Fused pyrimidines as MASP-2 inhibitors

Abstract

The present disclosure provides synthetic compositions useful as inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including compositions that selectively inhibit MASP-2 over thrombin, as well as methods for their production and use.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 385,597, filed November 30, 2022, and U.S. Provisional Patent Application No. 63 / 588,653, filed October 6, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] Sequence Listing Description The Sequence Listing XML associated with this application is provided in XML format and is hereby incorporated by reference. The XML file containing the Sequence Listing is named 4278-P6US_Seq_List.xml. The XML file is 2,415 bytes, was created on May 17, 2023, and was submitted electronically via the Patent Center along with the application.

[0003] FIELD OF THE INVENTION The present disclosure provides synthetic compositions useful as inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including compositions that selectively inhibit MASP-2 over thrombin, as well as methods for their production and use. [Background technology]

[0004] background The complement system is involved in inflammatory responses and is activated upon tissue injury or microbial infection. Complement activation must be tightly regulated to ensure selective targeting of invading microorganisms and to avoid self-damage (Ricklin et al., Nat. Immunol. 11:785-797, 2010).

[0005] It is now widely accepted that the complement system is activated by three distinct pathways: the classical, lectin, and alternative pathways. The classical pathway is typically triggered by a complex consisting of a host antibody bound to a foreign substance (i.e., an antigen) and generally requires prior exposure to the antigen for the generation of a specific antibody response. Because classical pathway activation depends on a prior adaptive immune response by the host, it is part of the adaptive immune system response. In contrast, both the lectin and alternative pathways are independent of adaptive immunity and are instead part of the innate immune system response.

[0006] 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 (Non-Patent Document 2); Ambrus et al., J Immunol. 170: 1374-1382, 2003 (Non-Patent Document 3); Schwaeble et al., PNAS 108:7523-7528, 2011 (Non-Patent Document 4)).

[0007] Inhibition of MASP-2 is believed not to interfere with the antibody-dependent classical complement activation pathway. As described in U.S. Patent No. 9,011,860 (assigned to Omeros Corporation), which is incorporated herein by reference in its entirety, a fully humanized monoclonal antibody targeting human MASP-2 has been generated that binds to human MASP-2 with high affinity and blocks lectin pathway complement activity.

[0008] MASP-2-dependent complement activation has been implicated as contributing to the pathogenesis of numerous acute and chronic conditions, including certain conditions caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

[0009] Thus, there is a need for compounds suitable for administration and treatment of subjects suffering from MASP-2-associated diseases and disorders, including diseases that are not adequately or effectively treated with large molecule biological inhibitors. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Patent No. 9,011,860 [Non-patent literature]

[0011] [Non-Patent Document 1] Ricklin et al., Nat. Immunol. 11 :785-797, 2010 [Non-patent document 2] Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000 [Non-patent document 3] Ambrus et al., J Immunol. 170: 1374-1382, 2003 [Non-patent document 4] Schwaeble et al., PNAS 108:7523-7528, 2011 Summary of the Invention

[0012] overview In some aspects, the structure (I): Provided herein is a compound having the formula: TIFF2025541737000001.tif43128, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 is a substituted aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl, or Cy 1 is R 5 or R 6together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl fused to a substituted or unsubstituted 5-10 membered heteroaryl, or a substituted or unsubstituted phenyl; Cy 2 is a substituted aryl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 5-10 membered heteroaryl, or hydrogen; R 2 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, or R 3 and R 4 together with the carbons to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted C5-C6 cycloalkenyl; R 5 and R 6 are each independently hydrogen, C1-C3 alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C3-C6 cycloalkyl; R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; L is hydrogen or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently identical or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted straight or branched C1-C3 alkyl, or R 8a and R 8b together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; and n is 1, 2, or 3; wherein C3-C6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; One or more hydrogen atoms in structure (I) may be replaced with deuterium atoms; provided that the compound of structure (I) has the structure: TIFF2025541737000002.tif20128, where R A is benzyl, phenethyl, or 3-CF3-benzyl.

[0013] In another aspect, the compound of structure (II): Provided herein are compounds having the formula TIFF2025541737000003.tif41128, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0014] In yet another aspect, the compound of structure (III): Provided herein is a compound having the formula: TIFF2025541737000004.tif51128, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; During the ceremony, Cy 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl; Cy 2 is a substituted aryl, a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 5-10 membered heteroaryl; R 2 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted cycloalkyl, or R3 and R 4 together with the carbons to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 5-6 membered cycloalkenyl; R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; L is absent or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently identical or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or R 8a and R 8b together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; m is 1 or 2; and n is 0, 1, 2, or 3; wherein C3-C6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; One or more hydrogen atoms may be replaced with deuterium atoms.

[0015] In some aspects, provided herein are pharmaceutical compositions comprising a compound having any one of structures (I), (II), or (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0016] In some aspects, provided herein are methods for inhibiting MASP-2 in a subject, comprising administering to the subject a compound of structure (I), (II) or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof in an amount effective to inhibit MASP-2.

[0017] In some aspects, provided herein are methods for treating a disease or disorder treatable by inhibiting MASP-2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I), (II) or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0018] In some aspects, provided herein are methods for inhibiting MASP-2-dependent complement activation in a subject. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials similar or equivalent to those described herein can be used to implement or test the subject matter of this disclosure, and suitable methods and materials are described below.Furthermore, the materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0020] I. Definition Certain embodiments herein refer to disclosed features and aspects, including method steps. All possible combinations of such features and aspects within the disclosed embodiments are included, at least to the extent that such combinations are not inconsistent. For example, if an embodiment describes aspects A, B, and C, it is understood that this also discloses embodiments including both aspects A and B, both aspects B and C, and both aspects A and C, as well as embodiments having aspects A, B, and C.

[0021] The terms "a," "an," or "the" not only include aspects having one element, but also aspects having a plurality of elements. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, and a reference to "the agent" includes a reference to one or more agents known to those of skill in the art.

[0022] The terms "about" and "approximately" refer to an acceptable degree of error for a measured quantity, given the nature or precision of the measurement. Typical and illustrative degrees of error are within ±20 percent (%) of a given value or range of values; preferably within ±10%; and more preferably within ±5%. Any reference to "about X" specifically refers to at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide support for a claim limitation, such as "0.98X." Alternatively, in biological systems, the terms "about" and "approximately" can refer to values ​​within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical values ​​given herein are approximate unless otherwise specified, meaning that the term "about" or "approximately" can be inferred unless explicitly stated. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5-20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 7, 9, or 11 mg / kg" is equivalent to "about 7, about 9, or about 11 mg / kg."

[0023] The term "essentially" refers to completely or nearly completely. For example, an essentially pure composition is one that is about 100% pure, at least about 99% pure, at least about 98% pure, or at least about 97% pure.

[0024] The term "or" refers to alternatives and should generally be construed as non-exclusive. For example, a reference to "a composition comprising A or B" would typically indicate an aspect having a composition that includes both A and B. However, "or" should be construed to exclude stated aspects that cannot be consistently combined (e.g., a composition pH of 9-10 or 7-8).

[0025] The group "A or B" is equivalent to the group "selected from the group consisting of A and B."

[0026] The transition words "comprising" or "comprise" are not exclusive. For example, a "composition comprising A" must include at least component A, but may also include one or more other components (e.g., B; B and C; B, C, and D; etc.). Thus, the term "comprising" should generally be interpreted as not excluding additional components. For example, a claim "a composition comprising A" would encompass compositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; etc.

[0027] The term "MASP-2" refers to mannan-binding lectin-associated serine protease-2. For example, the human MASP-2 protein may have UniProt accession code O00187 (SEQ ID NO:1). The serine protease domain ('B chain' = mannan-binding lectin serine protease 2 B chain, based on UniProtKB - O00187 (MASP-2_HUMAN)) comprises (or consists of) residues 445-686.

[0028] The term "MASP-2-dependent complement activation" refers to MASP-2-dependent activation of the lectin pathway, which under physiological conditions (i.e., Ca) leads to the formation of the lectin pathway C3 convertase C4b2a and, upon accumulation of the C3 cleavage product C3b, the subsequent formation of the C5 convertase C4b2a(C3b)n. ++ occurs in the presence of

[0029] The term "MASP-2-dependent complement-associated disease or disorder" refers to a disease or disorder associated with MASP-2-dependent complement activation.

[0030] The term "MASP-2-associated disease or disorder" refers to a disease or disorder associated with the activation or activity of MASP-2, including a MASP-2-dependent complement-associated disease or disorder, in which inhibition of MASP-2 is or is expected to be therapeutically beneficial.

[0031] Typically, the active site of serine proteases such as MASP-2 is shaped like a cleft where substrates or inhibitors bind.

[0032] The term "lectin pathway" refers to complement activation that occurs through the specific binding of serum and non-serum carbohydrate-binding proteins, including mannan-binding lectin (MBL), CL-11, and ficolins (e.g., H-ficolin, M-ficolin, or L-ficolin).

[0033] The term "subject" includes all mammals, including, but not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cattle, rabbits, pigs, and rodents.

[0034] "Mammal" includes humans; domestic animals such as laboratory animals and pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals such as wild animals.

[0035] As used herein, the terms "disease," "condition," and "disorder" may be used interchangeably or may differ in that a particular ailment, condition, disorder, or syndrome may not have a known causative agent (and thus its etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but is recognized only as an undesirable condition, disorder, or syndrome in which a more or less specific set of symptoms has been identified by clinicians or researchers, or is a disruption of normal processes and functions. In some embodiments, a disease is a pathological condition of an organ, body part, or system resulting from a variety of causes, such as infection, genetic defect, or environmental stress, characterized by a distinguishable group of symptoms.

[0036] A "therapeutically effective amount" or "effective amount" refers to the amount of a disclosed compound that, when administered to a mammal (e.g., a human), is sufficient to effect treatment, alleviation of symptoms, or cure of a disease or condition as defined herein in the mammal, preferably a human. The amount of a disclosed compound that constitutes a "therapeutically effective amount" will vary depending on the compound; the condition and its severity; the mode of administration; and the age, weight, and genetic characteristics of the mammal being treated, but can be routinely determined by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0037] The term "agent" refers to a compound or mixture of compounds that, when added to a composition, tends to affect the properties of the composition. For example, a composition that includes a thickening agent tends to be more viscous than an otherwise identical comparative composition without the thickening agent.

[0038] A "synthetic" compound means a compound that does not occur in nature or that has been synthesized by man. Reference herein to a compound may be understood to include reference to a synthetic compound unless the context indicates otherwise.

[0039] As used herein, the expressions "ambient temperature" and "room temperature" are art-recognized and generally refer to reaction temperatures that are about the same as, for example, the temperature of the room in which the reaction is carried out, e.g., from about 20°C to about 30°C.

[0040] At various places in this specification, certain features of compounds are disclosed in groups or ranges. It is specifically intended that such disclosure include every individual subcombination of the members of such groups and ranges. For example, "C 1~6 The terms "alkyl" and "C1-C6 alkyl" are specifically intended to independently disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, including all linear and branched compositions (e.g., for C4 alkyl, n-butyl, sec-butyl, tert-butyl).

[0041] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" means that at least one hydrogen atom has been replaced with a non-hydrogen substituent. Additionally, compounds can be substituted with hydrogen, and hydrogen can be a substituent. The term "substituted," unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, penta-, or higher, where such substitution is permitted. Substituents are independently selected, and substitution may occur at any chemically accessible position. It is understood that substitution at a given atom is limited by valency. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0042] The term "optionally substituted" means substituted or unsubstituted.

[0043] "C" where n and m are integers n~m " and "C n ~C mThe term "" refers to a group containing n to m carbon atoms, including both linear and branched configurations, and does not exclude substituents. Examples are C 1~4 , C 1~6 The term includes all members within the scope, i.e., C n , C n+1 , C n+2 ...C m-2 , C m-1 , C m For example, C 1~6 is intended to disclose C1, C2, C3, C4, C5, and C6. As used herein, "C n~m " is "C n ~C m " has the same meaning as ".

[0044] The term "n-membered" (e.g., 6-membered), where n is an integer, typically describes the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. The term "n- to m-membered" (e.g., 6- to 10-membered), where n and m are integers, describes a range of n to m ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocyclyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0045] "Alkyl" refers to a straight-chain or branched hydrocarbon group, consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, attached to the molecule by a single bond. An alkyl group may optionally contain one or more heteroatoms, where a carbon atom of the alkyl group is replaced with a heteroatom selected from oxygen, nitrogen, or sulfur. An alkyl group is an alkane in which one C-H bond is replaced at the point of attachment of the alkyl group to the remainder of the molecule. An alkyl group may be straight-chain or branched. For example, representative alkyl groups can be methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1,1-dimethylethyl (t-butyl), sec-butyl, isobutyl, n-pentyl, 3-methylhexyl, 2-methylhexyl, and the like. In another example, C1-C3 alkyl refers to methyl, ethyl, n-propyl, and isopropyl. In certain specific embodiments, an alkyl group may be substituted.

