 Heterocyclic compounds with substituents;

[0861] R 6Members selected from the group consisting of: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxyl (C1-C6 alkyl), and having 0 to 3 R groups. 13 C7-C of substituents 12 Arylalkyl or heteroarylalkyl, amino (C1-C8 alkyl) and amide (C1-C8 alkyl); or R 6 and R 5 Combined to form 0 to 3 R 13 Heterocyclic compounds with substituents; and

[0862] Each R 13 For independently selected members of the group consisting of: C1-C6 alkyl, C6-C 10 Aryl, carboxyl (C1-C6 alkyloxy), heteroaryl, heterocyclic, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amide, C1-C6 alkylamino, and halogen; or two R groups. 13 Groups combine to form fused C6-C 10 Aryl, C6-C 10 Heteroaryl or C5-C7 cycloalkyl ring,

[0863] The condition is that the compound is not a Maillard group.

[0864] In some respects, the compound has the formula VA.

[0865] In some respects, A 1 For –(C=NH)–. In some respects, A 1 –NH(C=O)R a In some respects, A 1 –NH(C=O)ZR b In some respects, Z can be O, S, or N.

[0866] In some respects, A 1 For –(C=NH)–. In some respects, Y 1 For –NH2. In some respects, Y 1 –NH(C=O)R a In some respects, Y 1 –NH(C=O)ZR b .

[0867] In some respects, A 1 –(C=NOR) a –. In some respects, Y 1 For –NH2. In some respects, Y 1 –NH(C=O)R a In some respects, Y 1–NH(C=O)ZR b .

[0868] In some respects, R a Or R b It is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some respects, R a Or R b For C3-C 10 Cycloalkyl groups, such as cyclohexyl, cyclopentyl, or cyclopropyl. In some respects, R a Or R b For C6-C 10 Aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In some respects, R a Or R b C7-C 12 Arylalkyl, such as benzyl or 4-methoxybenzyl.

[0869] In some respects, A 1 It is a fused heteroaryl group. In some respects, A 1 It is a quinolone. In some respects, A 1 It is isoquinoline. In some respects, A 1 It is benzimidazole. In some respects, Y 1 It is –NH2.

[0870] In some respects, Y 1 It is –NH2.

[0871] In some respects, the compound has the formula VB.

[0872] In some respects, A 2 It is a C6 aryl group. In some respects, A 2 It is a C3-C6 heteroaryl group.

[0873] In some respects, A 2 by m other R 1 Group substitution, such as halogen, hydroxyl, C2-C6 alkyl or C1-C4 methoxy.

[0874] In some respects, Y 2 It is a halogen (e.g., chlorine). In some respects, Y 2 It is 3-chloro. In some respects, Y 2 It is an aminomethyl group (e.g., 4-aminomethyl).

[0875] In some respects, A 2 It is a C2-C6 alkyl group.

[0876] In some respects, Y 2It is –NH(C=NH)NH2.

[0877] In some respects, Y 2 Selected from –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a and –NH(C=NH)NH(C=O)ZR b In some respects, Y 2 It is –NH(C=NH)NH2. In some respects, Y 2 –NH(C=NH)NH(C=O)R a In some respects, Y 2 –NH(C=NH)NH(C=O)ZR b .

[0878] In some respects, the compound has the following formula R 3 Stereochemistry

[0879]

[0880] In some respects, R 3 It is selected from members of the group consisting of hydrogen or methyl. In some respects, R 3 It is hydrogen. In some respects, R 3 It is a methyl group.

[0881] In some respects, R 4 It is selected from members of the group consisting of hydrogen or methyl. In some respects, R 4 It is hydrogen.

[0882] In some respects, R 3 and R 4 They combine to form nitrogen-containing heterocyclic butanes, pyrrolidines, or piperidine rings. In some respects, R 3 and R 4 They combine to form a pyrrolidine ring. In some respects, R 3 and R 4 They combine to form a piperidine ring.

[0883] In some respects, R 5 It is selected from members of the group consisting of 2,3-dihydro-1H-inden-2-yl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenethyl, and phenylpropyl, having 0 to 3 R groups. 13 Substituents.

[0884] In some respects, R 5 It is selected from members of the group including: phenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-fluorophenethyl, and phenylpropyl. In some respects, R 5It is selected from members of the group consisting of: phenethyl, 4-methylphenethyl, 4-chlorophenethyl, 4-fluorophenethyl, 3-methylphenethyl, 3-chlorophenethyl, 3-fluorophenethyl, 2-methylphenethyl, 2-chlorophenethyl, 2-fluorophenethyl, phenylpropyl, 4-methylphenylpropyl, 4-chlorophenylpropyl, 4-fluorophenylpropyl, 3-methylphenylpropyl, 3-chlorophenylpropyl, 3-fluorophenylpropyl, 2-methylphenylpropyl, 2-chlorophenylpropyl and 2-fluorophenylpropyl.

[0885] In some respects, R 6 For members selected from the group consisting of: amino (C1-C8 alkyl) and having 0 to 3 R... 13 C7-C of substituents 12 Arylalkyl,

[0886] In some respects, R 6 It is selected from members of the group including hydrogen and carboxymethyl.

[0887] In some respects, R 6 and R 5 They can combine to form pyrrolidine, octahydro-1H-indole, 3-phenylpyrrolidine, piperidine, 1,2,3,4-tetrahydroisoquinoline, 2,5-dihydro-1H-pyrrole, or 1,2,3,6-tetrahydropyridine rings.

[0888] In some respects, R 1 It is a hydroxyl or C1-C6 alkoxy group. In some respects, R 1 It is a hydroxyl group (e.g., 2-hydroxyl; 3-hydroxyl). In some respects, R 1 It is a methoxy group (e.g., 2-methoxy).

[0889] In some respects, m is 0. In some respects, m is 1. In some respects, n is 0. In some respects, n is 1. In some respects, both m and n are 0.

[0890] In some respects, p is 0. In other respects, p is 1.

[0891] In some respects, q is 1. In some respects, p is 0 and q is 1.

[0892] In some respects, each R 2a Or R 2b L is hydrogen. In some respects, L is methylene. In some respects, L is ethylene.

[0893] In some respects, compounds of formula (VA) are selected from compounds of formulas (VC), (VD), (VE), and (VF):

[0894]

[0895] and its salt; of which:

[0896] R 7 It is selected from members of the group consisting of hydrogen, hydroxyl and C1-C6 alkyl;

[0897] R 8 For members selected from the group consisting of: hydrogen and C1-C6 alkyl; and

[0898] m and n are each independently selected from integers between 0 and 2.

[0899] In some aspects, the compound has the formula (VC). In some aspects, the compound has the formula (VD). In some aspects, the compound has the formula (VE). In some aspects, the compound has the formula (VF).

[0900] In some respects, R 7 It is hydrogen. In some respects, R 8 It is hydrogen.

[0901] Compounds of formulas (VA) and (VB), and embodiments thereof, including compounds of formulas (VC), (VD), (VE), and (VF), are available as inhibitors of MASP-2 and for therapeutic use. Compounds of formulas (VA) and (VB), and embodiments thereof, are available for treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (VA) or (VB), or an embodiment thereof, optionally in salt form.

[0902] In some embodiments, a compound of formula (VA) or (VB) or an embodiment thereof is provided as 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.

[0903] In some aspects, the compound is one or more compounds selected from formulas (VA) and (VB) in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some aspects, R 1 R a R b R 2a R 2b R 3 R 4 R 5 R 6 Or R 13One or more of the corresponding substituents selected from the compounds of formulas (VA) and (VB) in the examples, said compounds including those listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[0904] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0905] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[0906] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is normally converted to its biologically active form (e.g., ester to acid form; carbamate to amino or hydroxyl form; hydroxymididine to amididine form) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Amididine-group prodrugs include amididine oximes, O-alkyl amididine oximes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0907] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0908] 3. Compounds of formulas (VIA) and (VIB)

[0909] In some respects, this disclosure provides MASP-2 inhibitory compounds for therapeutic use, said compounds having the formula (VIA) or (VIB):

[0910]

[0911] or its salt; wherein:

[0912] A 1 For members selected from the following: –(C=NH)–, –(C=NOR)– a )–、–[C=NO(C=O)R a ]–、–[C=N[O(C=O)ZR b ]}–, fused 5- or 6-membered heterocyclic groups and fused 5- or 6-membered heteroaryl groups;

[0913] When A 1 When Y is –(C=NH)–, 1 Selected from –NH2, –NH(C=O)R a and –NH(C=O)ZR b ;

[0914] When A 1 –(C=NOR) a )–、–[C=NO(C=O)R a ]–or–{C=N[O(C=O)ZR b When Y 1 For –NH2;

[0915] When A 1 When Y is a fused heterocyclic or heteroaryl group, 1 For –NH2 or halogen, and A 1 by m other R 1 Group substitution;

[0916] Each R aand R b Independently selected from C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl and C7-C 12 arylalkyl; wherein R a It has m substituents selected from the following: C1-C6 alkyl, hydroxy, hydroxy(C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or R a and R b The combination forms a heterocyclic ring having m substituents selected from the following: C1-C6 alkyl, hydroxyl, C1-C6 alkoxy and halogen;

[0917] Each Z is independently selected from O and S;

[0918] A 2 It is selected from the following members: C3-C6 heteroaryl and C2-C6 alkyl;

[0919] When A 2 When Y is a C3-C6 heteroaryl group, 2 Selected from –NH2, -CH2NH2, chlorine, –(C=NH)NH2, –(C=NH)NH(C=O)R a –(C=NH)NH(C=O)ZR b –(C=NOR) a )NH2、–[C=NO(C=O)R a ]NH2 and –{C=N[O(C=O)ZR b NH2; and A 2 by m other R 1 Group substitution;

[0920] When A 2 When Y is a C2-C6 alkyl group, 2 Selected from –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a and –NH(C=NH)NH(C=O)ZR b ;

[0921] Each R 1 It is independently selected from the following members: C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino and halogen;

[0922] m and n are each independently selected from integers from 0 to 3;

[0923] X and X 2 Each is selected from the following members: NR 8 CH and CR 10(Preferred NR) 8 ); or X and X 2 R 10 Groups combine to form groups with 0 to 3 R 13 Fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl rings with substituents;

[0924] Each R 8 It is independently selected from the following members: hydrogen and C1-C6 alkyl;

[0925] Each R 10 Individually selected from the following members: C1-C6 alkyl, having 0 to 3 R... 13 Substituent heteroaryl or C6-C 10 Aryl, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or two Rs 10 Groups combine to form groups with 0 to 3 R 13 Fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl rings with substituents;

[0926] r is an integer from 0 to 4; and

[0927] Each R 13 Individually selected from the following members: C1-C6 alkyl, C6-C 10 Aryl, carboxyl (C1-C6 alkyloxy), heteroaryl, heterocyclic, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amide, C1-C6 alkylamino, and halogen; or two R groups. 13 Groups combine to form fused C6-C 10 Aryl, C6-C 10 Heteroaryl or C5-C7 cycloalkyl ring or its salt.