[0046] "Alkenyl" refers to a straight-chain or branched hydrocarbon group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and attached to the molecule by a single bond. An alkenyl group is an alkene in which one C-H bond is replaced at the alkenyl group's point of attachment to the remainder of the molecule. For example, representative alkenyl groups can be ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. In certain embodiments, alkenyl groups are optionally substituted.

[0047] "Alkynyl" refers to a straight or branched chain hydrocarbon group, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably from 2 to 8 carbon atoms, and attached to the molecule by a single bond. An alkynyl group is an alkyne with one C-H bond replaced at the point of attachment of the alkynyl group to the remainder of the molecule. n~m alkynyl" and "C n ~C mThe term "alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In certain embodiments, an alkynyl group is optionally substituted.

[0048] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, that connects a molecule to another group or two portions of a molecule, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may optionally contain one or more heteroatoms, where a carbon atom of the alkylene chain is replaced with a heteroatom selected from oxygen, nitrogen, or sulfur. The alkylene chain is attached to a molecule through a single bond and to another group through a different single bond, or to two portions of the molecule through a single bond at each point of attachment. In some embodiments, the alkylene group may be substituted with one or more substituents.

[0049] The term "heteroalkyl" refers to a 3- to 18-membered non-aromatic, acyclic alkyl group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in the heteroalkyl group can be oxidized; the nitrogen atom can be quaternized; and the heteroalkyl group can be saturated or unsaturated (e.g., a heteroalkyl can contain one or more double bonds, which can alternatively be referred to as a "heteroalkenyl").

[0050] The term "hydroxyalkyl" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with a hydroxy group (i.e., -OH). n~m The term "hydroxyalkyl" refers to a C alkyl group having n to m carbon atoms and at least one hydroxy group. n~mThis refers to an alkyl group. In some embodiments, a hydroxyalkyl group contains one hydroxy group. In some embodiments, a hydroxyalkyl group contains two or more hydroxy groups (e.g., "dihydroxyalkyl"), where the hydroxy groups are attached to the same or different carbon atoms. In certain aspects, a hydroxyalkyl group has 1, 2, 3, 4, 5, 6, or more hydroxy groups. Examples can include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.

[0051] "Alkoxy" refers to a group having the formula "-O-alkyl," where alkyl is as defined herein. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Unless otherwise specified, an alkoxy group can be substituted with one or more substituents, which can be the same or different.

[0052] "Aminylalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with an aminyl or amino group (i.e., -NRR', where R and R' are each independently hydrogen, alkyl, alkenyl, or alkynyl as defined herein). In some embodiments, the aminylalkyl comprises one aminyl group. In some embodiments, the aminyl group is -NH.

[0053] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this disclosure, aryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from phenyl, benzene, naphthalene, anthracene, aceanthrylene, acenaphthylene, acephenanthrylene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, aryl groups may be unsubstituted or substituted. In those embodiments where aryls may be substituted, the aryl may be substituted with one or more substituents, 1 substituent, 2 substituents, 3 substituents, 4 substituents, or 5 substituents, each of which may be the same or different. In some embodiments, the term "aryl," when substituted, refers to a fused ring substituent, such as, for example: It may contain a structure such as TIFF2025541737000005.tif20128.

[0054] "Arylalkyl" refers to the group -alkylene-aryl, where the alkylene and aryl groups are each as defined herein. In some embodiments, arylalkyl is -C 1~3 Alkyl-C 6~10 In some embodiments, arylalkyl is -C 1~4 Alkyl-C 6~10 In some embodiments, arylalkyl is -C 1~4 In some embodiments, the arylalkyl is an optionally substituted benzyl. In some embodiments, the arylalkyl is an optionally substituted benzyl. In some embodiments, the arylalkyl group has the following structure: I have TIFF2025541737000006.tif26128.

[0055] "Aryloxy" refers to a group having the formula -O-aryl, where aryl is as defined herein. In some embodiments, the aryloxy group is -OC 6~10 In some embodiments, the aryloxy is substituted or unsubstituted phenyloxy (i.e., —O—C aryl).

[0056] "Arylalkoxy" refers to a group having the formula -alkoxy-aryl or -O-alkylene-aryl, where alkoxy and aryl are defined herein. In some embodiments, arylalkoxy is -C 1~3 Alkoxy-C 6~10 In some embodiments, the arylalkoxy is -C 1~4 Alkoxy-C 6~10 In some embodiments, the arylalkoxy is -C 1~3 Alkoxy-phenyl (eg, -O-benzyl).

[0057] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decalinyl, and the like. In some embodiments, cycloalkyl groups can be substituted with one or more substituents, where the one or more substituents are the same or different.

[0058] "Oxo" refers to the =O group. For example, oxo attached to a carbon atom forms a carbonyl group (i.e., C=O). Alternatively, when the oxo group is attached to a heteroatom, for example, a sulfoxide, sulfone, or N-oxide group is formed.

[0059] "Sulfide" refers to the =S group.

[0060] "Amino" refers to the group -NH2.

[0061] "Acyl" refers to a -C(O)R group, where R may be alkyl or aryl, as defined herein. "Acetyl" is an example of an acyl group where the R group is methyl.

[0062] "Heteroacyl" refers to the group -C(O)R, where the R group may be alkyl or aryl, as defined herein, and further containing one or more heteroatoms such as N, S, and O.

[0063] "Alkylsulfonyl" refers to -SO2R where the R group is an alkyl group. "Methanesulfonyl" is an example of an alkylsulfonyl where the R group is methyl.

[0064] "Carboxy" refers to the group --C(O)OH.

[0065] "Carbonyl" refers to the group C(=O), which may also be written as C(O).

[0066] "Cyano" or "nitrile" refers to the group -C≡N, which may also be written as -CN.

[0067] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0068] "Halo" or "halogen" refers to all of fluoro, chloro, bromo, and iodo, or a subrange of halogen atoms (eg, chloro, bromo, and iodo; chloro and bromo; or just chloro; etc.).

[0069] "Haloalkyl" refers to an alkyl group, as defined herein, in which a hydrogen is replaced by one or more halo groups, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc. The alkyl portion of a haloalkyl group can be substituted with one or more substituents, where the one or more substituents are independently the same or different.

[0070] The term "haloalkoxy" refers to a radical of the formula -O-haloalkyl, where haloalkyl is as defined herein. Exemplary haloalkoxy radicals include trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and the like.

[0071] "Heterocyclyl" refers to a 3- to 18-membered non-aromatic ring containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specified, a heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, bridged, and spiro ring systems; the nitrogen, carbon, or sulfur atoms in a heterocyclyl group can be oxidized; the nitrogen atom can be quaternized; and the heterocyclyl group can be saturated or unsaturated (e.g., a heterocyclyl contains one or more double bonds, which can alternatively be referred to as a "heterocycloalkenyl"). Examples of heterocyclyl groups are azetidinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1-azaspiro[3.3]heptan-1-yl, 5-azaspiro[2.3]hexan-5-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1-oxa-6-azaspiro[3.4]octan-6-yl, 1-oxa-6-azaspiro[3.5]octan-6-yl, 1-oxa-6-azaspiro[3.6]octan-6-yl, 1-oxa-6-azaspiro[3.7]octan-7-yl, 1-oxa-6-azaspiro[3.8]octan-7-yl, 1-oxa-6-azaspiro[3.9]octan-7-yl, 1-oxa-6-azaspiro[3 Pyro[3.3]heptan-6-yl, 6-oxa-1-azaspiro-[3.3]heptan-1-yl, 6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl, decahydro -isoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In certain embodiments, heterocyclyl groups are optionally substituted with one or more substituents, wherein the one or more substituents are independently the same or different.

[0072] "Heteroaryl" refers to a 5- to 14-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in a heteroaryl can be oxidized; and the nitrogen atom can be quaternized.Examples are azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzo Thienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolethionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazo Allyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, puriri Heteroaryl groups include, but are not limited to, midinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). In some embodiments, heteroaryl groups can be unsubstituted or substituted. In embodiments where a heteroaryl is substituted, the heteroaryl is substituted with one or more substituents, each of which can be the same or different. In some embodiments, the term "heteroaryl" can refer to, for example, the following: It may contain a structure such as TIFF2025541737000007.tif23128.

[0073] "Heteroarylalkyl" has the formula -R 100 R 101 where R 100 is alkylene as defined herein, and R 101 is heteroaryl as defined herein. Where specifically described herein, the heteroaryl portion of the heteroarylalkyl may be optionally substituted as defined herein. In some embodiments, the alkylene portion of the heteroarylalkyl may be optionally substituted as defined herein.

[0074] The compounds and methods of the present disclosure are intended to encompass all pharmaceutically acceptable isotopically labeled compounds of structure (I) having one or more atoms replaced by an atom having a different atomic mass or mass number.

[0075] Examples of isotopes that can be incorporated into the disclosed compounds are 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, 125The radioactive isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. These radiolabeled compounds may be useful, for example, to determine or measure the effectiveness of compounds by characterizing the site or mechanism of action or binding affinity. Certain isotopically labeled compounds of structure (I), for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and convenient means of detection.

[0076] Deuterium, i.e. 2 Substitution with isotopes such as H may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced required dosage, and therefore may be preferred in some circumstances. In some embodiments, the compounds of the present disclosure are enriched with deuterium. Such deuterated compounds can be achieved by methods known to those skilled in the art, such as exchanging protons for deuterium, or by synthesizing molecules with deuterium-enriched starting materials.

[0077] 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples below, substituting an appropriate isotopically labeled reagent for an unlabeled reagent.

[0078] "Substituted" refers to a group in which one or more hydrogens may be replaced by a non-hydrogen group to the extent that substitution is chemically feasible. Exemplary substituents include, but are not limited to, halogen (F, Cl, Br, I), =O, =N-CN, =N-OR, =NR, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, and NO2, where each R is independently H, C1-C6 alkyl, C2-C8 heteroalkyl, C1-C6 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C8 alkyl, C6-C8 heteroalkyl, C6-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C6-C8 hetero ... 10 Aryl, or C5-C 10 heteroaryl, wherein each R is optionally substituted with halogen (F, Cl, Br, I), =O, =N-CN, =N-OR', =NR', OR', NR'2, SiR'3, SR', S02R', S02NR'2, NR'S02R', NR'CONR'2, NR'C(O)OR', NR'C(O)R', CN, C(O)OR', C(O)NR'2, OC(O)R', C(O)R', and NO2, wherein each R' is independently selected from H, C1-C6 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C 10 Aryl, or C5-C 10 Alkyl, alkenyl, and alkynyl groups also include C1-C6 acyl, C2-C8 heteroacyl, C6-C 10 Aryl, or C5-C 10The aryl or heteroaryl group may be substituted, and each of these may be substituted with a suitable substituent for the specific group. The substituent on the aryl or heteroaryl group may be further substituted with a suitable group as described herein. Thus, for example, the aryl alkyl substituent may have the aryl moiety substituted with the substituents described herein for the aryl group. Alternatively, the aryl alkyl substituent may have the alkyl moiety substituted with the substituents described herein for the alkyl group. The aryl alkyl substituent may also have both the alkyl and aryl moieties substituted.

[0079] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs or where the event or circumstance does not occur. For example, "optionally substituted aryl" or "substituted or unsubstituted aryl" means that the aryl may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups that have no substitution ("unsubstituted")

[0080] If a functional group is described as being "optionally substituted," and in turn, a substituent on the functional group is also described as being "optionally substituted," etc., for purposes of this disclosure, such repetitions are limited to 5. Preferably, such repetitions are limited to 2.

[0081] As used herein, "optionally substituted" refers to a group in which one or more hydrogen atoms may be replaced with a non-hydrogen group. In some optionally substituted groups, one hydrogen atom is replaced with a non-hydrogen group, such as C1-C6 alkyl, C2-C6 heteroalkyl, alkynyl, halogen (F, Cl, Br, I), N3, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, oxo, and NO2, where each R is independently H, C1-C6 alkyl, 2- to 6-membered heteroalkyl, C6-C6 alkyl, alkynyl, halogen (F, Cl, Br, I), N3, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, oxo, and NO2. 10 aryl, 5-9 membered heteroaryl, or as otherwise disclosed herein. In some optionally substituted groups, more than one hydrogen atom is replaced with one or more of the same or different non-hydrogen substituents, such as C1-C6 alkyl, C2-C6 heteroalkyl, alkynyl, halogen (F, Cl, Br, I), N3, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, oxo, and NO2, where each R is independently H, C1-C6 alkyl, 2-6 membered heteroalkyl, C6-C 10 aryl, 5-9 membered heteroaryl, or as otherwise disclosed herein. In some optionally substituted groups, all hydrogen atoms are replaced with the same or different non-hydrogen substituents, such as C1-C6 alkyl, C2-C6 heteroalkyl, alkynyl, halogen (F, Cl, Br, I), N3, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, oxo, and NO2, where each R is independently H, C1-C6 alkyl, 2-6 membered heteroalkyl, C6-C6 heteroalkyl, alkynyl, halogen (F, Cl, Br, I), N3, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, oxo, and NO2. 10Aryl, 5- to 9-membered heteroaryl, or as otherwise disclosed herein. In some optionally substituted groups, one hydrogen atom, more than one hydrogen atom, or all hydrogen atoms are replaced with deuterium atoms. When an optional substituent is attached via a double bond, such as a carbonyl oxygen or oxo (=O), the substituent occupies two available valence positions, and the total number of possible substituents is reduced according to the number of available valence positions.

[0082] A "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," or "pharmaceutically acceptable carrier or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, pH adjuster, hydrogel, salt, inert solid, printed solid, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0083] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0084] Pharmaceutically acceptable acid addition salts are those which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and also include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, and the like. It refers to salts formed with organic acids such as gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0085] Pharmaceutically acceptable base addition salts refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0086] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure with a vehicle generally accepted in the art for delivery of the compound to a mammal, e.g., a human. Such a vehicle includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0087] As used herein, "treating" or "treatment" includes treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest; and (a) preventing the occurrence of a disease or condition in a mammal, particularly where such mammal is predisposed to the condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition, i.e., arresting the progression of the disease or condition; (c) alleviating (or ameliorating) the disease or condition, i.e., causing regression of the disease or condition; or (d) For example, alleviating (or ameliorating) symptoms caused by a disease or condition without addressing the underlying disease or condition. Includes.

[0088] "Stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof. The present disclosure includes enantiomers, which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. For a detailed description of the structure and properties of enantiomers and stereoisomers, see, for example, Smith, MB and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007). The present disclosure includes diastereomers, which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0089] The present disclosure includes essentially pure enantiomers or diastereomers. The present disclosure includes mixtures of enantiomers, diastereomers, or combinations thereof. The mixture may be a racemic mixture, such as a 50 / 50 mixture of enantiomers, as known to those skilled in the art. The mixture may also include any other ratio or relative composition of enantiomers, diastereomers, or combinations thereof.

[0090] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may contain one or more stereocenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be specified in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, (D)- or (L)-. The present disclosure is meant to include all such possible isomers, all combinations of such isomers, racemic mixtures, and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or separated using conventional techniques, e.g., chromatography or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers or diastereomers include chiral synthesis from suitable optically pure precursors, or resolution of a mixture (e.g., a racemate, or a racemate of a salt or derivative) using, e.g., chiral high-performance liquid chromatography (HPLC).

[0091] When compounds described herein contain olefinic double bonds or other centers that give rise to geometric asymmetry, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers, as well as all tautomeric forms.

[0092] "Tautomer" refers to a structural isomer in which a proton can shift from one atom in a molecule to another atom in the same molecule (e.g., keto-enol). The present disclosure includes tautomers of any such compounds.

[0093] The use of parentheses and square brackets in substituents is used herein to conserve space. Thus, the use of parentheses in a substituent indicates that the group enclosed in the parentheses is directly bonded to the atom preceding the parentheses (e.g., -C(O)- represents carbonyl). The use of square brackets in a substituent indicates that the group enclosed in the parentheses is also directly bonded to the atom preceding the parentheses.

[0094] The chemical naming protocols and structural diagrams used herein are modifications of the IUPAC nomenclature using the ChemDraw Professional Version 21.0.0 software program. In complex chemical names used herein, substituents are listed before the group to which they are attached. For example, cyclopropylethyl contains an ethyl skeleton with cyclopropyl substituents. In chemical structural diagrams, all bonds are identified except for some carbon atoms, which are assumed to be connected to sufficient hydrogen atoms to satisfy the valence.

[0095] At certain positions, the definitions or embodiments may refer to specific rings (e.g., azetidine rings, pyridine rings, etc.) Unless otherwise indicated, these rings can be attached to any ring member as long as the valence of the atom is not exceeded.

[0096] When any two groups or two instances of the same substituent are "independently" selected from a list of alternatives, the groups may be the same or the groups may be different. For example, R a and R b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, two R a group and two R b A molecule having groups may have all groups be alkyl groups (e.g., four different alkyl groups, or four identical alkyl groups). Alternatively, the first R a may be alkyl, and the second R a may be fluoro, and the first R b may be hydroxyalkyl, and the second R b Alternatively, R may be amino (or any other substituent selected from the group). a and the first R b while both R and R may be fluoro. bmay be alkyl (i.e., some pairs of substituents may be the same and other pairs may be different). Unless otherwise indicated, two or more groups with the same definition are present, but where the definition provides alternatives, each occurrence of the same group should be understood to be independently selected from the possible alternatives. For example, if a compound has two or more R a groups are present, and R a The definition of R a Each R present in the compound may be A, B, or C. a The R groups present in the compound are independently selected from A, B, and C. a It is to be understood that the groups may be the same or different.

[0097] The compounds and their salts, including pharmaceutically acceptable salts, may be found together with other substances such as water and solvents (eg, hydrates and solvates), or may be isolated.

[0098] The compounds and their salts may further include more than one salt form. For example, a salt of a compound having two basic groups may include, for example, two trifluoroacetates, or one trifluoroacetate and one hydrochloride.

[0099] II.Compounds In some aspects, the present disclosure provides a compound having the structure (I): TIFF2025541737000008.tif50128 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; During the ceremony, Cy 1 is a substituted aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl, or Cy 1 is R 5 or R 6together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl fused to a substituted or unsubstituted 5-10 membered heteroaryl, or a substituted or unsubstituted phenyl; Cy 2 is a substituted aryl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 5-10 membered heteroaryl, or hydrogen; R 2 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl, or R 3 and R 4 together with the carbons to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted C5-C6 membered cycloalkenyl; R 5 and R 6 are each independently hydrogen, C1-C3 alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C3-C6 cycloalkyl; R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; L is hydrogen or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently identical or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted straight or branched C1-C3 alkyl, or R 8a and R 8b together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; and n is 1, 2, or 3; wherein C3-C6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; One or more hydrogen atoms in structure (I) may be replaced with deuterium atoms; provided that the compound of structure (I) has the structure: TIFF2025541737000009.tif20128, where R A is benzyl, phenethyl, or 3-CF3-benzyl.

[0100] In some embodiments, R 2 is hydrogen.

[0101] In some embodiments, R 2 is a substituted or unsubstituted straight-chain or branched C1-C3 alkyl. 2 In embodiments where R is a substituted straight chain or branched C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy. 2 is methyl. In some embodiments, R 2 is ethyl.

[0102] In some embodiments, R 2 is a substituted or unsubstituted C3-C6 cycloalkyl. 2In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0103] In some embodiments, R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0104] In some embodiments, R 3 is hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is fluoro, chloro, bromo, or iodo. In some embodiments, R 3 is unsubstituted C1-C3 alkyl. In some embodiments, R 3 is a substituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl. R 3 In embodiments where R is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy. 3 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3is a substituted C3-C6 cycloalkyl. For example, the C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. R 3 In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0105] In some embodiments, R 4 is hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is fluoro, chloro, bromo, or iodo. In some embodiments, R 4 is unsubstituted C1-C3 alkyl. In some embodiments, R 4 is a substituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl. R 4 In embodiments where R is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy. 4 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 4 is a substituted C3-C6 cycloalkyl. For example, the C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. R 4In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0106] In some embodiments, R 3 and R 4 is hydrogen.

[0107] In some embodiments, R 3 and R 4 R, together with the carbons to which they are attached, form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted C5-C6 cycloalkenyl. For example, the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. In another example, the C5-C6 cycloalkenyl can be cyclopentenyl or cyclohexenyl. R 3 and R 4 forms a substituted C3-C6 cycloalkyl or a substituted C5-C6 cycloalkenyl, the C3-C6 cycloalkyl or C5-C6 cycloalkenyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0108] In some embodiments, R 3 and R 4 If a chiral center exists at the carbon atom to which is attached, the compound has (R) stereochemistry, (S) stereochemistry, is a racemic mixture, or contains a mixture of (R) and (S) stereoisomers.

[0109] In some embodiments, R 5 and R 6 are each independently hydrogen, C1-C3 alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C3-C6 cycloalkyl.

[0110] In some embodiments, R 5 is hydrogen, C1-C3 alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C3-C6 cycloalkyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is C1-C3 alkoxy. In some embodiments, R 5 is C1-C3 haloalkoxy. For example, R 5 The alkoxy and haloalkoxy in R are methoxy, ethoxy, propoxy, or isopropoxy. 5 is haloalkyl. R 5 In embodiments where R is haloalkyl or haloalkoxy, the halo is one or more of fluoro, chloro, bromo, or iodo. 5 is C3-C6 cycloalkyl. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. 5 is C1-C3 hydroxyalkyl.

[0111] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is methyl.

[0112] In some embodiments, R 6is hydrogen, C1-C3 alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C3-C6 cycloalkyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 6 is C1-C3 alkoxy. In some embodiments, R 6 is C1-C3 haloalkoxy. For example, R 6 The alkoxy and haloalkoxy in R are methoxy, ethoxy, propoxy, or isopropoxy. 6 is haloalkyl. R 6 In embodiments where R is haloalkyl or haloalkoxy, the halo is one or more of fluoro, chloro, bromo, or iodo. 6 is C3-C6 cycloalkyl. In some embodiments, R 6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclohexyl. 6 is C1-C3 hydroxyalkyl.

[0113] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is methyl.

[0114] In some embodiments, R 5 and R 6 are identical. In some embodiments, R 5 and R 6 In some embodiments, R 5 and R 6 are both hydrogen. In some embodiments, R 5 and R 6 In some embodiments, one of R 5 and R 6is methyl, ethyl, n-propyl, or isopropyl, and R 5 and R 6 The other is hydrogen, methyl, ethyl, n-propyl, or isopropyl.

[0115] In some embodiments, R 5 and R 6 If a chiral center exists at the carbon atom to which is attached, the compound has (R) stereochemistry, (S) stereochemistry, is a racemic mixture, or is a mixture of the (R) and (S) stereoisomers.

[0116] In some embodiments, R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl.

[0117] In some embodiments, R 7 is hydrogen.

[0118] In some embodiments, R 7 is fluoro, chloro, bromo, or iodo.

[0119] In some embodiments, R 7 is unsubstituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl.

[0120] In some embodiments, R 7 is a substituted C1-C3 alkyl. 7 In embodiments where is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0121] In some embodiments, R7 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 7 is a substituted C3-C6 cycloalkyl. For example, the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0122] R 7 In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0123] In some embodiments, R 7 is selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl.

[0124] In some embodiments, the compound of structure (I) has structure (IA): I have TIFF2025541737000010.tif41128.

[0125] In some embodiments, the compounds of structure (I) and (IA) have the structures (IA-1), (IA-2), (IA-3), (IA-4): TIFF2025541737000011.tif77128, or a combination thereof.

[0126] In some embodiments of structures (I), (IA), (IA-1), (IA-2), (IA-3), and (IA-4), R 6 is hydrogen. In some embodiments of structures (IA), (IA-1), (IA-2), (IA-3), and (IA-4), R 6 is methyl.

[0127] In some embodiments of structure (I), Cy 1 is R 5 or R 6 together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl fused to a substituted or unsubstituted 5-10-membered heteroaryl, or a substituted or unsubstituted phenyl. In some embodiments, the C3-C6 cycloalkyl of the C3-C6 cycloalkyl fused to a 5-10-membered heteroaryl or phenyl is unsubstituted. In some embodiments, the C3-C6 cycloalkyl of the C3-C6 cycloalkyl fused to a 5-10-membered heteroaryl or phenyl is substituted. In embodiments in which the C3-C6 cycloalkyl is substituted, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0128] In some embodiments of structure (I), Cy 1 is R 5 or R 6together with the carbon to which they are attached form a substituted or unsubstituted C5 cycloalkyl fused to a substituted or unsubstituted 5-10 membered heteroaryl, or a substituted or unsubstituted phenyl. In some embodiments, the C5 cycloalkyl of the C5 cycloalkyl fused to a 5-10 membered heteroaryl or phenyl is unsubstituted. In some embodiments, the C5 cycloalkyl of the C5 cycloalkyl fused to a 5-10 membered heteroaryl or phenyl is substituted. In embodiments in which the C5 cycloalkyl is substituted, the C5 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0129] In some embodiments of structure (I), Cy 1 is R 5 or R 6 together with the carbon to which they are attached, form a substituted or unsubstituted C6 cycloalkyl fused to a substituted or unsubstituted 5-10 membered heteroaryl, or a substituted or unsubstituted phenyl. In some embodiments, the C6 cycloalkyl of the C6 cycloalkyl fused to a 5-10 membered heteroaryl or phenyl is unsubstituted. In some embodiments, the C6 cycloalkyl of the C6 cycloalkyl fused to a 5-10 membered heteroaryl or phenyl is substituted. In embodiments in which the C6 cycloalkyl is substituted, the C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0130] In some embodiments of structure (I), Cy 1 is R5 or R 6 together with the carbon to which they are attached, form a substituted or unsubstituted C3-C6 cycloalkyl fused to a substituted or unsubstituted 5-6-membered heteroaryl. In some embodiments, the C3-C6 cycloalkyl of the C3-C6 cycloalkyl fused to a 5-6-membered heteroaryl is unsubstituted. In some embodiments, the C3-C6 cycloalkyl of the C3-C6 cycloalkyl fused to a 5-6-membered heteroaryl is substituted. In embodiments in which the C3-C6 cycloalkyl is substituted, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0131] In some embodiments of structure (I), Cy 1 is R 5 or R 6 together with the carbon to which they are attached, form a substituted or unsubstituted C5 cycloalkyl fused to a substituted or unsubstituted 5-6-membered heteroaryl. In some embodiments, the C5 cycloalkyl of the C5 cycloalkyl fused to a 5-6-membered heteroaryl is unsubstituted. In some embodiments, the C5 cycloalkyl of the C5 cycloalkyl fused to a 5-6-membered heteroaryl is substituted. In embodiments in which the C5 cycloalkyl is substituted, the C5 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0132] In some embodiments of structure (I), Cy 1 is R 5 or R6 together with the carbon to which they are attached, form a substituted or unsubstituted C6 cycloalkyl fused to a substituted or unsubstituted 5-6-membered heteroaryl. In some embodiments, the C6 cycloalkyl of the C6 cycloalkyl fused to a 5-6-membered heteroaryl is unsubstituted. In some embodiments, the C6 cycloalkyl of the C6 cycloalkyl fused to a 5-6-membered heteroaryl is substituted. In embodiments in which the C6 cycloalkyl is substituted, the C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0133] In some embodiments of structure (I), Cy 1 is R 5 or R 6 together with the carbon to which they are attached, form a substituted or unsubstituted C5 cycloalkyl fused to a substituted or unsubstituted 6-membered heteroaryl. In some embodiments, the C5 cycloalkyl of the C5 cycloalkyl fused to a 6-membered heteroaryl is unsubstituted. In some embodiments, the C5 cycloalkyl of the C5 cycloalkyl fused to a 6-membered heteroaryl is substituted. In embodiments in which the C5 cycloalkyl is substituted, the C5 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0134] In some embodiments, the compound of structure (I) has structure (IB): I have TIFF2025541737000012.tif49128.