[0928] In some respects, the compound has the formula (VIA).

[0929] In some respects, the compound has the formula (VIB).

[0930] In some respects, the compound has the formula (VIC) or (VID):

[0931]

[0932] Or its salt.

[0933] In some respects, each R 7 The value is selected from the following members: hydrogen, hydroxyl and C1-C6 alkyl; and m is an integer from 0 to 2.

[0934] In some respects, (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.

[0935] In some respects, X is NR 8 .

[0936] In some respects, R 8 It is hydrogen.

[0937] In some respects, X 2 For CH or CR 10 .

[0938] In some respects, R 10 Individually selected from the following members: C1-C6 alkyl, having 0 to 3 R... 13 Substituents include C6 aryl, C1-C6 alkoxy, and C2-C9 alkoxyalkyl groups.

[0939] In some respects, the two Rs 10 Groups combine to form groups with 0 to 3 R 13 Fused C6 aryl rings with substituents.

[0940] In some respects, R 7 It is hydrogen.

[0941] In some respects, R 3 It is selected from the following members: hydrogen or methyl. In some respects, R 3 It is a methyl group.

[0942] In some respects, Z is O.

[0943] In some respects, R 11 For (R) 14 (R) 14 )N(CO)-.

[0944] In some respects, R 11 For (R) 14 )(H)N(CO)-.

[0945] In some respects, R 14 It is a C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C8 cycloalkylalkyl.

[0946] In some respects, R 12 Hydrogen or C7-C 14 Arylalkyl.

[0947] In some respects, R 1 It is a hydroxyl or C1-C6 alkoxy group.

[0948] In some respects, each R 2aOr R 2b It is hydrogen.

[0949] In some respects, L stands for methylene.

[0950] In some respects, A 1 For –(C=NH)–. In some respects, Y 1 For –NH2. In some respects, Y 1 –NH(C=O)R a In some respects, Y 1 –NH(C=O)ZR b .

[0951] In some respects, A 1 –(C=NOR) a –. In some respects, Y 1 For –NH2. In some respects, Y 1 –NH(C=O)R a In some respects, Y 1 –NH(C=O)ZR b .

[0952] In some respects, A 1 For –(C=NH)–. In some respects, A 1 –NH(C=O)R a In some respects, A 1 –NH(C=O)ZR b In some respects, Z can be O, S, or N.

[0953] In some respects, A 1 It is a fused heteroaryl group. In some respects, A 1 It is a quinolone. In some respects, A 1 It is isoquinoline. In some respects, A 1 It is benzimidazole. In some respects, Y 1 It is –NH2.

[0954] In some respects, R a Or R b It is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some respects, R a Or R b For C3-C 10 Cycloalkyl groups, such as cyclohexyl, cyclopentyl, or cyclopropyl. In some respects, R a Or R b For C6-C 10 Aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In some respects, R a Or Rb C7-C 12 Arylalkyl, such as benzyl or 4-methoxybenzyl.

[0955] In some respects, R 7 It is hydrogen.

[0956] In some respects, the compound has the formula (VIB).

[0957] In some respects, A 2 It is a C3-C6 heteroaryl group.

[0958] In some respects, A 2 by m other R 1 Group substitution, such as halogen, C2-C6 alkyl, or C1-C4 methoxy groups,

[0959] In some respects, Y 2 Selected from –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a and –NH(C=NH)NH(C=O)ZR b In some respects, Y 2 It is –NH(C=NH)NH2. In some respects, Y 2 –NH(C=NH)NH(C=O)R a In some respects, Y 2 –NH(C=NH)NH(C=O)ZR b .

[0960] In some respects, Y 2 It is a halogen (e.g., chlorine, such as 3-chloro). In some respects, Y 2 It is an aminomethyl group (e.g., 4-aminomethyl).

[0961] In some respects, A 2 It is a C2-C6 alkyl group.

[0962] In some respects, X is NR 8 (e.g., NH or NMe). In some respects, X is CH. In some respects, X is CR. 10 (e.g., CMe).

[0963] In some respects, each Z is independently selected from the following members: O and NR. 8 ; and each R 8 Independently selected from the following members: hydrogen and C1-C6 alkyl. In some respects, one Z or each Z is NR. 8 In some respects, each R 8 It is hydrogen.

[0964] In some respects, X2 For NR 8 (e.g., NH or NMe). In some respects, B is CH. In some respects, X 2 For CR 10 (e.g., CMe).

[0965] In some respects, the compound has the following formula R 3 Stereochemistry

[0966]

[0967] In some respects, R 3 It is selected from the following members: hydrogen or methyl. In some respects, R 3 It is hydrogen. In some respects, R 3 It is a methyl group.

[0968] In some respects, R 1 It is a hydroxyl or C1-C6 alkoxy group. In some respects, R 1 It is a hydroxyl group (e.g., 2-hydroxyl; 3-hydroxyl). In some respects, R 1 It is a methoxy group (e.g., 2-methoxy).

[0969] In some respects, m is 0. In some respects, m is 1. In some respects, n is 0. In some respects, n is 1. In some respects, both m and n are 0.

[0970] In some respects, p is 0. In other respects, p is 1.

[0971] In some respects, q is 1. In some respects, p is 0 and q is 1.

[0972] In some respects, each R 2a Or R 2b L is hydrogen. In some respects, L is methylene. In some respects, L is ethylene.

[0973] In some respects, each R 10 Individually selected from the following members: C1-C6 alkyl, having 0 to 3 R... 13 Substituent heteroaryl or C6-C 10 Aryl, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or two Rs 10 Groups combine to form groups with 0 to 3 R 13 Fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl rings with substituents. In some respects, R 10 It is an amino group. In some respects, R 10 and R 1 It is an amino group.

[0974] In some respects, r is an integer from 0 to 5 (i.e., 0, 1, 2, 3, 4, or 5). In some respects, r is an integer from 0 to 4 (i.e., 0, 1, 2, 3, and 4). In some respects, r is an integer from 0 to 3 (i.e., 0, 1, 2, or 3).

[0975] In some respects, each R 13 Individually selected from the following members: C1-C6 alkyl, C6-C 10 Aryl, carboxyl (C1-C6 alkyloxy), heteroaryl, heterocyclic, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amide, C1-C6 alkylamino, and halogen; or two R groups. 13 Groups combine to form fused C6-C 10 Aryl, C6-C 10 Heteroaryl or C5-C7 cycloalkyl rings or their salts. In some respects, R 13 It is phenyl. In some respects, R 13 It is a substituted phenyl group.

[0976] Compounds of formulas (VIA) and (VIB) and embodiments thereof, including compounds of formulas (VIC) and (VID), are available as inhibitors of MASP-2 and for therapeutic use. Compounds of formulas (VIA) and (VIB) and embodiments thereof are available for treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of compounds of formulas (VIA) and (VIB) or embodiments thereof, optionally in salt form.

[0977] In some embodiments, compounds of formulas (VIA) and (VIB) or embodiments thereof are provided as pharmaceutical compositions comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0978] In some aspects, the compound is one or more compounds selected from formulas (VIA) and (VIB) in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some aspects, R 1 R a R b R 2a R 2b R 3 R 4 R 5 R 6Or R 13 The corresponding substituents in one or more of the compounds selected from formulas (VIA) and (VIB) in the examples, said compounds including those listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[0979] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0980] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[0981] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is normally converted to its biologically active form (e.g., ester to acid form; carbamate to amino or hydroxyl form; hydroxymididine to amididine form) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Amididine-group prodrugs include amididine oximes, O-alkyl amididine oximes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0982] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0983] 4. Compounds of formulas VIIA and VIIB

[0984] In some respects, this disclosure provides MASP-2 inhibitory compounds for therapeutic use, said compounds having formula (VIIA) or (VIIB):

[0985]

[0986] or its salt; wherein:

[0987] A 1 For members selected from the following: –(C=NH)–, –(C=NOR)– a )–、–[C=NO(C=O)R a ]–、–[C=N[O(C=O)ZR b ]}–, fused 5- or 6-membered heterocyclic groups and fused 5- or 6-membered heteroaryl groups;

[0988] When A 1 When Y is –(C=NH)–, 1 Selected from –NH2, –NH(C=O)R a and –NH(C=O)ZR b ;

[0989] When A 1 –(C=NOR) a )–、–[C=NO(C=O)R a ]–or–{C=N[O(C=O)ZR b When Y 1 For –NH2;

[0990] When A 1 When Y is a fused heterocyclic or heteroaryl group, 1 For –NH2 or halogen, and A 1 by m other R 1 Group substitution;

[0991] Each R aand R b Independently selected from C1-C6 alkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl and C7-C 12 arylalkyl; wherein R a It has m substituents selected from the following: C1-C6 alkyl, hydroxy, hydroxy(C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or R a and R b The combination forms a heterocyclic ring having m substituents selected from the following: C1-C6 alkyl, hydroxyl, C1-C6 alkoxy and halogen;

[0992] Each Z is independently selected from O and S;

[0993] A 2 It is selected from the following members: C3-C6 heteroaryl and C2-C6 alkyl;

[0994] When A 2 When Y is a C3-C6 heteroaryl group, 2 Selected from –NH2, -CH2NH2, chlorine, –(C=NH)NH2, –(C=NH)NH(C=O)R a –(C=NH)NH(C=O)ZR b –(C=NOR) a )NH2、–[C=NO(C=O)R a ]NH2 and –{C=N[O(C=O)ZR b NH2; and A 2 by m other R 1 Group substitution;

[0995] When A 2 When Y is a C2-C6 alkyl group, 2 Selected from –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a and –NH(C=NH)NH(C=O)ZR b ;

[0996] Each R 1 It is independently selected from the following members: C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino and halogen;

[0997] m and n are each independently selected from integers from 0 to 3;

[0998] L is –(O) p –(C(R 2a (R) 2b ))q –,

[0999] Each R 2a Or R 2b It is a member independently selected from hydrogen and fluorine;

[1000] p is an integer between 0 and 1;

[1001] q is an integer from 1 to 2;

[1002] R 3 It is selected from the following members: hydrogen, C1-C6 alkyl, and carboxyl (C1-C6 alkyl);

[1003] Each R 11 Individually selected from the following members: C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, halogen, and (R 14 (R) 14 )N(CO)-; or two R 11 Groups combine to form groups with 0 to 3 R 13 Fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl rings with substituents;

[1004] r is an integer from 0 to 4; and

[1005] Each Z is independently selected from the following members: O and NR 8 ;

[1006] Each R 8 It is independently selected from the following members: hydrogen and C1-C6 alkyl;

[1007] Each R 12 Individually selected from the following members: hydrogen, C1-C6 alkyl, and having 0 to 3 R... 13 C7-C of substituents 14 Arylalkyl;

[1008] Each R 13 For each of the following members independently selected: C1-C6 alkyl, hydroxy, hydroxy(C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or two R 13 The groups combine to form fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl rings; and

[1009] Each R 14 Individually selected from the following members: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C7-C 14 Arylalkyl and heteroaryl (C1-C6 alkyl); or two R 13 Groups combine to form fused heterocyclic rings.