[0135] In some embodiments of structure (IB), m is 1. In some embodiments of structure (IB), m is 2.

[0136] In some embodiments, the compound of structure (IB) has structure (IB-1), (IB-2), (IB-3), (IB-4): TIFF2025541737000013.tif92129, or a combination thereof.

[0137] In some embodiments of structures (I), (IA), and (IB), Cy 1 is unsubstituted C6~C 10 In some embodiments of structures (I), (IA), and (IB), Cy is aryl. 1 is unsubstituted phenyl.

[0138] In some embodiments of structures (I), (IA), and (IB), Cy 1 is substituted C6~C 10 In some embodiments of structures (I), (IA), and (IB), Cy is aryl. 1 is a substituted phenyl.

[0139] In some embodiments of structures (I), (IA), and (IB), Cy 1 is hydrogen, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 )NH2, C(=NOH)NH2, C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 C6-C substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl 10 aryl or C6-C 10When an aryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is a C6-C6 10 fused to an aryl, where R 8 , R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14, N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0140] In some embodiments of structures (I), (IA), and (IB), Cy 1 is hydrogen, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR8 )NH2, C(=NOH)NH2, C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl; or, when the phenyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the phenyl; where R 8 , R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0141] In some embodiments of structures (I), (IA), and (IB), Cy 1 is phenyl substituted with at least one substituent selected from the group consisting of -C(=NH)NH2, halogen, haloalkyl, aminyl, aminylalkyl, and tetrazole.

[0142] In some embodiments of structures (I), (IA), and (IB), Cy 1 are -C(=NH)NH2, chloro, fluoro, -CHF2, -NH2, -CF3, -CH2NH2, -CH(CH3)NH2, and TIFF2025541737000014.tif13128.

[0143] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000015.tif68135.

[0144] In some embodiments of structure (IB), Cy 1 teeth TIFF2025541737000016.tif43146.

[0145] In some embodiments of structure (IB), Cy 1 teeth TIFF2025541737000017.tif20128.

[0146] In some embodiments of structures (I), (IA), and (IB), Cy 1 is a substituted or unsubstituted 5-10 membered heteroaryl.

[0147] In some embodiments of structures (I), (IA), and (IB), Cy 1 is an unsubstituted 5-10 membered heteroaryl.

[0148] In some embodiments of structures (I), (IA), and (IB), Cy 1 is a substituted 5-10 membered heteroaryl.

[0149] In some embodiments of structures (I), (IA), and (IB), Cy 1 is hydrogen, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10)NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 a 5-10 membered heteroaryl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl; or, when the heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the heteroaryl; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0150] In some embodiments of structures (I), (IA), and (IB), Cy 1 is pyridinyl, pyrrolopyridinyl, imidazopyridinyl, thienopyridinyl, benzimidazolyl, isoindolinyl, thiophenyl, or benzothiazolyl.

[0151] In some embodiments of structures (I), (IA), and (IB), Cy 1 is substituted or unsubstituted pyridinyl.

[0152] In some embodiments of structures (I), (IA), and (IB), Cy 1 is unsubstituted pyridinyl.

[0153] In some embodiments of structures (I), (IA), and (IB), Cy 1 is a substituted pyridinyl.

[0154] In some embodiments of structures (I), (IA), and (IB), Cy 1 is hydrogen, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 pyridinyl substituted by one or more, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl; or, when the pyridinyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the pyridinyl; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; one or more, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13, C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0155] In some embodiments of structures (I), (IA), and (IB), Cy 1 is one or more hydrogens, deuteriums, C 1~6 Alkyl, C 1~6 Deuterated alkyl, halogen, aminyl alkyl, amino, C 1~3 Alkoxy, C 1~6 and pyridinyl substituted with haloalkyl, or a combination thereof.

[0156] In some embodiments of structures (I), (IA), and (IB), Cy 1 is pyridinyl substituted with one or more hydrogen, methyl, ethyl, CD3, amino, aminylmethyl, F, Cl, Br, methoxy, or combinations thereof.

[0157] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000018.tif75147.

[0158] In some embodiments of structure (I) and structure (IA), Cy 1 teeth TIFF2025541737000019.tif25128.

[0159] In some embodiments of structure (I) and structure (IA), Cy 1 teeth TIFF2025541737000020.tif18128.

[0160] In some embodiments of structure (IB), Cy 1 teeth The file is TIFF2025541737000021.tif22128.

[0161] In some embodiments of structure (IB), Cy 1 teeth TIFF2025541737000022.tif22128.

[0162] In some embodiments of structure (IB), Cy 1 teeth TIFF2025541737000023.tif18128.

[0163] In some embodiments of structures (I), (IA), and (IB), R 1a are hydrogen, deuterium, and C 1~6 Alkyl, and C 1~6 deuterated alkyls.

[0164] In some embodiments of structures (I), (IA), and (IB), R 1a is selected from the group consisting of hydrogen, methyl, ethyl, and CD3.

[0165] In some embodiments of structures (I), (IA), and (IB), R 1a is hydrogen.

[0166] In some embodiments of structures (I), (IA), and (IB), R 1b , R 1c , R 1d , and R 1e are hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 Deuterated alkyl, halogen, aminyl alkyl, amino, C 1~3 Alkoxy, and C 1~6 haloalkyl.

[0167] In some embodiments of structures (I), (IA), and (IB), R 1b , R 1c , R 1d , and R 1e is selected from the group consisting of hydrogen, methyl, ethyl, CD3, amino, aminylmethyl, F, Cl, Br, and methoxy.

[0168] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000024.tif204139TIFF2025541737000025.tif216140TIFF2025541737000026.tif155154.

[0169] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000027.tif30128.

[0170] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000028.tif42148.

[0171] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000029.tif70147.

[0172] In some embodiments of structures (I) and (IA), Cy 1 teeth TIFF2025541737000030.tif69147.

[0173] In some embodiments of structures I and (IB), Cy 1 teeth TIFF2025541737000031.tif58148.

[0174] In some embodiments of structures I and (IB), Cy 1 teeth TIFF2025541737000032.tif19128.

[0175] In some embodiments, the compound has the structure (IC): I have TIFF2025541737000033.tif50128.

[0176] In some embodiments, the compound has the structure (ID): TIFF2025541737000034.tif50128, where R 1b is hydrogen or methyl, and R 6 is hydrogen or methyl.

[0177] In some embodiments, the compound has the structure (IE): TIFF2025541737000035.tif41128, where R 1a is hydrogen or C1-C3 alkyl, and R 6 is hydrogen or methyl.

[0178] In some embodiments of structure (IE), R 1a is hydrogen.

[0179] In some embodiments of structure (IE), R 6 is methyl.

[0180] In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), n is 1, 2, or 3. In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), n is 1. In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), n is 2. In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), n is 3.

[0181] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), each -(CR 8a R 8bIn some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), each -(CR 8a R 8b In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), each -(CR 8a R 8b In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), -(CR 8a R 8b )- are identical, and -(CR 8a R 8b )-Some of them are different.

[0182] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a and R 8b are each independently hydrogen or substituted or unsubstituted C1-C3 alkyl. In such embodiments, R 8a and R 8b are identical or R 8a and R 8b is different.

[0183] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a , R 8b , or R 8a and R 8b Both are hydrogen.

[0184] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a , R 8b , or R 8a and R 8b and both are unsubstituted C1-C3 alkyl.

[0185] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R8a , R 8b , or R 8a and R 8b and both are substituted C1-C3 alkyl. 8a , R 8b , or R 8a and R 8b In embodiments where both and are substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0186] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a , R 8b , or R 8a and R 8b and both are unsubstituted methyl, ethyl, n-propyl, or isopropyl.

[0187] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a , R 8b , or R 8a and R 8b Both R and R are substituted methyl, ethyl, n-propyl, or isopropyl. 8a , R 8b , or R 8a and R 8b In embodiments where both are substituted methyl, ethyl, n-propyl, or isopropyl, the methyl, ethyl, n-propyl, or isopropyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0188] R 8a and R 8b In embodiments where both R and R are methyl, ethyl, n-propyl, or isopropyl, 8a and R 8b are identical. R 8a and R 8b In embodiments where both R and R are methyl, ethyl, n-propyl, or isopropyl, 8a and R 8b is different.

[0189] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a and R 8b is hydrogen and R 8a and R 8b The other is methyl.

[0190] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), R 8a and R 8b R, together with the carbon to which they are attached, form a substituted or unsubstituted C3-C6 cycloalkyl. 8a and R 8b In embodiments where R forms a substituted or unsubstituted C3-C6 cycloalkyl, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. 8a and R 8b In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0191] In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), L is -CH-, -CHCH-, -CH(CH)-, or -CHCHCH-. In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), L is -CH(CH)-. In some embodiments of Structures (I), (IA), (IB), (IC), (ID), and (IE), L is -CH-.

[0192] In embodiments where a chiral center is present, L has (R) stereochemistry, (S) stereochemistry, is a racemic mixture, or is a mixture of (R) and (S) stereoisomers.

[0193] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is substituted C6~C 10 It is aryl.

[0194] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 C6-C substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl 10 aryl or C6-C 10 When an aryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is a C6-C6 10 fused to an aryl, where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1-5, 1-4, 1-3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0195] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a substituted phenyl.

[0196] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl; or, when the phenyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the phenyl; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0197] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 teeth TIFF2025541737000036.tif85149, where R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and 5- or 6-membered heterocyclyl containing from 1 to 4 heteroatoms selected from the group consisting of N, S, and O; or R 2a , R 2b , R 2c , R 2d , and R 2e When any two of are bonded to adjacent carbon atoms, they are taken together with the carbon atoms to which they are bonded to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl.

[0198] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2is phenyl independently substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0199] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a phenyl substituted on two adjacent carbon atoms of the phenyl such that, together with the carbon atoms to which the substituents are attached, they form a phenyl-fused dioxane, a phenyl-fused furan, or a phenyl-fused difluorodioxolane.

[0200] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 teeth TIFF2025541737000037.tif76128TIFF2025541737000038.tif221148TIFF2025541737000039.tif113145.

[0201] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 teeth TIFF2025541737000040.tif76130TIFF2025541737000041.tif224148TIFF2025541737000042.tif92147.

[0202] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is an unsubstituted C3-C6 cycloalkyl.

[0203] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10C3-C6 cycloalkyl substituted by one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl; where R 9 and R 10 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl. one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0204] In the foregoing embodiment, the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0205] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2is a C3-C6 cycloalkyl substituted with one or more hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, or a combination thereof.

[0206] In the foregoing embodiment, the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0207] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a C5-C6 cycloalkyl substituted with one or more methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, COOH, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, or combinations thereof.

[0208] In the foregoing embodiment, the C5-C6 cycloalkyl is cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0209] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a C5 cycloalkyl substituted with one or more methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, COOH, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, or combinations thereof.

[0210] In the foregoing embodiment, the C5 cycloalkyl is cyclopentyl or bicyclopentyl.

[0211] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 teeth TIFF2025541737000043.tif20128.

[0212] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is an unsubstituted 5-10 membered heteroaryl.

[0213] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a substituted 5-10 membered heteroaryl.

[0214] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 or a 5-10-membered heteroaryl substituted with one or more, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4-10-membered heterocyclyl; or, when the heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the heteroaryl, and wherein the substituted C5-C6 cycloalkyl fused to the heteroaryl and the substituted 5- or 6-membered heterocyclic ring fused to the heteroaryl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 and R 10 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0215] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a 5- to 10-membered heteroaryl substituted with one or more substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1-4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof.

[0216] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is an unsubstituted 5- to 6-membered heteroaryl.

[0217] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a substituted 5- to 6-membered heteroaryl.

[0218] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a 5-6 membered heteroaryl substituted with one or more substituents independently selected from hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0219] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is an unsubstituted pyrazole.

[0220] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a substituted pyrazole.

[0221] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2is a pyrazole substituted with one or more substituents independently selected from hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0222] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 is a phenyl-substituted pyrazole.

[0223] In some embodiments of structures (I), (IA), (IB), (IC), (ID), and (IE), Cy 2 teeth The file is TIFF2025541737000044.tif13128.

[0224] In some embodiments of structures (I), (IA), (IC), (ID), and (IE), Cy 2 is hydrogen.

[0225] In some embodiments of structures (I), (IA), (ID), and (IE), the compound has a structure selected from the structures in Table 1 below.

[0226] In some embodiments of structures (I), (IB), and (IC), the compound has a structure selected from the structures in Table 2 below.

[0227] In some aspects, the present disclosure provides a compound having structure (II): TIFF2025541737000045.tif41128, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 teeth Selected from the group consisting of TIFF2025541737000046.tif111142; Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, Amino C 1~6 Alkyl, C 1~6 Alkyloxy, cyano, cyanomethyl, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10or phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl, or phenyl is substituted at two adjacent carbon atoms and the substituents, together with the carbon atoms to which they are attached, form a C5 to C6 cycloalkyl or a 5 to 6-membered heterocycle fused to the phenyl, and each of the C5 to C6 cycloalkyl or 5 to 6-membered heterocycle fused to the phenyl is selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 and R 10 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 6 is hydrogen, C 1~3 Alkyl, or C 1~3 is haloalkyl; R 7 are hydrogen, deuterium, and C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, or halogen; L is -CH2-, -CH2CH2-, -CH(CH3)-, or -CH2CH2CH2-, and One or more hydrogen atoms may be replaced with one or more deuterium atoms.

[0228] In some embodiments of structure (II), R 6 is hydrogen or methyl.

[0229] In some embodiments of structure (II), R 7 is hydrogen.

[0230] In some embodiments of structure (II), Cy 1 teeth TIFF2025541737000047.tif65149.

[0231] In some embodiments, the compound has the structure (II-A): TIFF2025541737000048.tif45128, where R 1b is selected from the group consisting of hydrogen, methyl, ethyl, and CD3; and R 6 is hydrogen or methyl.

[0232] In some embodiments of structure (II-A), R 1b is hydrogen.

[0233] In some embodiments of structure (II-A), R 1b is methyl.

[0234] In some embodiments of structure (II-A), R 6 is hydrogen.

[0235] In some embodiments of structure (II-A), R 6 is methyl.

[0236] In some embodiments, the compound has structure (II-B): TIFF2025541737000049.tif43128, where R 1a is hydrogen or C1-C3 alkyl, and R 6 is hydrogen or methyl.

[0237] In some embodiments of structure (II-B), R 1a is hydrogen.

[0238] In some embodiments of structure (II-B), R 6 is hydrogen.

[0239] In some embodiments of structure (II-B), R 6 is methyl.

[0240] In some embodiments, the compound has the structure (II-C): TIFF2025541737000050.tif46128, where R 1a is hydrogen or C1-C3 alkyl, and R 6 is hydrogen or methyl.

[0241] In some embodiments of structure (II-C), R 1a is hydrogen.

[0242] In some embodiments of structure (II-C), R 6 is hydrogen.

[0243] In some embodiments of structure (II-C), R 6 is methyl.

[0244] In some embodiments, the compound has structure (II-D): TIFF2025541737000051.tif44128, where R 6 is hydrogen or methyl.

[0245] In some embodiments of structure (II-D), R 6 is hydrogen.

[0246] In some embodiments of structure (II-D), R 6 is methyl.

[0247] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), L is —CH 2 — or —CH(CH 3 )—.

[0248] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), L is —CH 2 —.

[0249] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), L is —CH(CH 3 )—.

[0250] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), Cy 2 teeth TIFF2025541737000052.tif85138, where R 2a , R 2b , R 2c , R 2d , and R 2eare each independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and 5- or 6-membered heterocyclyl containing from 1 to 4 heteroatoms selected from the group consisting of N, S, and O; or R 2a , R 2b , R 2c , R 2d , and R 2e When any two of are bonded to adjacent carbon atoms, they are combined with the carbon atoms to which they are bonded to form the adjacent R 2a , R 2b , R 2c , R 2d , and R 2e form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- to 6-membered heterocyclic ring is fused to a phenyl, and wherein the substituted C5-C6 cycloalkyl fused to the phenyl and the substituted 5- to 6-membered heterocyclic ring fused to the phenyl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6It may be optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens.

[0251] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), Cy 2 teeth TIFF2025541737000053.tif184137TIFF2025541737000054.tif239155.

[0252] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), Cy 2 teeth TIFF2025541737000055.tif206137TIFF2025541737000056.tif121155.

[0253] In some embodiments of structures (II), (II-A), (II-B), (II-C), and (II-D), the compound has a structure selected from the structures in Table 1 below.

[0254] In some aspects, the present disclosure provides a compound of structure (III): TIFF2025541737000057.tif51128, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl; Cy 2 is a substituted aryl, a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 5-10 membered heteroaryl; R 2 is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted cycloalkyl, or R 3 and R 4 together with the carbons to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 5-6 membered cycloalkenyl; R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl; L is absent or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently identical or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted C1-C3 alkyl, or R 8a and R 8b together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; m is 1 or 2; and n is 1, 2, or 3; wherein C3-C6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; One or more hydrogen atoms may be replaced with deuterium atoms.

[0255] In some embodiments of structure (III), m is 1.

[0256] In some embodiments of structure (III), m is 2.

[0257] In some embodiments of structure (III), R 2 is a substituted or unsubstituted C1-C3 alkyl. 2 In embodiments where R is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy. 2 is methyl. In some embodiments, R 2 is ethyl.

[0258] In some embodiments of structure (III), R 2 is a substituted or unsubstituted C3-C6 cycloalkyl. 2 In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0259] In some embodiments of structure (III), R 2 is hydrogen.

[0260] In some embodiments of structure (III), R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0261] In some embodiments of structure (III), R 3 is hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3is hydrogen. In some embodiments, R 3 is fluoro, chloro, bromo, or iodo. In some embodiments, R 3 is unsubstituted C1-C3 alkyl. In some embodiments, R 3 is a substituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl. R 3 In embodiments where R is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy. 3 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3 is a substituted C3-C6 cycloalkyl. For example, the C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. R 3 In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0262] In some embodiments of structure (III), R 4 is hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is fluoro, chloro, bromo, or iodo. In some embodiments, R 4is unsubstituted C1-C3 alkyl. In some embodiments, R 4 is a substituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl. R 4 In embodiments where R is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy. 4 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 4 is a substituted C3-C6 cycloalkyl. For example, the C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. R 4 In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0263] In some embodiments of structure (III), R 3 and R 4 R, together with the carbons to which they are attached, form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted C5-C6 cycloalkenyl. For example, the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl. In another example, the C5-C6 cycloalkenyl can be cyclopentenyl or cyclohexenyl. R 3 and R 4forms a substituted C3-C6 cycloalkyl or a substituted C5-C6 cycloalkenyl, the C3-C6 cycloalkyl or C5-C6 cycloalkenyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0264] In some embodiments of structure (III), R 3 and R 4 If a chiral center exists at the carbon atom to which is attached, the compound has (R) stereochemistry, (S) stereochemistry, is a racemic mixture, or contains a mixture of (R) and (S) stereoisomers.

[0265] In some embodiments of structure (III), R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl.

[0266] In some embodiments of structure (III), R 7 is hydrogen.

[0267] In some embodiments of structure (III), R 7 is fluoro, chloro, bromo, or iodo.

[0268] In some embodiments of structure (III), R 7 is unsubstituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl.

[0269] In some embodiments of structure (III), R 7 is a substituted C1-C3 alkyl. For example, C1-C3 alkyl is methyl, ethyl, n-propyl, or isopropyl. R 7In embodiments where is a substituted C1-C3 alkyl, the C1-C3 alkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0270] In some embodiments of structure (III), R 7 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R 7 is a substituted C3-C6 cycloalkyl. For example, C3-C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0271] R 7 In embodiments where is a substituted C3-C6 cycloalkyl, the C3-C6 cycloalkyl is substituted with one or more of C1-C3 alkyl, halogen, C1-C3 alkoxy, or combinations thereof, including combinations of one or more of the same or different C1-C3 alkyl, one or more of the same or different halogen, and / or one or more of the same or different C1-C3 alkoxy.

[0272] In some embodiments of structure (III), R 7 is selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl.

[0273] In some embodiments, the compound has the structure (III-A): I have TIFF2025541737000058.tif46128.

[0274] In some embodiments of structures (III) and (III-A), the compound has the structure: TIFF2025541737000059.tif92128, or a combination thereof.

[0275] In some embodiments of structures (III) and (III-A), L is -CH2-, -CH2CH2-, -CH(CH3)-, or -CH2CH2CH2-.

[0276] In some embodiments of structures (III) and (III-A), L is —CH 2 —.

[0277] In some embodiments of structures (III) and (III-A), Cy 1 is hydrogen, C(NH)NH2, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH2, C(=NOC(=O)OR 8 )NH2, C(=NOH)NH2, C(=NH)NHC(=O)NHC(=O)N(CH3)R 13 , C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl; or, when the phenyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the phenyl; where R 8 , R 9 , R 10 , R 11 , and R 12is independently selected at each occurrence from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, aryl, arylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; R 13 is C6 to C optionally substituted with CH2OC(=O)CH3 10 aryl or 5- to 10-membered heteroaryl; One or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C1-C6 alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halo, CN, OR e , S.R. e , C(O)R e , C(O)NR e R f , C(O)OR e ,OC(O)R e , OC(O)NR e R f , N.R. e R f , N.R. e C(O)R f , N.R. e C(O)NR f R g , N.R. e C(O)OR f , C(=NR e )NR f R g , N.R. e C(=NR f )NR g R h , S(O)R e , S(O)NRe R f , S(O)2R e , N.R. e S(O)2R f , S(O)NR e R f and oxo, wherein R e , R f , R g , and R h is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, C1-C6 alkoxy, aryl, arylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0278] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000060.tif26128, where R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 is selected from the group consisting of deuterated alkyl, amino, and aminyl alkyl; or R 1a , R 1b , R 1c , and R 1d When any two of 1a , R 1b , R 1c , and R 1dtwo of which, together with the carbon atoms to which they are attached, are connected to form a substituted or unsubstituted 5- or 6-membered carbocyclic ring or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted 5- or 6-membered carbocyclic ring or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl.

[0279] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000061.tif43146.

[0280] In some embodiments of structures (III) and (III-A), Cy 1 is phenyl substituted with amino.

[0281] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000062.tif18128.

[0282] In some embodiments of structures (III) and (III-A), Cy 1 is a substituted or unsubstituted 5-10 membered heteroaryl.

[0283] In some embodiments of structures (III) and (III-A), Cy 1 is an unsubstituted 5-10 membered heteroaryl.

[0284] In some embodiments of structures (III) and (III-A), Cy 1 is hydrogen, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9, C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10or a 5-10-membered heteroaryl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4-10-membered heterocyclyl; or when the 5-10-membered heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a 5-10-membered heteroaryl, and wherein the substituted C5-C6 cycloalkyl fused to the 5-10-membered heteroaryl and the substituted 5- or 6-membered heterocyclic ring fused to the 5-10-membered heteroaryl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0285] In some embodiments of structures (III) and (III-A), Cy 1 is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0286] In some embodiments of structures (III) and (III-A), Cy 1 is an unsubstituted 5- to 6-membered heteroaryl.

[0287] In some embodiments of structures (III) and (III-A), Cy 1 is hydrogen, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10or a 5- to 6-membered heteroaryl substituted with one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; or, when the heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the heteroaryl, wherein the substituted C5-C6 cycloalkyl fused to the 5- to 6-membered heteroaryl and the substituted 5- or 6-membered heterocyclic ring fused to the 5- to 6-membered heteroaryl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; One or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0288] In some embodiments of structures (III) and (III-A), Cy 1 is substituted or unsubstituted pyridinyl.

[0289] In some embodiments of structures (III) and (III-A), Cy 1 is unsubstituted pyridinyl.

[0290] In some embodiments of structures (III) and (III-A), Cy 1 is hydrogen, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10or pyridinyl substituted with one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4-10 membered heterocyclyl; or, when the pyridinyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the pyridinyl, and wherein the substituted C5-C6 cycloalkyl fused to the pyridinyl and the substituted 5- or 6-membered heterocyclic ring fused to the pyridinyl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; One or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo; R 13 , R 14 , R15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0291] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000063.tif33135, where R 1a , R 1b , and R 1c are independently hydrogen, C 1~6 Deuterated alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10, C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH3)R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or when pyridinyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the pyridinyl, and wherein the substituted C5-C6 cycloalkyl fused to the pyridinyl and the substituted 5- or 6-membered heterocyclic ring fused to the pyridinyl are C 1~6Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 1a , R 1b , and R 1c But substitution C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When R is cycloalkyl or substituted 4-10 membered heterocyclyl, 1a , R 1b , and R 1c is halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14, C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 is C6 to C optionally substituted with CH2OC(=O)CH3 10 It is aryl or 5- to 10-membered heteroaryl.