[1010] In some respects, the compound has formula (VIIA).

[1011] In some respects, the compound has formula (VIIB).

[1012] In some respects, the compound has formula (VIIC):

[1013]

[1014] Among them, each R 7 It is selected from the following members: hydrogen, hydroxyl and C1-C6 alkyl.

[1015] In some respects, R 7 It is hydrogen.

[1016] In some respects, X is NR 8 .

[1017] In some respects, R 8 It is hydrogen.

[1018] In some respects, X 2 For CH or CR 10 .

[1019] In some respects, R 10 Individually selected from the following members: C1-C6 alkyl, having 0 to 3 R... 13 Substituents include C6 aryl, C1-C6 alkoxy, and C2-C9 alkoxyalkyl groups.

[1020] In some respects, the two Rs 10 The groups combine to form a fused C6 aryl ring with 0 to 3 R13 substituents.

[1021] In some respects, R 7 It is hydrogen.

[1022] In some respects, R 3 It is selected from the following members: hydrogen or methyl. In some respects, R 3 It is a methyl group.

[1023] In some respects, Z is O.

[1024] In some respects, R 11 For (R) 14 (R) 14 )N(CO)-.

[1025] In some respects, R 11 For (R) 14 )(H)N(CO)-.

[1026] In some respects, R 14 It is a C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C8 cycloalkylalkyl.

[1027] In some respects, R 12 Hydrogen or C7-C 14 Arylalkyl.

[1028] In some respects, R 1 It is a hydroxyl or C1-C6 alkoxy group.

[1029] In some respects, each R 2a Or R 2b It is hydrogen.

[1030] In some respects, L stands for methylene.

[1031] In some respects, A 1 For –(C=NH)–. In some respects, Y 1 For –NH2. In some respects, Y 1 –NH(C=O)R a In some respects, Y 1 –NH(C=O)ZR b .

[1032] In some respects, A 1 –(C=NOR) a –. In some respects, Y 1 For –NH2. In some respects, Y 1 –NH(C=O)R a In some respects, Y 1 –NH(C=O)ZR b .

[1033] In some respects, A 1 For –(C=NH)–. In some respects, A 1 –NH(C=O)R a In some respects, A 1 –NH(C=O)ZR b In some respects, Z can be O, S, or N.

[1034] In some respects, A 1 It is a fused heteroaryl group. In some respects, A 1 It is a quinolone. In some respects, A 1 It is isoquinoline. In some respects, A 1 It is benzimidazole. In some respects, Y 1 It is –NH2.

[1035] In some respects, R a Or Rb It is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some respects, R a Or R b For C3-C 10 Cycloalkyl groups, such as cyclohexyl, cyclopentyl, or cyclopropyl. In some respects, R a Or R b For C6-C 10 Aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In some respects, R a Or R b C7-C 12 Arylalkyl, such as benzyl or 4-methoxybenzyl.

[1036] In some respects, R 7 It is hydrogen.

[1037] In some respects, the compound has formula (VIIB).

[1038] In some respects, A 2 It is a C3-C6 heteroaryl group.

[1039] In some respects, A 2 by m other R 1 Group substitution, such as halogen, C2-C6 alkyl or C1-C4 methoxy groups.

[1040] In some respects, Y 2 Selected from –NH(C=NH)NH2, –NH(C=NH)NH(C=O)R a , and –NH(C=NH)NH(C=O)ZR b In some respects, Y 2 It is –NH(C=NH)NH2. In some respects, Y 2 –NH(C=NH)NH(C=O)R a In some respects, Y 2 –NH(C=NH)NH(C=O)ZR b .

[1041] In some respects, Y 2 It is a halogen (e.g., chlorine, such as 3-chloro). In some respects, Y 2 It is an aminomethyl group (e.g., 4-aminomethyl).

[1042] In some respects, A 2 It is a C2-C6 alkyl group.

[1043] In some respects, X is NR 8(e.g., NH or NMe). In some respects, X is CH. In some respects, X is CR. 10 (e.g., CMe).

[1044] In some respects, each Z is independently selected from the following members: O and NR. 8 ; and each R 8 Independently selected from the following members: hydrogen and C1-C6 alkyl. In some respects, one Z or each Z is NR. 8 In some respects, each R 8 It is hydrogen.

[1045] In some respects, X 2 For NR 8 (e.g., NH or NMe). In some respects, B is CH. In some respects, X 2 For CR 10 (e.g., CMe).

[1046] In some respects, the compound has the following formula R 3 Stereochemistry

[1047]

[1048] In some respects, R 3 It is selected from the following members: hydrogen or methyl. In some respects, R 3 It is hydrogen. In some respects, R 3 It is a methyl group.

[1049] In some respects, R 1 It is a hydroxyl or C1-C6 alkoxy group. In some respects, R 1 It is a hydroxyl group (e.g., 2-hydroxyl; 3-hydroxyl). In some respects, R 1 It is a methoxy group (e.g., 2-methoxy).

[1050] In some respects, m is 0. In some respects, m is 1. In some respects, n is 0. In some respects, n is 1. In some respects, both m and n are 0.

[1051] In some respects, p is 0. In other respects, p is 1.

[1052] In some respects, q is 1. In some respects, p is 0 and q is 1.

[1053] In some respects, each R 2a Or R 2b L is hydrogen. In some respects, L is methylene. In some respects, L is ethylene.

[1054] In some respects, each R 10Individually selected from the following members: C1-C6 alkyl, having 0 to 3 R... 13 Substituent heteroaryl or C6-C 10 Aryl, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halogen; or two Rs 10 Groups combine to form groups with 0 to 3 R 13 Fused C6 aryl, heteroaryl, or C5-C7 cycloalkyl rings with substituents. In some respects, R 10 It is an amino group. In some respects, R 10 and R 1 It is an amino group.

[1055] In some respects, r is an integer from 0 to 5 (i.e., 0, 1, 2, 3, 4, or 5). In some respects, r is an integer from 0 to 4 (i.e., 0, 1, 2, 3, and 4). In some respects, r is an integer from 0 to 3 (i.e., 0, 1, 2, or 3).

[1056] In some respects, each R 13 Individually selected from the following members: C1-C6 alkyl, C6-C 10 Aryl, carboxyl (C1-C6 alkyloxy), heteroaryl, heterocyclic, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amide, C1-C6 alkylamino, and halogen; or two R groups. 13 Groups combine to form fused C6-C 10 Aryl, C6-C 10 Heteroaryl or C5-C7 cycloalkyl rings or their salts. In some respects, R 13 It is phenyl. In some respects, R 13 It is a substituted phenyl group.

[1057] Compounds of formulas (VIIA) and (VIIB) and embodiments thereof, including compounds of formulas (VIIC) and (VIID), are available as inhibitors of MASP-2 and for therapeutic use. Compounds of formulas (VIIA) and (VIIB) and embodiments thereof are available for treating MASP-2-related diseases and conditions, and for preparing medicaments for treating MASP-2-related diseases and conditions. This disclosure also provides methods for treating MASP-2-related diseases and conditions, comprising administering to a patient a therapeutically effective amount of compounds of formulas (VIIA) and (VIIB) or embodiments thereof, optionally in salt form.

[1058] In some embodiments, compounds of formulas (VIIA) and (VIIB) or embodiments thereof are provided as pharmaceutical compositions comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[1059] In some aspects, the compound is one or more compounds selected from formulas (VIIA) and (VIIB) in the examples, including compounds listed in Table 31, such as compounds selective for MASP-2 relative to thrombin. In some aspects, R 1 R a R b R 2a R 2b R 3 R 4 R 5 R 6 Or R 13 One or more of the corresponding substituents selected from the compounds of formulas (VIIA) and (VIIB) in the examples, said compounds including those listed in Table 31, preferably those compounds that are selective for MASP-2 relative to thrombin.

[1060] In some aspects, the present invention proposes stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more chiral centers). Unless otherwise specifically indicated, for any inventive compound having one or more stereocenters, the present invention is intended to include and describe pure (+) and (-) enantiomers, any other diastereomers, mixtures rich in enantiomers or diastereomers (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[1061] In some aspects, the present invention proposes pharmaceutically acceptable salts (e.g., hydrohalides, such as hydrochlorides or dihydrochlorides) with the chemical structures shown. Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. These include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, aryl sulfonates, alkyl sulfonates, salts of fatty acids, etc. Salts can be prepared by various methods known to those skilled in the art (including precipitation with conjugate acids or bases) (e.g., treatment with gaseous HCl or HCl solution).

[1062] In some respects, the present invention proposes prodrugs. A prodrug is a compound that is normally converted into its biologically active form (e.g., ester to acid form; carbamate to amino or hydroxyl form; hydroxymididine to amididine form) under physiological conditions through hydrolysis, oxidation, or reduction. Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; and Peterlin-Masic et al., Curr. Pharma. Design 2006, 12, 73-91. Amididine-group prodrugs include amidothimes, O-alkyl amidothimes, acylmididines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[1063] In some aspects, the compound can be used to selectively inhibit MASP-2 relative to thrombin, the method comprising administering the compound described herein. In some aspects, the MASP-2:thrombin selectivity ratio is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[1064] F. Compounds defined by reference to the rules of combination

[1065] In some respects, this disclosure provides compounds having MASP-2 inhibitory activity, particularly for therapeutic purposes. These compounds with MASP-2 inhibitory activity interact with the MASP-2 serine protease domain in the enzyme-inhibitor complex using a variety of intermolecular interactions. In some respects, molecules are described using empirically derived rule sets, such as interaction rule sets, with complete specificity and a description based on the number and type of intermolecular interactions within the MASP-2 binding site.