[0292] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000064.tif32134, wherein R 1a , R 1b , and R 1c are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, amino, aminylalkyl, alkoxy, and halogen.

[0293] In some embodiments of structures (III) and (III-A), Cy 1 is an amino-substituted pyridinyl.

[0294] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000065.tif57146.

[0295] In some embodiments of structures (III) and (III-A), Cy 1 teeth TIFF2025541737000066.tif20128.

[0296] In some embodiments, the compound has the structure (III-B): I have TIFF2025541737000067.tif48128.

[0297] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a substituted or unsubstituted C3-C6 cycloalkyl.

[0298] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is an unsubstituted C3-C6 cycloalkyl.

[0299] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is hydrogen, C 2~6Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 C3-C6 cycloalkyl substituted by one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl; where R 9 and R 10 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, each of the one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents is / are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0300] In the aforementioned embodiment, Cy 2 The C3-C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0301] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a C5-C6 cycloalkyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof.

[0302] In some embodiments of structures (III), (III-A), and (III-B), Cy2 is a C5-C6 cycloalkyl independently substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, and combinations thereof.

[0303] In the aforementioned embodiment, Cy 2 The C5-C6 cycloalkyl is cyclopentyl, cyclohexyl, bicyclopentyl, or bicyclohexyl.

[0304] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 teeth TIFF2025541737000068.tif20128.

[0305] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is unsubstituted or substituted 5-10 membered heteroaryl.

[0306] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is an unsubstituted 5-10 membered heteroaryl.

[0307] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10or a 5-10-membered heteroaryl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4-10-membered heterocyclyl; or when the 5-10-membered heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a 5-10-membered heteroaryl, and wherein the substituted C5-C6 cycloalkyl fused to the 5-10-membered heteroaryl and the substituted 5- or 6-membered heterocyclic ring fused to the 5-10-membered heteroaryl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 and R 10 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are each halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0308] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a 5-10 membered heteroaryl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof.

[0309] In some embodiments of structures (III), (III-A), and (III-B), Cy 2is a 5-10 membered heteroaryl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0310] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a 5- to 10-membered heteroaryl substituted on two adjacent carbon atoms of the heteroaryl such that the substituents, together with the carbon atoms to which they are attached, form a heteroaryl-fused dioxane, a heteroaryl-fused furan, or a heteroaryl-fused difluorodioxolane.

[0311] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is unsubstituted or substituted 5- to 6-membered heteroaryl.

[0312] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is an unsubstituted 5- to 6-membered heteroaryl.

[0313] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 or a 5- to 6-membered heteroaryl substituted with one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; or when the 5- to 6-membered heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the 5- to 6-membered heteroaryl, and wherein the substituted C5-C6 cycloalkyl fused to the 5- to 6-membered heteroaryl and the substituted 5- or 6-membered heterocyclic ring fused to the 5- to 6-membered heteroaryl are C 1~6Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 and R 10 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; One or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13, OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0314] In some embodiments of structures (III), (III-A), and (III-B), Cy 2is a 5- to 6-membered heteroaryl substituted with one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof.

[0315] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a 5-6 membered heteroaryl substituted with one or more, 1 to 3, 1 or 2, 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0316] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a 5- to 10-membered heteroaryl substituted on two adjacent carbon atoms of the heteroaryl such that the substituents, together with the carbon atoms to which they are attached, form a heteroaryl-fused dioxane, a heteroaryl-fused furan, or a heteroaryl-fused difluorodioxolane.

[0317] In some embodiments of structures (III), (III-A), and (III-B), Cy 2is unsubstituted or substituted pyrazolyl.

[0318] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is unsubstituted pyrazolyl.

[0319] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is pyrazolyl substituted with one or more substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof.

[0320] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is pyrazolyl substituted with one or more substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0321] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 teeth TIFF2025541737000069.tif13128.

[0322] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is substituted C6~C 10 It is aryl.

[0323] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10, S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 C6-C substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4 to 10-membered heterocyclyl 10 aryl or C6-C 10 When an aryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is a C6-C6 10 fused to an aryl, and wherein C6-C 10 Substituted C5-C6 cycloalkyl and C6-C aryl fused 10 The substituted 5- or 6-membered heterocyclic ring fused to the aryl is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0324] In some embodiments of structures (III), (III-A), and (III-B), Cy 2is a C6-C alkyl group substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof. 10 It is aryl.

[0325] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a C6-C alkyl group substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof. 10 It is aryl.

[0326] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a C-C alkyl group substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, fluoro, chloro, methoxy, CN, cyanomethyl, trifluoromethyl, difluoromethyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof; 10 It is aryl.

[0327] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a substituted phenyl.

[0328] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 or, when the phenyl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to the phenyl, and wherein the substituted C5-C6 cycloalkyl fused to the phenyl and the substituted 5- or 6-membered heterocyclic ring fused to the phenyl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; where R 9 , R10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are substituted C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When cycloalkyl or substituted 4-10 membered heterocyclyl, one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0329] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof.

[0330] In some embodiments of structures (III), (III-A), and (III-B), Cy 2is phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0331] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is phenyl substituted with one or more, 1 to 5, 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of methyl, fluoro, chloro, methoxy, CN, cyanomethyl, trifluoromethyl, difluoromethyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

[0332] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is phenyl substituted with one or more methyls, 1 to 5 methyl groups, 1 to 4 methyl groups, 1 to 3 methyl groups, 1 or 2 methyl groups, 3 methyl groups, 2 methyl groups, or 1 methyl group.

[0333] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 teeth TIFF2025541737000070.tif83148, where R 2a , R 2b , and R 2care each independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof; or R 2a , R 2b , and R 2c When any two of are bonded to adjacent carbon atoms, they together with the carbon atoms to which they are bonded form R 2a , R 2b , and R 2c form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl, and wherein the substituted C5-C6 cycloalkyl fused to the phenyl and the substituted 5- or 6-membered heterocyclic ring fused to the phenyl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 It may be optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens.

[0334] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 is a phenyl substituted on two adjacent carbon atoms of the phenyl such that, together with the carbon atoms to which the substituents are attached, they form a phenyl-fused dioxane, a phenyl-fused furan, or a phenyl-fused difluorodioxolane.

[0335] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 teeth TIFF2025541737000071.tif76128TIFF2025541737000072.tif221139TIFF2025541737000073.tif124140.

[0336] In some embodiments of structures (III), (III-A), and (III-B), Cy 2 teeth TIFF2025541737000074.tif150153.

[0337] In some embodiments, the compound has the structure (III-C): TIFF2025541737000075.tif48128, where R 2a , R 2b , R 2c , R 2d , and R 2e are independently hydrogen, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 1~6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9, OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O)2R 9 , N(R 9 )S(O)2R 10 , S(O)NR 9 R 10 , oxo, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted C 6~10 Aryl alkyl, substituted or unsubstituted C 6~10 Aryloxy, substituted or unsubstituted C 6~10 Arylalkoxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3~10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or R 2a , R 2b , R 2c , R 2d , and R 2e When any two of the groups are connected to a phenyl at adjacent carbon atoms, R 2a , R 2b, R 2c , R 2d , and R 2e two of which, together with the carbon atoms to which they are attached, are connected to form a substituted or unsubstituted C5-C6 cycloalkyl or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and the substituted or unsubstituted C5-C6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl, and wherein the substituted C5-C6 cycloalkyl fused to the phenyl and the substituted 5- or 6-membered heterocyclic ring fused to the phenyl are C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 halocycloalkyl, halogen, and one or more of the same or different C 1~6 Alkyl, one or more of the same or different C 3~6 Cycloalkyl, one or more of the same or different C 1~6 Haloalkyl, one or more of the same or different C 3~6 optionally substituted with 1 to 4 or 1 to 8 substituents selected from the group consisting of halocycloalkyl, and / or combinations thereof, including combinations of one or more of the same or different halogens; R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; R 2a , R 2b , R 2c , R 2d, and R 2e But substitution C 1~6 Alkyl, substituted C 6~10 Aryl, substituted C 6~10 Aryl alkyl, substituted C 6~10 Aryloxy, substituted C 6~10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3~10 When R is cycloalkyl or substituted 4-10 membered heterocyclyl, 2a , R 2b , R 2c , R 2d , and R 2e is halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O)2R 13 , N.R. 13 S(O)2R 14 , S(O)NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, Hydroxyl, C 1~6 Alkoxy, aryl, arylalkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 It is selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0338] In some embodiments of structure (III-C), R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkyloxy, C3-C6 cycloalkyloxy, CN, cyanoalkyl, COOH, CONH2, hydroxyalkyl, C1-C3 alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C1-C3 alkylsulfonyl, C2-C6 alkynyl, C1-C3 acyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O.

[0339] In some embodiments of structure (III-C), R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pyrazole, cyclopropoxy, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and morpholinyl.

[0340] In some embodiments of structure (III-C), R 2a, R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, methoxy, CN, cyanomethyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, trifluoromethyl, and difluoromethyl.

[0341] In some embodiments of structure (III-C), R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of hydrogen and methyl.

[0342] In some embodiments of structure (III-C), R 2a , R 2b , R 2c , R 2d , and R 2e 1 to 5, 1 to 4, 1 to 3, 1, 2, 3, 4, or 5 of these are methyl.

[0343] In some embodiments of structure (III-C), R 2a , R 2b , R 2c , R 2d , and R 2e In some embodiments of structure (III-C), one of R 2a , R 2b , R 2c , R 2d , and R 2e In some embodiments of structure (III-C), two of R 2a , R 2b , R 2c , R 2d , and R 2e Three of them are methyl.

[0344] In some embodiments of structure (III-C), R 2a and R 2b , R 2b and R 2c, R 2c and R 2d , R 2d and R 2e , or a combination thereof, R 2a , R 2b , R 2c , R 2d , and R 2e together with the carbon atom to which it is attached to form a phenyl-fused dioxane, a phenyl-fused furan, or a phenyl-fused difluorodioxolane.

[0345] In some embodiments of structure (III-C), R 2a , R 2b , R 2c , R 2d , and R 2e The phenyl having TIFF2025541737000076.tif153151.

[0346] In some embodiments of structures (III), (III-A), (III-B), and (III-C), the compound has a structure selected from the structures in Table 2 below.

[0347] In some embodiments of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), one or more hydrogen atoms are replaced with one or more deuterium atoms.

[0348] Compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C) and embodiments thereof are useful in the methods and applications of the present disclosure, optionally in the form of a salt, e.g., a pharmaceutically acceptable salt, or as a stereoisomer or tautomer.

[0349] Certain embodiments provide pharmaceutically acceptable salts of the indicated chemical compounds (e.g., hydrogen halides such as hydrogen chloride). Examples of pharmaceutically acceptable salts are described, for example, in Burge, SM et al., J. Pharm. Sci 1977, 66, 1-19. Pharmaceutically acceptable salts include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, fatty acid salts, and the like. Salts can be prepared by a variety of methods known to those skilled in the art, including precipitation with or exposure to acids or bases in solution (e.g., treatment with HCl gas or HCl solution).

[0350] In some embodiments of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), the salt for the pharmaceutically acceptable salt is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, and gluconic acid.

[0351] In some embodiments of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), the salt for the pharmaceutically acceptable salt is selected from the group consisting of trifluoroacetic acid, hydrogen chloride, and acetic acid.

[0352] In some embodiments of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), the salt is trifluoroacetate. In some embodiments of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), the salt for the pharmaceutically acceptable salt is hydrochloride.

[0353] In some aspects, the compounds of the present disclosure are compounds in Table 1 and / or Table 2 below.

[0354] In some embodiments, compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C) and embodiments thereof are as described in the Examples, including the compounds listed in Table 1 and Table 2.

[0355] In some embodiments, compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C) and embodiments thereof are provided in the form of a pharmaceutical composition comprising the compound, a stereoisomer, tautomer, or salt thereof, e.g., a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0356] In some embodiments, compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C) and embodiments thereof are described as stereochemically pure enantiomers or diastereomers (e.g., optically active compounds having one or more stereocenters). Unless specifically indicated, any compound having one or more stereocenters is intended to include and describe the respective (+) and (-) pure enantiomers, any other diastereomers, enantiomerically or diastereomerically enriched mixtures (e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess), and racemic mixtures of enantiomers or diastereomers.

[0357] In some embodiments, the compound is a prodrug. A prodrug is a compound that is converted into a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine). Exemplary prodrugs are described, for example, in Tilley, JW, "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for amidine groups include amidoximes, O-alkylamidoximes, acylamidines, carbamates, 1,2,4-oxadiazolin-4-ones, etc.

[0358] III.MASP-2 damage prevention method Compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use.