[1066] In some respects, compounds possessing MASP-2 inhibitory activity interact with the MASP-2 serine protease domain, which is an enzyme-inhibitor complex. These compounds possessing MASP-2 inhibitory activity have 1 to 100 intermolecular interactions with themselves and MASP-2, for example, with residues 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, and 51 of the MASP-2 serine protease domain (residues 445-686 of SEQ ID NO: 1). 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. These intermolecular interactions can be hydrogen bonds, ionic bonds, electrostatic bonds, π-π interactions, van der Waals interactions, the binding of water molecules, or combinations thereof. Count the number of each type of intermolecular interaction to obtain the total.

[1067] In some respects, multiple intermolecular interactions of the same type exist. For example, enzyme-inhibitor complexes can have 1-40 hydrogen bonds, 1-40 ionic bonds, 1-40 electrostatic bonds, 1-40 π-π interactions, 1-40 van der Waals interactions, 1-40 water molecule bonds, and combinations thereof, where each of the above 1-40 ranges refers to 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 some respects, multiple or various intermolecular interactions with the same amino acid within the binding site may exist.

[1068] In some cases, inhibitory molecules are described by a set of rules. Compounds with MASP-2 inhibitory activity interact with the MASP-2 serine protease domain in the enzyme-inhibitor complex using a variety of intermolecular interactions or rules. In some respects, molecules are described by their complete structural and functional specificity, as well as by the number and type of intermolecular interactions. These rules have been empirically derived and discovered using crystallization data from a certain number of enzyme-inhibitor complex cocrystals. In some cases, the crystallization data comes from at least 1, 10, 20, 30, 40, 50, or up to 100 enzyme-inhibitor complex crystals. For example, 30 cocrystals can be used, 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, or 30 or even more enzyme-inhibitor complex crystals can be used to generate a set of rules. Using eutectic structure information, binding sites and inhibitory compounds can be described in detail and within limits at the angstrom level.

[1069] In some cases, multiple amino acids within the MASP-2 serine protease domain participate in intermolecular interactions. The amino acids within the MASP-2 serine protease domain (amino acid residues 445-686 of SEQ ID NO:1) 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, MET658, TYR 669, ASN 659, CYS 660, and GLN 665.

[1070] In some respects, the number of amino acids in the serine protease domain that interacts with compounds having MASP-2 inhibitory activity or constitutes a regular set is approximately 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 in the MASP-2 serine protease domain.

[1071] In some cases, the inhibitors of this disclosure bind to MASP-2, thereby inactivating MASP-2. The amino acids of MASP-2 interact with the inhibitory compounds through intermolecular interactions, and the types of these interactions are described in more detail below.

[1072] In some respects, the type of interaction includes hydrogen bonds (H-bonds). The enzyme-inhibitor complex may include 1-40 intermolecular H-bonds with one or more of the following eight amino acids: ASP 627, SER 628, SER 654, GLY 656, GLN665, ARG 630, PRO 606, and SER 657. The enzyme-inhibitor complex may also include 1-40 intermolecular H-bonds with one or more of the following six amino acids: ASP 627, SER 628, SER 654, GLY 656, GLN 665, ARG 630, PRO 606, and SER 657. These 1-40 intermolecular H-bonds may include one or more inhibitor atoms and 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 may include one or more inhibitor atoms and one or more atoms of ASP 627, SER 628, SER 654, GLY 656, GLN 665, and SER 657. Each amino acid may have more than one H-bond interaction with the inhibitor. In some cases, the same atom may hydrogen bond to one or more ligands. In other words, a single atom of the inhibitor molecule may interact with two or more atoms on the protein. In some cases, each unit compound has 1-10 H-bonds, or 2-8 H-bonds, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 H-bonds.

[1073] In some respects, the types of interactions include ionic and / or electrostatic interactions. An enzyme-inhibitor complex may include 1-10 intermolecular ionic and / or electrostatic interactions with ASP 627 or ARG 630. An enzyme-inhibitor complex may include 1-10 intermolecular ionic and / or electrostatic interactions with ASP 627. ASP 627 may have more than one ionic and / or electrostatic interaction with the inhibitor.

[1074] In some other respects, the type of interaction is the binding of water molecules to ASP 627, GLN 665, SER 657, ASN659, SER 628, GLU 662, ARG 630, VAL 668, TYR 602, and TYR 607. The enzyme-inhibitor complex may comprise 1-30 (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) water molecules bound to various amino acids, other water molecules, or water molecules bound to the compound or combinations thereof.

[1075] In some other cases, the type of interaction includes one or more (e.g., multiple or 1-40) π-π interactions with one or more (1, 2, or 3 amino acids) of the following amino acids: PHE 529, TYR 607, and / or TRP 655. Each of the above amino acids may have more than one π-π interaction.

[1076] In some respects, the types of interactions also include one or more (e.g., 1-40) with ALA 468, ALA469, 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, ARG 630, GLY 631, ASP 632, SER 633, GLY634, GLY635, VAL 653, SER 654, TRP 655, GLY656, SER 657, MET 658, ASN 659, CYS 660, GLN 665, GLY 667, TYR 669 and its combination of van der Waals interactions, which are specific MASP-2 amino acids within the serine protease domain of MASP-2.

[1077] In some respects, the types of interactions also include one or more (e.g., 1-40) van der Waals interactions with HIS 483, PHE529, 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 are specific MASP-2 amino acids within the serine protease domain of MASP-2.

[1078] In some respects, the MASP-2 inhibitory compound may be a compound described elsewhere herein, including compounds of formula (I), (II), (III), (IV), (V), (VI), or (VII) or any embodiment thereof.

[1079] In some respects, compounds with MASP-2 inhibitory activity include compounds of formula (VIII):

[1080]

[1081] In some aspects, the compounds of this disclosure may have five segments, referred to as M1, M2, M3, M4, and M5. These segments or regions bind to the active binding site of MASP-2. In some aspects, the various segments bind to the active site using affinity. The inhibitor recognition site or pocket includes the binding site of the inhibitor. Using the Schechter and Berger nomenclature, P1–P1' denote the cleavable peptide residues of the substrate (inhibitor), while S1–S1' denote the corresponding enzyme-binding pockets of these segments. The inhibitor-MASP-2 interaction extends beyond the S1 site and includes additional binding of the inhibitor to MASP-2. In one aspect, M1–M5 may bind substantially to one or more binding pockets of MASP-2. These binding pockets correspond to S1', S1, S2, S3, and S4'.

[1082] In some respects, this disclosure provides compounds, wherein M1 is selected from the following:

[1083] Among them, each R 1 It is independently selected from the following members: C1-C6 alkyl, hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino and halogen (e.g. chlorine);

[1084] Each n is an independent integer selected from 0 to 4;

[1085] R 7 It is selected from the following members: hydrogen, hydroxyl, and C1-C6 alkyl; and

[1086] R 8 It is selected from the following members: hydrogen and C1-C6 alkyl.

[1087] In some respects, the M5 has the following characteristics:

[1088]

[1089] R 5 Members selected from the group consisting of: C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and having 0 to 3 R groups. 13 C7-C of substituents 12 arylalkyl or heteroarylalkyl; or R 5 and R 6 Combined to form 0 to 3 R 13 Heterocyclic compounds with substituents;

[1090] R 6 It is selected from the following members: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxyl (C1-C6 alkyl), having 0 to 3 R groups. 13 C7-C of substituents 12 Arylalkyl or heteroarylalkyl, amino (C1-C8 alkyl) and amide (C1-C8 alkyl); or R 6 and R 5 Combined to form 0 to 3 R 13 Heterocyclic compounds with substituents; and

[1091] Each R 13 For independently selected members of the group consisting of: C1-C6 alkyl, C6-C 10 Aryl, carboxyl (C1-C6 alkyloxy), heteroaryl, heterocyclic, hydroxyl, hydroxyl (C1-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amide, C1-C6 alkylamino, and halogen; or two R groups. 13 Groups combine to form fused C6-C 10 Aryl, C6-C 10 Heteroaryl or C5-C7 cycloalkyl ring.

[1092] In some respects, M 2-4 It has the following formula:

[1093]

[1094] Where R 3For members selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxyl (C1-C6 alkyl); or R 3 and R 4 Combined to form a nitrogen-containing heterocyclic butane, pyrrolidine, or piperidine ring; and

[1095] R 4 For members selected from the group consisting of: hydrogen and C1-C6 alkyl; or R 4 and R 3 They combine to form nitrogen-containing heterocyclic butanes, pyrrolidines, or piperidine rings.

[1096] In some respects, compounds of formula VIII that possess MASP-2 inhibitory activity have the following formula VIIIA:

[1097]

[1098] Various interactions between compounds of formula VIIIA and the active site of MASP-2 can exist as shown in schemes 1 and 2 below:

[1099]

[1100]

[1101] Segment M1 of the compound of formula (VIIIA) may have an interaction, which is an ionic interaction between the carboxyl group of ASP 627 and the positive (protonable group) moiety in the compound of formula (VIIIA). For example, as shown above, the nitrogen on the amidine can be a protonable moiety and interact with ASP 627 by an ionic bond.

[1102] In some other aspects, regarding hydrogen bonding analysis, certain compounds of this disclosure interact with one or more of the following amino acids in MASP-2 via intermolecular hydrogen bonding: ASP 627, SER 628, SER 654, GLY656, GLN 665, ARG 630, PRO606, SER 633, CYS660, and SER 657. In some aspects, said compounds interact with one or more of the following acids in MASP-2 via intermolecular hydrogen bonding: ASP 627, SER 628, SER 654, GLY 656, GLN 665, and SER 657.

[1103] In some respects, the compound is bound by H-bonds to 1, 2, 3, 4, 5, or all of the following residues: ASP 627, SER 628, SER 654, GLY 656, GLN 665, ARG 630, PRO606, SER 633, CYS660, and SER 657. Each amino acid may have more than one H-bond. In some respects, the number of hydrogen bonds between the inhibitory molecule and the active site can be 1-40. In some respects, an amino acid (e.g., GLY 656) may have more than one hydrogen bond. The compounds disclosed herein may have about 1 to about 10 hydrogen bonds, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 H-bonds.