[0359] Compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof, are useful in methods for treating diseases or disorders treatable by inhibiting MASP-2.

[0360] Compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof, are useful in methods for inhibiting MASP-2.

[0361] Compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof, are useful in methods for inhibiting MASP-2 complement activation in a subject.

[0362] Compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof, are useful in methods for inhibiting MASP-2 or MASP-2 complement activation in a subject by administering to the subject a therapeutically effective amount of a compound effective to inhibit MASP-2 or MASP-2 complement activation.

[0363] Compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof, are useful in the manufacture of a medicament for treating a disease or disorder treatable by inhibiting MASP-2.

[0364] The present disclosure also provides a method for treating a disease or disorder treatable by inhibiting MASP-2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt, and embodiment thereof.

[0365] In some embodiments, compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments are used after a subject has been diagnosed with a need for treatment for a lectin complement-associated disease or disorder.

[0366] In some embodiments, compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments are selected as compounds that exhibit selectivity for MASP-2 over thrombin, and the method comprises administering a compound described herein. In some embodiments, the selective ratio of MASP-2:thrombin is at least 1.1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

[0367] In some aspects, the present disclosure provides a compound having structure (I): and (c) administering to the subject a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 is a substituted aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl, or Cy 1 is R 5 or R 6 together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl fused to a substituted or unsubstituted 5-10 membered heteroaryl, or a substituted or unsubstituted phenyl; Cy 2 is a substituted aryl, a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 5-10 membered heteroaryl, or hydrogen; R 2is hydrogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted cycloalkyl; R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted cycloalkyl, or R 3 and R 4 together with the carbons to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted C5-C6 cycloalkenyl; R 5 and R 6 are each independently hydrogen, C1-C3 alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C3-C6 cycloalkyl; R 7 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; L is hydrogen or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently identical or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted straight or branched C1-C3 alkyl, or R 8a and R 8b together with the carbon to which they are attached form a substituted or unsubstituted C3-C6 cycloalkyl; and n is 1, 2, or 3; wherein C3-C6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; One or more hydrogen atoms in structure (I) may be replaced with deuterium atoms; provided that the compound of structure (I) has the structure: TIFF2025541737000078.tif20128, where R A is benzyl, phenethyl, or 3-CF3-benzyl.

[0368] In some aspects, the present disclosure provides a method for inhibiting MASP-2 in a subject, comprising administering to the subject any one of compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and the invention.

[0369] In some aspects, the present disclosure provides a method for inhibiting MASP-2 in a subject, comprising administering to the subject a compound having a structure in Table 1.

[0370] In some aspects, the present disclosure provides a method for inhibiting MASP-2 in a subject, comprising administering to the subject a compound having a structure in Table 2.

[0371] In some aspects, the present disclosure provides a method for inhibiting MASP-2 in a subject, comprising administering a compound disclosed herein, its stereoisomer, tautomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient as a pharmaceutical composition.

[0372] IV. Treatment methods In some aspects, the present disclosure provides a method for treating or preventing a subject suffering from or at risk of developing a MASP-2-related disease or disorder, such as a MASP-2-dependent complement-related disease or disorder, comprising administering an inhibitor of MASP-2.

[0373] As disclosed herein, the compound may be a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts, and embodiments thereof.

[0374] U.S. Patent No. 7,919,094; U.S. Patent No. 8,840,893; U.S. Patent No. 8,652,477; U.S. Patent No. 8,951,522; U.S. Patent No. 9,011,860; U.S. Patent No. 9,475,885; U.S. Patent No. 9,644,035; U.S. Patent No. 9,644,035; U.S. Patent No. 10,736,960; U.S. Patent No. 10,059,776; U.S. Patent No. 10,870,708; U.S. Patent Application Publication No. 2013 / 0344 073, 2015 / 0166675, 2017 / 0137537, 2017 / 0166660, 2017 / 0253667, 2018 / 0105604, and 2020 / 0140570; and WO 2018 / 045054, WO 2019 / 036460, and WO 2021 / 178902 (each of which is incorporated herein by reference in its entirety). As described in U.S. Patent No. 8,951,522, a primary function of the complement system, which is part of the innate immune system, is to protect the host from infectious agents.

[0375] However, inappropriate or excessive activation of the complement system can lead to serious diseases such as thrombotic microangiopathy (TMA, including aHUS, TTP, and HUS), in which endothelial damage and fibrin- and platelet-rich clots in the microvasculature lead to organ damage.

[0376] The lectin pathway plays a major role in activating complement under conditions of endothelial cell stress or injury, preventing the activation of MASP-2. The lectin pathway stops the series of enzymatic reactions that lead to the formation of the membrane attack complex, platelet activation, and leukocyte recruitment. In addition to initiating the lectin pathway, MASP-2 can also activate the coagulation system by cleaving prothrombin to thrombin, as described in U.S. Patent No. 8,652,477.

[0377] Thus, in some embodiments, the method includes treating or preventing a disease or disorder by administering to a patient suffering from or at risk of developing a MASP-2-dependent complement-related disease or disorder an amount of a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and embodiments thereof, in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the methods may further include determining that the patient is suffering from or at risk of developing a lectin complement-associated disease or disorder prior to administering to the patient a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and embodiments.

[0378] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of thrombotic microangiopathy (TMA), renal condition, inflammatory response due to tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, cardiovascular disease or disorder, inflammatory gastrointestinal disorder, pulmonary disorder, eye disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, venous occlusive disease, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome, fluid overload, and combinations thereof.

[0379] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), factor H-independent atypical hemolytic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplantation, TMA associated with hematopoietic stem cell transplantation, and combinations thereof.

[0380] In some embodiments, the MASP-2-dependent complement-related disease or disorder is graft-versus-host disease. In some embodiments, the method comprises treating or preventing the disease or disorder by administering to a subject suffering from or at risk of developing graft-versus-host disease (GVHD), including acute GVHD, chronic GVHD, or steroid-resistant GVHD, an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing GVHD has previously undergone, is undergoing, or will undergo hematopoietic stem cell transplantation.

[0381] In some embodiments, the MASP-2-dependent complement-related disease or disorder is diffuse alveolar hemorrhage (DAH). In some embodiments, the method comprises treating or preventing the disease or disorder by administering to a subject suffering from or at risk of developing diffuse alveolar hemorrhage (DAH) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing DAH has previously undergone, is undergoing, or will undergo hematopoietic stem cell transplantation.

[0382] In some embodiments, the MASP-2-dependent complement-related disease or disorder is veno-occlusive disease (VOD). In some embodiments, the method comprises treating or preventing the disease or disorder by administering to a subject suffering from or at risk of developing veno-occlusive disease (VOD) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing VOD has previously undergone, is undergoing, or will undergo hematopoietic stem cell transplantation.

[0383] In some embodiments, the method includes treating or preventing a disease or disorder by administering to a subject suffering from or at risk of developing idiopathic pneumonia syndrome (IPS) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing IPS has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0384] In some embodiments, the method includes treating or preventing a disease or disorder by administering to a subject suffering from or at risk of developing capillary leak syndrome (CLS) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing CLS has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0385] In some embodiments, the method includes treating or preventing a disease or disorder by administering to a subject suffering from or at risk of developing engraftment syndrome (ES) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing ES has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0386] In some embodiments, the method includes treating or preventing a disease or disorder by administering to a subject suffering from or at risk of developing fluid overload (FO) an amount of a disclosed compound in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject. In some embodiments, the subject suffering from or at risk of developing FO has previously undergone, is undergoing, or is about to undergo a hematopoietic stem cell transplant.

[0387] In some embodiments, the method comprises administering to a subject suffering from or at risk of developing any of the above-referenced diseases or conditions an amount of a compound disclosed in International Application No. PCT / US19 / 34225, the entire contents of which are incorporated herein.

[0388] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a renal disease, which may be selected from the group consisting of mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, microimmune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, tubulointerstitial disease, or a combination thereof.

[0389] In some embodiments, the MASP-2-dependent complement-related disease or disorder is chronic kidney disease, chronic renal failure, glomerular disease (e.g., focal segmental glomerulosclerosis), immune complex disorders (e.g., IgA nephropathy, membranous nephropathy), lupus nephritis, nephrotic syndrome, diabetic nephropathy, tubulointerstitial injury and glomerulonephritis (e.g., C3 glomerulopathy), or nephrotic syndrome, pre-eclampsia, eclampsia, toxic nephropathy, amyloidosis, collagen vascular disease (e.g., systemic lupus erythematosus), dehydration, or the like. , glomerular diseases (e.g., membranous glomerulonephritis, focal segmental glomerulonephritis, C3 glomerulopathy, minimal change disease, lipid nephropathy), strenuous exercise, stress, benign orthostatic (postural) proteinuria, focal segmental glomerulosclerosis, IgA nephropathy (i.e., Berger's disease), IgM nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, minimal change disease, sarcoidosis, Alport syndrome, diabetes (diabetic nephropathy), drug-induced toxicity (e.g., NSAIDs, nicotine, penicillamine, lithium carbonate, Gold and other heavy metals, ACE inhibitors, antibiotics (e.g., adriamycin), opiates (e.g., heroin), or other nephrotoxins), Fabry disease, infectious diseases (e.g., HIV, syphilis, hepatitis A, B, or C, post-streptococcal infections, urinary schistosomiasis), aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, sickle cell disease, hemoglobinuria, multiple myeloma, myoglobinuria, organ rejection (e.g., renal transplant rejection), Ebola hemorrhagic fever Renal fibrosis (e.g., tubulointerstitial fibrosis) and / or proteinuria in a subject suffering from or at risk of developing a disease or condition associated with proteinuria, including, but not limited to, nail-patella syndrome, familial Mediterranean fever, HELLP syndrome, systemic lupus erythematosus, Wegener's granulomatosis, rheumatoid arthritis, glycogen storage disease type 1, Goodpasture's syndrome, Henoch-Schönlein purpura, urinary tract infection that has spread to the kidney, Sjogren's syndrome, or post-infectious glomerulonephritis.

[0390] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of renal fibrosis, proteinuria, or a combination thereof.

[0391] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory response resulting from tissue or solid organ transplantation, including allografts or xenografts of whole organs (e.g., kidney, heart, liver, pancreas, lung, cornea, etc.) or tissue transplants (e.g., valve, tendon, bone marrow, etc.).

[0392] In some embodiments, the MASP-2-dependent complement-related disease or disorder is ischemia-reperfusion injury (I / R), including myocardial I / R, gastrointestinal I / R, renal I / R, and I / R after aortic aneurysm repair, I / R associated with cardiopulmonary bypass, cerebral I / R, stroke, organ transplant, or reattachment of a severed or traumatized limb or digit, spinal cord injury, revascularization of a graft and / or regraft, complex regional pain syndrome, and shock, hemodynamic resuscitation after surgical treatment, etc., or combinations thereof.

[0393] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a complication associated with non-obese diabetes (type 1 diabetes or insulin-dependent diabetes) and / or a complication associated with type 1 or type 2 (adult-onset) diabetes, including diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, diabetic macular edema, etc., or a combination thereof.

[0394] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a cardiovascular disease or disorder, including Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis (also known as malignant rheumatoid arthritis), immune complex vasculitis, and Takayasu's disease; dilated cardiomyopathy; diabetic angiopathy; Kawasaki disease (arteritis); venous gas embolism (VGE); and inhibition of restenosis after stent placement, rotational atherectomy, percutaneous transluminal coronary angioplasty (PTCA), and the like; or combinations thereof.

[0395] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory gastrointestinal disorder, including Crohn's disease, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease (IBD), including pancreatitis, diverticulitis, and intestinal disorders, or combinations thereof.

[0396] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a pulmonary disorder, including acute respiratory distress syndrome, transfusion-related acute lung injury, ischemia / reperfusion acute lung injury, chronic obstructive pulmonary disease, asthma, Wegener's granulomatosis, anti-glomerular basement membrane disease (Goodpasture's disease), meconium aspiration syndrome, aspiration pneumonia, bronchiolitis obliterans syndrome, idiopathic pulmonary fibrosis, acute lung injury secondary to burns, non-cardiogenic pulmonary edema, transfusion-related respiratory depression, emphysema, etc., or a combination thereof.

[0397] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an inflammatory response caused by extracorporeal exposure, and the method includes treating a subject undergoing extracorporeal circulation or pretreating the subject before undergoing extracorporeal circulation. In some embodiments, the extracorporeal circulation includes hemodialysis, plasma exchange, leukopheresis, extracorporeal membrane oxygenation (ECMO), heparin-induced extracorporeal membrane oxygenation LDL precipitation (HELP), cardiopulmonary bypass (CPB), etc., or a combination thereof. In some embodiments, the method further includes treating the subject undergoing extracorporeal circulation.

[0398] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from inflammatory or non-inflammatory arthritis and other musculoskeletal disorders, such as osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, neuropathic arthropathy, psoriatic arthritis, ankylosing spondylitis or other spondyloarthropathy and crystalline arthropathies, muscular dystrophies, systemic lupus erythematosus (SLE), etc., or combinations thereof.