[1104] Generally speaking, although crystal structure information does not directly show or detect hydrogen bonding, the LigPlot+ software used to describe eutectic structure information does include algorithms that assess (or “predict”) the presence of such H-bonds based on, for example, bond distance. Therefore, throughout the disclosure, when H-bonds are considered to be present and described, it can be said that they have been assessed as present by the software based on crystallographic data.

[1105] In some respects, the compound binds to ASP 627 or ARG 630 via ionic or electrostatic interactions or hydrogen bonding. In some respects, the compound does not bind to ASP 627 or ARG 630 via ionic interactions. In some respects, the compound does bind to ASP 627 via ionic or electrostatic interactions or hydrogen bonding. In some respects, the compound does not bind to ASP 627 via ionic interactions. In some respects, the compound binds to ASP 627 via ionic interactions.

[1106] As shown above, a hydrogen atom from the compound of formula (VIIIA) in segment M1 is hydrogen-bonded to SER 628, and another hydrogen atom from the compound is hydrogen-bonded to SER 657. Furthermore, the hydrogen atom on SER 628 and another hydrogen atom on SER 657 are hydrogen-bonded to nitrogen atoms in the compound of segment M1. Generally, a hydrogen bond is a partial electrostatic attraction between a hydrogen atom (H) bonded to a more electronegative atom such as nitrogen (N) or oxygen (O) and another adjacent atom with a lone pair of electrons.

[1107] As shown, in some respects, atoms in segment M3 interact with SER 654. In some respects, atoms in segment M3, such as nitrogen, are hydrogen-bonded with SER 654. Furthermore, in some respects, atoms in M3, such as nitrogen, act as both hydrogen bond acceptors and donors when interacting with GLY 656. On the other hand, atoms in segment M3, such as oxygen, interact with water molecules.

[1108] In some respects, inhibitory compounds interact with water molecules. Water molecules can bind to both the compound and amino acid residues, only the compound, only the amino acid, or a combination thereof. Water molecules can be bridged by binding M1 to 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, and VAL 668.

[1109] In some respects, the M4 segment of the compound interacts with either TYR 607 and / or PHE 529 and near TRP 655 via π-π stacking interactions. In other respects, the compound interacts with one, two, three, or all of the following residues via π-π interactions: PHE 529, TYR 607, and TRP 655. In some respects, edge-face π-π interactions or T-type interactions are present.

[1110] In some other respects, in order to minimize interactions with serine proteases other than MASP-2, such as thrombin, the large aromatic group of the M4 segment of the compound increases the specificity of MASP-2 relative to thrombin.

[1111] In some other respects, in order to minimize interactions with serine proteases other than MASP-2, such as thrombin, the methylated chlorozaindole M1 segment of the compound increases its specificity for MASP-2 relative to thrombin.

[1112] In some other respects, in order to minimize interactions with serine proteases other than MASP-2, such as thrombin, large substituents, such as glutamine acyl derivatives, or small substituents, such as fluorine on the carbon of glycine or substituents on the nitrogen atom of the central glycine of the M3 moiety, increase the specificity of thrombin for MASP-2.

[1113] In some other respects, in order to minimize interactions with serine proteases other than MASP-2, such as thrombin, the planar aromatic groups such as 5-membered rings such as pyrazoles in the M3 region and M4 segment of the linker compound increase the specificity of MASP-2 relative to thrombin.

[1114] In some respects, the compound is bound to two residues via three H-bonds: SER 654 and GLY 656. In some respects, GLY 656 has two (2) H-bonds. For example, in some cases, only three hydrogen bonds exist between the compound and the active site of MASP-2. In some respects, π-π stacking interactions (T-type or edge-face) can occur with TYR 607 or PHE 529 and near TRP 655. In other respects, there are no ionic bonds between the inhibitory compound and the active site of MASP-2. In other respects, there are ionic bonds between the inhibitory compound and the active site of MASP-2.

[1115] In some respects, Figure 1-57 The images show certain amino acids of MASP-2 with radiating arcs to show interactions with atoms of the inhibitors of this disclosure, such as van der Waals interactions.

[1116] In some respects, the compound interacts via van der Waals contacts with residues 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, TRP655, GLY656, SER 657, MET 658, ASN. 659, CYS 660, GLN 665, GLY 667, TYR 669 and their combinations.

[1117] In some respects, the compound interacts with residues 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 via van der Waals contacts: GLY 667, SER 657, GLY 656, TRP 655, SER654, 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.

[1118] Figure 1-57 2D ligand-MASP-2 interaction diagrams representing specific compounds of this disclosure. These diagrams are schematic representations of atoms from various compounds and atoms of MASP-2 amino acids, calculated using models derived from the co-structures of the corresponding crystalline MASP-2 compounds with hydrogen bond calculation parameters set by LigPlot++ software. The atoms of the amino acids interacting with the compound atoms and the compound atoms with sufficient 2fo-fc electron density based on crystallographic data are depicted. MASP-2 amino acid residue numbers (MASP-2AA#) are based on Uniprot accession number O00187, and amino acid atom numbers (AA atoms) are based on conventions established for protein databases and correspond to those in Table A1 (Appendix). Hydrogen bonds and polar contacts are depicted as dashed lines, with distances provided in angstroms.

[1119] Turn now Figure 1 An example of how the MASP-2CCP2-SP amino acid interacts with (1129) via hydrogen bonds.

[1120]

[1121] As shown, there are six distinct hydrogen bonds between the (1129) compound atoms and the MASP-2 amino acid residue atoms. Furthermore, a total of four water molecules are shown within the crystal structure in this region of the active site, two of which appear to participate in hydrogen bonding, either bonded to one or more atoms of the (1129) compound, or act as bridging water molecules between specific (1129) compound atoms and MASP-2 amino acid residue atoms. As shown, amidine nitrogen N19 interacts with the oxygen OD1 of ASP 627 as a hydrogen bond donor. As used herein, when nitrogen is stated as a “hydrogen bond donor,” it means that hydrogen (H) bonded to a more electronegative atom, such as nitrogen (N), is electrostatically attracted to a neighboring atom with a lone pair of electrons, such as oxygen. Nitrogen N19 also interacts with the oxygen of SER628 as a hydrogen bond donor. Additionally, amidine N20 interacts with the oxygen OE1 of GLN 665 and the O of SER657 as a hydrogen bond donor. The nitrogen N10 of the amide bond acts as a donor, interacting with the oxygen of SER 654 via H-bonding. Furthermore, oxygen O07 acts as a hydrogen bond acceptor, interacting with the nitrogen of GLY 656 via H-bonding. Similarly, as stated above, when oxygen acts as a "hydrogen bond acceptor," it means that hydrogen (H) bonded to a more electronegative atom, such as nitrogen (N), is electrostatically attracted to or "accepted" by an adjacent atom carrying a lone pair of electrons, such as oxygen. Oxygen O08 interacts with water molecules near TRP 655. The oxygen of O26 interacts with water molecules, as does the secondary amine N21, while the same water molecules further interact with the oxygen O3 of the nearby buffer molecule succinic acid (Sin1). Additionally, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1122]

[1123] Figure 2 This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1034) via hydrogen bonds. As shown, there are seven distinct hydrogen bonds 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. Amidine nitrogen N19 acts as a hydrogen bond donor interacting with the oxygen at SER657. N19 also acts as a hydrogen bond donor interacting with the oxygen at OE1 at GLN665. Nitrogen N20 acts as a hydrogen bond donor interacting with the oxygen at OE1 at GLN665, the oxygen at SER628, and the OD1 oxygen at ASP627. Nitrogen N10 acts as a donor interacting with the oxygen at SER654 via H-bonding. Oxygen O07 acts as an acceptor interacting with the nitrogen at GLY656 via H-bonding. Furthermore, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1124]

[1125] Figure 3 This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1024) via hydrogen bonds. As shown, there are five distinct hydrogen bonds between the atoms of the (1024) compound and the MASP-2 residue atoms. Furthermore, a total of six water molecules are shown within the crystal structure at the depicted active sites, four of which are shown to participate in hydrogen bonding, or bonded to one or more atoms of the (1024) compound, or act as bridging water molecules between specific (1024) compound atoms and MASP-2 amino acid residue atoms. As shown, O2 (oxygen) acts as a hydrogen bond acceptor interacting with nitrogen at GLY 656. Nitrogen N1 interacts with two distinct water molecules near TRP655, one of which also interacts with oxygen O1. Nitrogen N2 interacts with another water molecule. Nitrogen N3 acts as a hydrogen bond donor interacting with oxygen at SER 654. Amidine nitrogen N4 acts as a donor interacting with oxygen at SER628 via H-bonding, and as a donor interacting with OD2 oxygen at ASP 627 via H-bonding. Another amidine nitrogen N5 acts as a hydrogen bond donor, interacting with the oxygen in SER 657 and with nearby water molecules. The same water molecules that interact with nitrogen N5 also interact with the oxygen OG in SER 657 and the oxygen in GLN 665 via hydrogen bonds, and act as bridging water molecules with the oxygen OD2 in ASP 627.

[1126] In addition, the compound binds to ASP 627 via ionic or electrostatic interactions (not shown).

[1127]

[1128] Figure 4This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1059) via hydrogen bonds. As shown therein, there are eight distinct H-bonds between the (1059) compound atoms and the MASP-2 residue atoms. Furthermore, a total of six water molecules are shown included within the crystal structure at the depicted active sites, four of which are shown to participate in hydrogen bonding, either bonded to one or more atoms of the (1059) compound, or acting as bridging water molecules between specific (1059) compound atoms and MASP-2 amino acid residue atoms. As shown therein, the amine nitrogen N6 of the benzimidazole moiety acts as a donor to form hydrogen bonds with the OD2 oxygen of ASP 627, the oxygen of GLN665, and the oxygen OG of SER 657. Nitrogen N6 can also interact with water molecules. The same water molecules that interact with nitrogen N6 also act as bridging water molecules to interact with the oxygen OG of SER 657 and the oxygen of ASN 659. The hydrogen atoms of benzimidazole can interconvert between N4 and N5. Despite having only one hydrogen atom, the software shows that benzimidazole nitrogen N4 acts as an H-bond donor interacting with the oxygen OD1 of ASP 627, and another imidazole nitrogen N5 acts as a hydrogen bond donor interacting with the oxygen of SER 657. Nitrogen N1 acts as a hydrogen bond donor interacting with the oxygen of SER 654. Oxygen O1 interacts with a nearby water molecule, which is a bridging water molecule that further interacts with nitrogen NH1 (surrounding cross) of ARG 630 and nitrogen N3 of (1059). N3 nitrogen acts as a hydrogen bond donor interacting with another water molecule near TRP 655 and the oxygen of GLY 656. Oxygen O2 acts as a hydrogen bond acceptor interacting with nitrogen of GLY 656. N2 nitrogen interacts with a water molecule near PHE 529. In addition, the compounds bind to ASP627 (not shown) via ionic or electrostatic interactions. The molecular label So41 indicates the sulfate ion.

[1129]

[1130] Figure 5This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1088) via hydrogen bonds. As shown therein, there are five distinct hydrogen bonds between the atoms of the (1088) compound and the atoms of the MASP-2 amino acid residues. Furthermore, 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 involved in hydrogen bonding with compound (1088), or with one or more atoms of (1088), or as bridging water molecules between specific (1088) compound atoms and MASP-2 amino acid residue atoms. As shown therein, nitrogen N31 (the primary amine nitrogen of the isoquinoline moiety) interacts as a hydrogen bond donor with the OG oxygen of SER 628 and the OD1 oxygen of ASP 627. N31 nitrogen also interacts with nearby water molecules. The same water molecules interacting with nitrogen N31 also interact as bridging water molecules with the OG oxygen of SER 628 and the oxygen of VAL 668. The nitrogen N29 of the isoquinoline ring acts as a donor, forming a hydrogen bond with the oxygen OD2 of ASP 627 and also forming contact with nearby water molecules. The same water molecule interacting with N29 also acts as a bridging water molecule, interacting with the oxygen OD2 of ASP 627, the nitrogen and oxygen OG of SER 657, and the oxygen atom of GLN665. Nitrogen N01 acts as a hydrogen bond donor, interacting with the oxygen of SER 654. Nitrogen N05 interacts with water molecules near GLY 656 and PHE 529, and oxygen O03 also interacts with two distinct water molecules located between PHE 529 and SER 654. Oxygen O07 acts as a hydrogen bond acceptor, interacting with the nitrogen of GLY 656. Nitrogen N18 interacts with two distinct water molecules, one of which also acts as a bridging water molecule, interacting with the nitrogen NH1 of ARG 630. Furthermore, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1131]

[1132] Figure 6This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1036) via hydrogen bonds. As shown, there are six distinct hydrogen bonds between the (1036) compound atoms and the MASP-2 residue atoms. Furthermore, a total of four water molecules are shown to be included within the crystal structure, three of which are shown to participate in hydrogen bonding, either bonded to one or more atoms of the (1036) compound, or act as bridging water molecules between specific (1036) compound atoms and MASP-2 amino acid residue atoms. As shown, amidine nitrogen N26 acts as a hydrogen bond donor interacting with the oxygen of SER 657. Nitrogen N26 also interacts with water molecules. The same water molecules interacting with nitrogen N26 also act as bridging water molecules interacting with the oxygen OG of SER 657, the oxygen of ASN 659, the oxygen of GLN 665, and the oxygen OD2 of ASP 627. Additionally, amidine N27 acts as a donor forming hydrogen bonds with the oxygen OD2 of ASP 627 and the oxygen of SER 628. Nitrogen N17 acts as a hydrogen bond donor, interacting with the oxygen in SER 654, and oxygen O16 interacts with the water molecule located between ARG 630 and SER 654. Oxygen O29 acts as a hydrogen bond acceptor, interacting with the nitrogen in GLY 656, and the nitrogen NO3 in the pyrrolidine moiety interacts with the water molecule. Furthermore, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1133]

[1134] Figure 7 This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1081) via hydrogen bonds. As shown therein, there are four distinct hydrogen bonds between the atoms of the (1081) compound and the atoms of the MASP-2 amino acid residues. Furthermore, it is shown that a single water molecule is included within the crystal structure, exhibiting its role as a water molecule in hydrogen bonding, bridging between one atom of the compound and multiple MASP-2 amino acid residue atoms. As shown therein, amidine nitrogen N26 acts as a hydrogen donor interacting with the oxygen atom of SER 657. Nitrogen N26 also interacts with water molecules. The same water molecule interacting with nitrogen N26 also acts as a bridging water molecule interacting with the oxygen OG of SER 657, the oxygen atom of GLN665, the oxygen atom of ASN 659, and the oxygen OD2 of ASP 627. Another amidine nitrogen N27 acts as a hydrogen bond donor interacting with the oxygen atom of SER 628. Nitrogen N17 interacts with the oxygen in SER 654 as a hydrogen bond donor, and nitrogen NO3 interacts with the oxygen in GLY 656 as a hydrogen bond donor. Furthermore, the compounds bind to ASP 627 (not shown) via ionic or electrostatic interactions.

[1135]

[1136] Figure 8This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1063) via hydrogen bonds. As shown, there are four distinct hydrogen bonds between the (1063) compound atom and the MASP-2 amino acid residue atom. Furthermore, a total of two water molecules are shown to be included within the crystal structure, one of which is shown to participate in a hydrogen bond with one atom of the (1063) compound. As shown, amidine nitrogen N5 acts as a hydrogen bond donor interacting with the oxygen at SER 657, and another amidine nitrogen N4 acts as a hydrogen bond donor interacting with the oxygen at SER 628. Nitrogen N3 acts as a hydrogen bond donor interacting with the oxygen at SER 654, oxygen O2 interacts with the nearby water molecule, and oxygen O1 acts as a hydrogen bond acceptor interacting with the nitrogen at GLY 656. Additionally, the compound binds to ASP 627 via ionic or electrostatic interactions (not shown).

[1137]

[1138] Figure 9 This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1065) via hydrogen bonds. As shown therein, there are four distinct hydrogen bonds between the (1065) compound atoms and the MASP-2 residue atoms. Furthermore, a total of seven water molecules are shown to be included within the crystal structure, five of which are shown to participate in hydrogen bonding, either bonded to one or more atoms of the (1065) compound, or acting as bridging water molecules between specific (1065) compound atoms and MASP-2 amino acid residue atoms. As shown therein, amidine nitrogen N28 interacts with two distinct bridging water molecules, one of which further interacts with the oxygen atom of SER657, while the second water molecule interacts with the nitrogen atom of SER 657, the oxygen OH of TYR 602, the oxygen atom of GLN 665, and the oxygen OD2 of ASP 627. Nitrogen N28 also acts as a donor to form a hydrogen bond with the oxygen OD2 of ASP 627. Another amidine nitrogen N29 acts as a hydrogen bond donor to interact with the OD1 oxygen of ASP 627. Nitrogen N29 also interacts with nearby water molecules, which bridge the gap between N29, the oxygen atom of VAL 668, and the oxygen OG of SER 628. Nitrogen N14 acts as a hydrogen bond donor, interacting with the oxygen atom of SER 654, and oxygen O13 interacts with water molecules. The same water molecule interacting with O13 also acts as a bridging water molecule, interacting with the oxygen atom of ARG 630. Oxygen O09 acts as a hydrogen bond acceptor, interacting with the nitrogen of GLY 656, and the nitrogen N06 of the piperidine moiety interacts with nearby water molecules. Furthermore, the compounds bind to ASP 627 (not shown) via ionic or electrostatic interactions.

[1139]

[1140] Figure 10 This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1030) via hydrogen bonds. As shown, there are five distinct H-bonds between the (1030) compound atoms and the MASP-2 atoms. Furthermore, a total of three water molecules are shown to be included within the crystal structure, with two water molecules exhibiting involvement in hydrogen bonding with two distinct atoms of the compound. As shown, amidine nitrogen N4 acts as a hydrogen bond donor interacting with the oxygen at SER 657, and another amidine nitrogen N5 acts as a hydrogen bond donor interacting with the oxygen at SER 628. Nitrogen N3 acts as a hydrogen bond donor interacting with the oxygen at SER 654, oxygen O1 interacting with a water molecule near PHE 529, and nitrogen N2 interacting with another nearby water molecule. Oxygen O2 acts as a hydrogen bond acceptor interacting with the nitrogen at GLY 656, while the nitrogen N1 of the pyrrole moiety acts as a hydrogen bond donor interacting with the oxygen at GLY 656. Additionally, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1141]

[1142] Figure 11 This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1037) via hydrogen bonds. As shown, there are four distinct hydrogen bonds between the (1037) molecular atoms and the MASP-2 amino acid residue atoms. The figure does not depict the presence of any water molecules in the crystal structure. Amidine nitrogen N18 acts as a hydrogen bond donor, interacting with the oxygen of SER 657. Another amidine nitrogen N19 acts as a donor, forming a hydrogen bond with the oxygen OD2 of ASP 627. Nitrogen O9 acts as a hydrogen donor, interacting with the oxygen of SER 654, and oxygen O04 acts as a hydrogen acceptor, interacting relatively weakly with the nitrogen of GLY 656. Furthermore, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1143]

[1144] Figure 12This is an example of the interaction between the MASP-2CCP2-SP amino acid and (1118) via hydrogen bonds. As shown, there are five distinct hydrogen bonds between the (1118) atom and the MASP-2 amino acid atom. Furthermore, a total of 17 water molecules are shown included within the crystal structure, five of which are shown to participate in hydrogen bonding, either bonded to a single atom of the (1118) compound or acting as bridging water molecules between specific (1118) compound atoms and MASP-2 amino acid residue atoms. As shown, one of the amidine nitrogens, N4, interacts as a hydrogen bond donor with the oxygen atom of SER 657. Nitrogen N4 also interacts with bridging water molecules that bridge between N4, the oxygen OG of SER 657, the oxygen atom of GLN 665, the oxygen OD2 of ASP 627, and the oxygen atom of ASN 659. Another amidine nitrogen, N5, interacts as a hydrogen bond donor with the oxygen OG of SER 628. Nitrogen (N3) acts as a donor, forming a hydrogen bond with the oxygen atom in SER 654, while oxygen (O2) interacts with two distinct water molecules near PHE 529. Nitrogen (N2) also interacts with nearby water molecules. Oxygen (O1) acts as a hydrogen bond acceptor, interacting with the nitrogen atom in GLY 656, while nitrogen (N1) acts as a hydrogen bond donor, interacting with the oxygen atom in GLY 656. Nitrogen (N1) also interacts with water molecules.

[1145] In addition, the compound binds to ASP 627 (not shown) via ionic or electrostatic interactions.

[1146] [1147...

Claims

1. Use of a compound of formula (I-1) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting MASP-2 in a subject, wherein formula (I-1) is: in: Cy 1A is unsubstituted or substituted C 6-10 Aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein Cy 1A The ring atoms of the 5-10 membered heteroaryl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein Cy 1A The substituted C 6-10 The aryl or substituted 5-10 membered heteroaryl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1A , halogen, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R Cy1A Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1A The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein R Cy1A C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein R Cy1A C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R 11 and R 12 Together with the groups to which they are attached, they form a 4-6 membered heterocycloalkyl ring; A 11 CR 13 R 15 or NH, N-naphthyl, N-benzyl or N-(2-methyl)benzyl; and Each R 13 Independently for Cy 1B , (CR 13A R 13B ) n3 Cy 1B , (C 1-6 Alkylene)Cy 1B , (C 2-6 Cy 1B , (C 2-6 Alkynylidene)Cy 1B or OCy 1B , where R 13 C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 The alkynylene moiety is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R 14 Independently selected from H and C 1-6 Alkyl, and R 15 Selected from H, R 13 , C 1-6 Alkyl and OH, or A pair of R connected to adjacent carbon atoms 14 A group or a pair of R connected to adjacent carbon atoms 14 and R 15 The group can, independently of R 14 The other occurrences of R are replaced by bonds connecting adjacent carbon atoms to the pair of R 14 A group or a pair of R 14 and R 15 The adjacent carbon atoms are connected by double bonds, and each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A pair of R attached to the same carbon atom 14 A group or a pair of R attached to the same carbon atom 13 and R 15 The group can, independently of R 14 The other occurrences, connected with the pair R 14 A group or a pair of R 13 and R 15 The carbon atoms of the group together form a spiro-fused C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the spiro-fused C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A pair of R connected to adjacent carbon atoms 14 A group or a pair of R connected to adjacent carbon atoms 14 and R 15 The group can, independently of R 14 The other occurrences, connected with the pair R 14 A group or a pair of R 14 and R 15 The adjacent carbon atoms of the group are joined together to form a fused C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the fused C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A group of four R attached to two adjacent carbon atoms 14 A group or a group of two R attached to two adjacent carbon atoms 14 , an R 13 and an R 15 The group can, independently of R 14 The other occurrences, connected with the set of four R 14 A group or a set of two R 14 , an R 13 and an R 15 Two adjacent carbon atoms of a group are joined together to form a fused C 6-10 Aryl or 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the formed 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, and wherein the formed fused C 6-10 Aryl or 5-10 membered heteroaryl, C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; and n1 is 1 or 2; and n2 is 0, 1 or 2; and The condition is that the sum of n1 and n2 is 1, 2 or 3; and The condition is that if n1 is 1 or n2 is 0, then A 11 CR 13 R 15 ; and n3 is 0, 1 or 2; and Each R 13A independently H or C 1-6 Alkyl; and Each R 13B independently H or C 1-6 Alkyl; or R attached to the same carbon atom 13A and R 13B , independent of any other R 13A and R 13B groups, which can come together to form –(CH2) 2-5 -, thereby forming a 3-6 membered cycloalkyl ring; and Cy 1B is unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein Cy 1B The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and The formation of Cy 1B The substituted C 6-10 Aryl, substituted 5-10 membered heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1B , halogen, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R Cy1B Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1B The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein R Cy1B C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and wherein R Cy1B C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R 16 H, Cy 1C , C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, which forms R 16 C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from Cy 1C 、Halogen、CN、OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, provided that not more than one R 16 The substituent is Cy 1C ;and Cy 1C is unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein Cy 1C The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and The formation of Cy 1C The substituted C 6-10 Aryl, substituted 5-10 membered heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1C , halogen, C 1-6 Haloalkyl, CN, OR a11 , S Ra11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Among them, each R Cy1C Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1C The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein R Cy1C C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and wherein R Cy1C C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R a11 and R b11 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Alkyl, which forms R a11 and R b11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; and R c11 and R d11 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Alkyl, which forms R c11 and R d11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; or R attached to the same N atom c11 and R d11 Together with the N atom to which they are both attached, they form a 4-, 5-, 6- or 7-membered heterocycloalkyl or a 5-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; and R a12 and R b12 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Alkyl, which forms R a12 and R b12 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; and R c12 and R d12 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Alkyl, which forms R c12 and R d12 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; or R attached to the same N atom c12 and R d12 Together with the N atom to which they are both attached, they form a 4-, 5-, 6- or 7-membered heterocycloalkyl or a 5-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; and R e11 and Re 12 Each is independently H, CN or NO2.

2. The method of claim 1, wherein the compound has formula (I-2):

3. The use of claim 1, wherein Cy 1A By at least one OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 or C(=NR e11 )NR c11 C(O)OR a11 replace.

4. The use of claim 1, wherein Cy 1A Having any of the following formulas: Among them, each R Cy1A , R a11 and R b11 independently H or C 1-6 alkyl.

5. The use of claim 1, wherein Cy 1A Having any of the following formulas: Each R connected to a carbon atom Cy1A Independently for C 1-6 alkyl, halogen or amino, and each R connected to the carbon nitrogen atom Cy1A H or C 1-6 alkyl.

6. The use according to claim 1, wherein the compound is according to any one of the following formulas (I-3) to (I-9):

7. The use of claim 1, wherein the compound is according to any one of the following formulas (I-9a) to (I-9z):

8. The use of claim 7, wherein R 13 Cy 1B 、CH2Cy 1B 、CH2CH2Cy 1B or OCy 1B , and Cy 1B is substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5-10 membered heteroaryl.

9. The use of claim 8, wherein Cy 1B is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1B , halogen and C 1-6 Haloalkyl; Among them, each R Cy1B Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 6-10 Aryl or 5-10 membered heteroaryl, wherein R Cy1B C 6-10 The aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents, each of which is independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and haloalkyl.

10. The use according to claim 1, wherein the compound is according to any one of the following formulas (I-8a) to (I-8z):

11. The use according to claim 10, wherein R 13 Cy 1B 、CH2Cy 1B 、CH2CH2Cy 1B or OCy 1B , and Cy 1B is substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted 5-10 membered heteroaryl.

12. The use of claim 11, wherein Cy 1B is substituted by 1 or 2 substituents, each of which is independently selected from R Cy1B , halogen, C 1-6 Haloalkyl, CN, OR a11 and NR c11 C(O)R b11 ; Among them, each R Cy1B Independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, ORa11, haloalkoxy, cyano, arylalkyl, C 3-6 Cycloalkyl, aminoalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R Cy1B C 6-10 The aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1 or 2 substituents, each of which is independently selected from halogen, CN and C(O)NR c11 R d11 .

13. The use of claim 1, wherein R 13 is a group selected from the group consisting of: Where R Cy1B H, C 1-6 Alkyl or halogen.

14. The use according to claim 1, wherein R 13 For hydrogen.

15. The use of claim 1, wherein each R 14 For hydrogen.

16. The use according to claim 1, wherein R 15 For hydrogen.

17. The use of claim 1, wherein R 16 is hydrogen, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 2-6 Alkenyl or unsubstituted or substituted C 2-6 Alkynyl.

18. The use according to claim 1, wherein the compound of formula (I-1) has a structure selected from the group consisting of: and stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

19. The use of claim 1, wherein the compound of formula (I-1) or its stereoisomer, tautomer or pharmaceutically acceptable salt is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or excipient.

20. Use of a compound of formula (I-1) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a MASP-2-related disease or condition, wherein formula (I-1) is: in: Cy 1A is unsubstituted or substituted C 6-10 Aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein Cy 1A The ring atoms of the 5-10 membered heteroaryl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein Cy 1A The substituted C 6-10 The aryl or substituted 5-10 membered heteroaryl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1A , halogen, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R Cy1A Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1A The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein R Cy1A C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein R Cy1A C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R 11 and R 12 Together with the groups to which they are attached, they form a 4-6 membered heterocycloalkyl ring; and A 11 CR 13 R 15 or NH, N-naphthyl, N-benzyl or N-(2-methyl)benzyl; and Each R 13 Independently for Cy 1B , (CR 13A R 13B ) n3 Cy 1B , (C 1-6 Alkylene)Cy 1B , (C 2-6 Cy 1B , (C 2-6 Alkynylidene)Cy 1B or OCy 1B , where R 13 C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 The alkynylene moiety is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R 14 Independently selected from H and C 1-6 Alkyl, and R 15 Selected from H, R 13 , C 1-6 Alkyl and OH, or A pair of R connected to adjacent carbon atoms 14 A group or a pair of R connected to adjacent carbon atoms 14 and R 15 The group can, independently of R 14 The other occurrences of R are replaced by bonds connecting adjacent carbon atoms to the pair of R 14 A group or a pair of R 14 and R 15 The adjacent carbon atoms are connected by double bonds, and each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A pair of R attached to the same carbon atom 14 A group or a pair of R attached to the same carbon atom 13 and R 15 The group can, independently of R 14 The other occurrences, connected with the pair R 14 A group or a pair of R 13 and R 15 The carbon atoms of the group together form a spiro-fused C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the spiro-fused C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A pair of R connected to adjacent carbon atoms 14 A group or a pair of R connected to adjacent carbon atoms 14 and R 15 The group can, independently of R 14 The other occurrences, connected with the pair R 14 A group or a pair of R 14 and R 15 The adjacent carbon atoms of the group are joined together to form a fused C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the fused C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A group of four R attached to two adjacent carbon atoms 14 A group or a group of two R attached to two adjacent carbon atoms 14 , an R 13 and an R 15 The group can, independently of R 14 The other occurrences, connected with the set of four R 14 A group or a set of two R 14 , an R 13 and an R 15 Two adjacent carbon atoms of a group are joined together to form a fused C 6-10 Aryl or 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the formed 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, and wherein the formed fused C 6-10 Aryl or 5-10 membered heteroaryl, C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; and n1 is 1 or 2; and n2 is 0, 1 or 2; and The condition is that the sum of n1 and n2 is 1, 2 or 3; and The condition is that if n1 is 1 or n2 is 0, then A 11 CR 13 R 15 ; and n3 is 0, 1 or 2; and Each R 13A independently H or C 1-6 Alkyl; and Each R 13B independently H or C 1-6 Alkyl; or R attached to the same carbon atom 13A and R 13B , independent of any other R 13A and R 13B groups, which can come together to form –(CH2) 2-5 -, thereby forming a 3-6 membered cycloalkyl ring; and Cy 1B is unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein Cy 1B The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and The formation of Cy 1B The substituted C 6-10 Aryl, substituted 5-10 membered heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1B , halogen, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R Cy1B Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1B The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein R Cy1B C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and wherein R Cy1B C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R 16 H, Cy 1C , C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, which forms R 16 C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from Cy 1C 、Halogen、CN、OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, provided that not more than one R 16 The substituent is Cy 1C ;and Cy 1C is unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein Cy 1C The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and The formation of Cy 1C The substituted C 6-10 Aryl, substituted 5-10 membered heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1C , halogen, C 1-6 Haloalkyl, CN, OR a11 , S Ra11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Among them, each R Cy1C Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1C The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein R Cy1C C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and wherein R Cy1C C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R a11 and R b11 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Alkyl, which forms R a11 and R b11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; and R c11 and R d11 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Alkyl, which forms R c11 and R d11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; or R attached to the same N atom c11 and R d11 Together with the N atom to which they are both attached, they form a 4-, 5-, 6- or 7-membered heterocycloalkyl or a 5-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; and R a12 and R b12 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Alkyl, which forms R a12 and R b12 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; and R c12 and R d12 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Alkyl, which forms R c12 and R d12 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; or R attached to the same N atom c12 and R d12 Together with the N atom to which they are both attached, they form a 4-, 5-, 6- or 7-membered heterocycloalkyl or a 5-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; and R e11 and Re 12 Each is independently H, CN or NO2.

21. The use of claim 20, wherein the MASP-2-associated disease or disorder is thrombotic microangiopathy (TMA), graft-versus-host disease (GVHD), diffuse alveolar hemorrhage (DAH), veno-occlusive disease (VOD), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), engraftment syndrome (ES), fluid overload (FO), mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangial capillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, lupus erythematosus, Nephritis, Henoch-Schmeier purpura nephritis, IgA nephropathy, renal fibrosis, proteinuria, nephrotic syndrome, preeclampsia, eclampsia, toxic damage to the kidney, amyloidosis, collagen vascular disease, dehydration, glomerular disease, strenuous exercise, stress, benign orthostatic (postural) proteinuria, focal segmental glomerulosclerosis, IgA nephropathy, IgM nephropathy, membranoproliferative glomerulonephritis, membranous glomerulonephritis, minimal change nephropathy, sarcoidosis, Alport syndrome, diabetes mellitus, drug-induced toxicity, Fabry disease, infection, aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, sickle cell disease, hemoglobinuria, multiple myeloma, myoglobinuria, organ rejection, Ebola hemorrhagic fever , finger-patella syndrome, familial Mediterranean fever, HELLP syndrome, systemic lupus erythematosus, Wegener's granulomatosis, rheumatoid arthritis, glycogen storage disease type I, Goodpasture's syndrome, Henoch-Schonlein purpura, urinary tract infection that has spread to the kidneys, Sjogren's syndrome, post-infectious glomerulonephritis, inflammatory response due to tissue or solid organ transplantation, ischemia-reperfusion injury (I / R), complications associated with type 1 or type 2 diabetes, cardiovascular disease or disorder, inflammatory gastrointestinal disorder, pulmonary disorder, inflammatory response triggered by extracorporeal exposure, inflammatory or non-inflammatory arthritis, skin disorder, thermal burns, chemical burns, capillary leak caused by thermal or chemical burns, peripheral nerve parathyroid (PNS) disorder or injury, central nervous system (CNS) disorder or injury, sepsis, a condition caused by sepsis, a genitourinary disorder, an inflammatory response in a subject treated with chemotherapy and / or radiation therapy, angiogenesis-dependent cancer, angiogenesis-dependent benign tumors, an endocrine disorder, an ophthalmic disease or disorder, an ocular angiogenic disease or condition, disseminated intravascular coagulation (DIC), acute radiation syndrome, dense deposit disease, Degos' disease, catastrophic antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia; paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease, aHUS, HSCT-TMA, IgAN, or lupus nephritis (LN).

22. Use of a compound of formula (I-1) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition treatable by inhibiting MASP-2, wherein formula (I-1) is: in: Cy 1A is unsubstituted or substituted C 6-10 Aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein Cy 1A The ring atoms of the 5-10 membered heteroaryl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein Cy 1A The substituted C 6-10 The aryl or substituted 5-10 membered heteroaryl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1A , halogen, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R Cy1A Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1A The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein R Cy1A C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein R Cy1A C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R 11 and R 12 Together with the groups to which they are attached, they form a 4-6 membered heterocycloalkyl ring; and A 11 CR 13 R 15 or NH, N-naphthyl, N-benzyl or N-(2-methyl)benzyl; and Each R 13 Independently for Cy 1B , (CR 13A R 13B ) n3 Cy 1B , (C 1-6 Alkylene)Cy 1B , (C 2-6 Cy 1B , (C 2-6 Alkynylidene)Cy 1B OCy 1B , where R 13 C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 The alkynylene moiety is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R 14 Independently selected from H and C 1-6 Alkyl, and R 15 Selected from H, R 13 , C 1-6 Alkyl and OH, or A pair of R connected to adjacent carbon atoms 14 A group or a pair of R connected to adjacent carbon atoms 14 and R 15 The group can, independently of R 14 The other occurrences of R are replaced by bonds connecting adjacent carbon atoms to the pair of R 14 A group or a pair of R 14 and R 15 The adjacent carbon atoms are connected by double bonds, and each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A pair of R attached to the same carbon atom 14 A group or a pair of R attached to the same carbon atom 13 and R 15 The group can, independently of R 14 The other occurrences, connected with the pair R 14 A group or a pair of R 13 and R 15 The carbon atoms of the group together form a spiro-fused C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the spiro-fused C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A pair of R connected to adjacent carbon atoms 14 A group or a pair of R connected to adjacent carbon atoms 14 and R 15 The group can, independently of R 14 The other occurrences, connected with the pair R 14 A group or a pair of R 14 and R 15 The adjacent carbon atoms of the group are joined together to form a fused C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, wherein the fused C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; or A group of four R attached to two adjacent carbon atoms 14 A group or a group of two R attached to two adjacent carbon atoms 14 , an R 13 and an R 15 The group can, independently of R 14 The other occurrences, connected with the set of four R 14 A group or a set of two R 14 , an R 13 and an R 15 Two adjacent carbon atoms of a group are joined together to form a fused C 6-10 Aryl or 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the formed 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S, and wherein the formed fused C 6-10 Aryl or 5-10 membered heteroaryl, C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, and wherein each unpaired R 14 Is H or C 1-6 Alkyl, and each unpaired R 15 Selected from H, R 13 , C 1-6 Alkyl and OH; and n1 is 1 or 2; and n2 is 0, 1 or 2; and The condition is that the sum of n1 and n2 is 1, 2 or 3; and The condition is that if n1 is 1 or n2 is 0, then A 11 CR 13 R 15 ; and n3 is 0, 1 or 2; and Each R 13A are independently H or C 1-6 Alkyl; and Each R 13B are independently H or C 1-6 Alkyl; or R attached to the same carbon atom 13A and R 13B , independent of any other R 13A and R 13B groups, which can come together to form –(CH2) 2-5 -, thereby forming a 3-6 membered cycloalkyl ring; and Cy 1B is unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein Cy 1B The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and The formation of Cy 1B The substituted C 6-10 Aryl, substituted 5-10 membered heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1B , halogen, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Each R Cy1B Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1B The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein R Cy1B C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and wherein R Cy1B C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R 16 H, Cy 1C , C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, which forms R 16 C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from Cy 1C 、Halogen、CN、OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo, provided that not more than one R 16 The substituent is Cy 1C ;and Cy 1C is unsubstituted or substituted C 6-10 Aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-10 Cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein Cy 1C The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and The formation of Cy 1C The substituted C 6-10 Aryl, substituted 5-10 membered heteroaryl, substituted C 3-10 The cycloalkyl or substituted 4-10 membered heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each of which is independently selected from R Cy1C , halogen, C 1-6 Haloalkyl, CN, OR a11 , S Ra11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 、C(=NOR a11 )NR c11 R d11 、C(=NOC(O)R b11 )NR c11 R d11 、C(=NR e11 )NR c11 C(O)OR a11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and Among them, each R Cy1C Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl, wherein R Cy1C The ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are composed of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein R Cy1C C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and wherein R Cy1C C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 The cycloalkyl and 4-10 membered heterocycloalkyl groups are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 、OC(O)R b11 、OC(O)NR c11 R d11 NR c11 R d11 NR c11 C(O) Rb11 NR c11 C(O)NR c11 R d11 NR c11 C(O)OR a11 、C(=NR e11 )NR c11 R d11 NR c11 C(=NR e11 )NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 NR c11 S(O)2R b11 、S(O)2NR c11 R d11 and oxo; and R a11 and R b11 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Alkyl, which forms R a11 and R b11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; and R c11 and R d11 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Alkyl, which forms R c11 and R d11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-3 Alkyl, 5-10 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-10 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; or R attached to the same N atom c11 and R d11 Together with the N atom to which they are both attached, they form a 4-, 5-, 6- or 7-membered heterocycloalkyl or a 5-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from C 1-6 Alkyl, halogen, CN, OR a12 , SR a12 、C(O)R b12 、C(O)NR c12 R d12 、C(O)OR a12 、OC(O)R b12 、OC(O)NR c12 R d12 NR c12 R d12 NR c12 C(O)R b12 NR c12 C(O)NR c12 R d12 NR c12 C(O)OR a12 、C(=NR e12 )NR c12 R d12 NR c12 C(=NR e12 )NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 NR c12 S(O)2R b12 、S(O)2NR c12 R d12 and oxo; and R a12 and R b12 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Alkyl, which forms R a12 and R b12 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; and R c12 and R d12 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Alkyl, which forms R c12 and R d12 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 3-7 Cycloalkyl-C 1-3 Alkyl and 4-7 membered heterocycloalkyl-C 1-3 Each alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; or R attached to the same N atom c12 and R d12 Together with the N atom to which they are both attached, they form a 4-, 5-, 6- or 7-membered heterocycloalkyl or a 5-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and oxo; and R e11 and Re 12 Each is independently H, CN or NO2.

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