[0399] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a skin disorder, such as psoriasis, autoimmune bullous dermatosis, eosinophilic spongiosis, bullous pemphigoid, epidermolysis bullosa acquisita, atopic dermatitis, herpes gestationis, and other skin disorders. In some embodiments, the MASP-2-dependent complement-related disease or disorder is a thermal injury, a chemical burn, or a combination thereof, including capillary leakage caused thereby.

[0400] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a disorder or injury of the peripheral nervous system (PNS) and / or central nervous system (CNS), including multiple sclerosis (MS), myasthenia gravis (MG), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Guillain-Barré syndrome, reperfusion after stroke, complex regional pain syndrome, intervertebral disc degeneration, spinal cord injury, brain trauma, Parkinson's disease (PD), Alzheimer's disease (AD), Miller-Fisher syndrome, brain trauma and / or hemorrhage, traumatic brain injury, demyelination, meningitis, etc., or combinations thereof.

[0401] In some embodiments, the MASP-2-dependent complement-related disease or disorder is sepsis or a condition resulting from sepsis, including severe sepsis, septic shock, sepsis-induced acute respiratory distress syndrome, hemolytic anemia, systemic inflammatory response syndrome, hemorrhagic shock, etc., or a combination thereof.

[0402] In some embodiments, the MASP-2-dependent complement-related disease or disorder is a urogenital disorder, including painful bladder disease, sensory bladder disease, chronic sterile cystitis and interstitial cystitis, male and female infertility, placental insufficiency and miscarriage, preeclampsia, etc., or combinations thereof. In some embodiments, the MASP-2-dependent complement-related disease or disorder is an inflammatory response in a subject being treated with chemotherapy, radiation therapy, or a combination thereof.

[0403] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory response in a subject being treated with chemotherapy and / or radiation therapy, including treatment of a cancerous disease.

[0404] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an angiogenesis-dependent cancer, including solid tumors, blood-borne tumors, high-risk carcinoid tumors, tumor metastasis, etc., or a combination thereof.

[0405] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an angiogenesis-dependent benign tumor, including hemangioma, acoustic neuroma, neurofibroma, trachoma, carcinoid tumor, pyogenic granuloma, etc., or a combination thereof.

[0406] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an endocrine disorder, including Hashimoto's thyroiditis, stress, anxiety, other underlying hormonal disorders, etc., involving regulated release of prolactin, growth or insulin-like growth factors, adrenocorticotropic hormones from the pituitary gland, or combinations thereof.

[0407] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an ocular disease or disorder, including age-related macular degeneration, glaucoma, endophthalmitis, etc., or a combination thereof.

[0408] In some embodiments, the MASP-2-dependent complement-related disease or disorder is an ocular neovascular disease or disorder, including age-related macular degeneration, uveitis, ocular melanoma, corneal neovascularization, primary pterygium, HSV stromal keratitis, HSV-1-induced corneal lymphangiogenesis, proliferative diabetic retinopathy, diabetic macular edema, retinopathy of prematurity, retinal vein occlusion, corneal graft rejection, neovascular glaucoma, vitreous hemorrhage secondary to proliferative diabetic retinopathy, neuromyelitis optica, rubeosis, and the like, or a combination thereof.

[0409] In some embodiments, the MASP-2-dependent complement-related disease or disorder is disseminated intravascular coagulation (DIC) or other complement-mediated coagulation disorder, including DIC secondary to sepsis, severe trauma including neurological trauma (e.g., acute head injury; see Kumura et al, Acta Neurochirurgica 55:23-28(1987)), infection (e.g., bacterial, viral, fungal, parasitic), cancer, obstetric complications, liver disease, severe toxic reactions (e.g., snake bite, insect bite, transfusion reaction), shock, heat stroke, transplant rejection, vascular aneurysm, liver failure, cancer treatment with chemotherapy or radiation therapy, burns, or accidental radiation exposure.

[0410] In some embodiments, the MASP-2-dependent complement-related disease or disorder is selected from the group consisting of acute radiation syndrome, dense deposit disease, Degos disease, fulminant antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia, paroxysmal nocturnal hemoglobinuria ("PNH"), cold agglutinin disease, or a combination thereof.

[0411] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is atypical hemolytic uremic syndrome (aHUS).

[0412] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is hematopoietic stem cell transplantation-associated TMA.

[0413] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is immunoglobulin A nephropathy (IgAN).

[0414] In some embodiments, the MASP-2 dependent complement-associated disease or disorder is lupus nephritis (LN).

[0415] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is COVID-19-induced acute respiratory distress syndrome (ARDS), COVID-19-induced pneumonia, COVID-19 or a similar systemic infectious disease, or long COVID.

[0416] In some embodiments, the method includes treating or preventing a disease, disorder, or condition associated with fibrin-induced activation of the complement system and associated activation of the coagulation and / or contact systems by administering to a subject suffering from or at risk of developing a disease, disorder, or condition associated with fibrin-induced activation of the complement system and associated activation of the coagulation and / or contact systems a quantity of a compound according to any one of the above-mentioned embodiments (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments) in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject, thereby treating or preventing the disease or disorder.

[0417] In some embodiments, the subject is suffering from or at risk of developing a disease, disorder, or condition associated with complement-associated inflammation, excessive coagulation, or activation of the contact system initiated by fibrin or activated platelets. In some embodiments, the subject suffers from or is at risk of developing a disease or disorder selected from the group consisting of arterial thrombosis, venous thrombosis, deep vein thrombosis, postoperative thrombosis, restenosis after coronary artery bypass surgery and / or interventional cardiovascular procedures (e.g., angioplasty or stent placement), atherosclerosis, plaque rupture, plaque instability, restenosis, hypotension, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation (DIC), venous occlusive disease (VOD), thrombotic microangiopathy, lupus nephritis, superficial thrombophlebitis, factor V Leiden mutation, ischemic / reperfusion injury, human immunodeficiency virus (HIV) infection, receiving hormone replacement therapy (HRT), Alzheimer's disease, and / or suffers from a hypercoagulable state.

[0418] In some embodiments, the subject is receiving treatment with a drug selected from the group consisting of: 5-FU, GM-CSF, cisplatin, heparin, COX-2 inhibitors, contrast agents, corticosteroids, and antipsychotics; venous congestion (restriction, surgery, etc.), antiphospholipid syndrome, cancer (promyelocytic leukemia, tumors of the lung, breast, prostate, pancreas, stomach, and colon), tissue damage from trauma or surgery, presence of a catheter in a central vein, acquired deficiency of a protein involved in blood clot formation (e.g., protein C), paroxysmal nocturnal hemoglobinuria (PNH), elevated homocysteine ​​levels, heart failure, presence of a mechanical valve, pulmonary hypertension with in situ thrombosis, atrial fibrillation, heparin-induced thrombocytopenia (HI). The patient has or is at risk of developing an acquired hypercoagulable state due to at least one or more of: heparin-induced thrombocytopenia and thrombosis (HITT), Kawasaki disease with in situ thrombosis, Takayasu's arteritis with in situ thrombosis, thrombophilia due to metastatic cancer, elevated factor VIII levels, pregnancy, inflammatory bowel disease (IBD), or due to a genetic abnormality that causes or increases the risk of developing a hypercoagulable state, such as a genetic abnormality selected from the group consisting of a prothrombin 20210 gene mutation, an MTHFR mutation, a protein C deficiency, a protein S deficiency, a protein A deficiency, a protein Z deficiency, an antithrombin deficiency, and a genetic disease that results in a thrombophilia.

[0419] In some embodiments, the subject suffers from or is at risk of developing a disease or disorder suitable for treatment with a kallikrein inhibitor. In some embodiments, the subject suffers from or is at risk of developing a disease or disorder suitable for treatment with a kallikrein inhibitor selected from the group consisting of hereditary angioedema, diabetic macular edema, and bleeding during cardiopulmonary bypass. In some embodiments, the subject suffers from or is at risk of developing a disease or disorder suitable for treatment with a thrombin inhibitor, such as arterial thrombosis, venous thrombosis, pulmonary embolism, atrial fibrillation, heparin-induced thrombocytopenia, conversion from one anticoagulant to another, or off-label use of continuous renal replacement therapy (CRRT) to maintain extracorporeal circuit patency in severely ill subjects with HIT.

[0420] In some embodiments, the subject has previously experienced, is currently suffering from, or is at risk of developing atrial fibrillation, and a MASP-2 inhibitory compound (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof) is administered in an amount sufficient to reduce the risk of stroke in the subject. In some embodiments, the subject is suffering from or at risk of developing a disease or disorder suitable for treatment with a Factor XII inhibitor, such as deep vein thrombosis (both primary prevention and long-term treatment), pulmonary embolism, non-valvular atrial fibrillation, prevention of recurrent ischemia after acute coronary syndrome in subjects with or without atrial fibrillation, end-stage renal disease, cerebral ischemia, angina pectoris, or reducing or preventing clotting associated with medical devices (e.g., valves, small caliber grafts, etc.) and / or extracorporeal circuits.

[0421] In some embodiments, the subject has previously experienced, is currently suffering from, or is at risk of developing non-valvular atrial fibrillation, and a MASP-2 inhibitory compound (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof) is administered in an amount sufficient to reduce the risk of stroke and / or embolism in the subject. In some embodiments, the subject has an acquired disease or disorder that increases the propensity for thromboembolism, such as a disease or disorder selected from the group consisting of atherosclerosis, antiphospholipid antibodies, cancer (e.g., promyelocytic leukemia, lung, breast, prostate, pancreas, stomach, and colon), hyperhomocysteinemia, infection, tissue injury, venous congestion (such as due to surgery, orthopedic or paralytic restraints, heart failure, pregnancy, or obesity), and the subject taking estrogen-containing oral contraceptives.

[0422] In some embodiments, the subject requires anticoagulant therapy, and a MASP-2 inhibitory compound (e.g., a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and embodiments thereof) is used as a substitute for standard anticoagulant therapy (e.g., warfarin). In some embodiments, the subject has a condition for which standard anticoagulant therapy is normally contraindicated, such as CNS amyloid angiopathy. In some embodiments of the method, the MASP-2 inhibitory compound is administered as a bridging agent perioperatively in subjects who would normally receive standard anticoagulant therapy. In some embodiments, the subject has sickle cell disease, a vaso-occlusive disorder involving platelet activation.

[0423] Atypical hemolytic uremic syndrome (aHUS) is part of a spectrum of conditions referred to as "thrombotic microangiopathy." In atypical forms of HUS (aHUS), the disease is associated with dysregulation of complement and can be either sporadic or familial. Familial cases of aHUS are associated with mutations in genes encoding complement activation or complement regulatory proteins, including complement factors H, I, and B, the CD46 membrane cofactor, and complement factor H-related protein 1 (CFHR1) and 3 (CFHR3) (Zipfel, PF, et al., PloS Genetics 3(3):e41 (2007)). A unifying feature of this diverse set of genetic mutations associated with aHUS is a predisposition to enhanced complement activation on cell or tissue surfaces. A subject is at risk of developing aHUS upon the occurrence of at least one or more symptoms indicative of aHUS (e.g., the presence of anemia, thrombocytopenia and / or renal failure) and / or the presence of thrombotic microangiopathy in a biopsy obtained from the subject. Determining whether a subject is at risk for developing aHUS includes determining whether the subject has a genetic predisposition to developing aHUS, which may be done by evaluating genetic information (e.g., from a database containing the subject's genotype) or performing at least one genetic screening test on the subject via either genomic sequencing or gene-specific analysis (e.g., PCR analysis) to determine the presence or absence of a genetic marker associated with aHUS (i.e., determining the presence or absence of a genetic mutation associated with aHUS in genes encoding complement factor H (CFH), factor I (CFI), factor B (CFB), membrane complement factors CD46, C3, complement factor H-related protein 1 (CFHR1), or THBD (which encodes the anticoagulant protein thrombomodulin) or complement factor H-related protein 3 (CFHR3), or complement factor H-related protein 4 (CFHR4)), and / or determining whether the subject has a family history of aHUS.Methods for genetic screening for mutations in genes associated with aHUS are well established; see, e.g., Norris M et al. "Atypical Hemolytic-Uremic Syndrome," 2007 Nov 16 [Updated 2011 Mar 10]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™, Seattle (WA): University of Washington, Seattle.

[0424] Hematopoietic stem cell transplant-associated TMA (HSCT-TMA) is a life-threatening complication caused by endothelial injury. While the kidney is the most commonly affected organ, HSCT-TMA can be a multisystem disease involving the lungs, intestine, heart, and brain. Even mild cases of TMA are associated with long-term renal dysfunction. The incidence of post-allo-HSCT-associated TMA varies based on various diagnostic criteria and conditions, as well as graft-versus-host disease prophylaxis regimens, with calcineurin inhibitors being the most frequently implicated medications (Ho VT et al., Biol Blood Marrow Transplant, 11(8):571-5, 2005). Treatment with the MASP-2 inhibitor antibody, narsoplimab, is being investigated in clinical trials for lectin pathway-mediated conditions in which MASP-2 is thought to play an important role in the pathophysiology. In hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), plasma concentrations of MASP-2 are elevated compared to healthy controls, and narsoplimab has been shown to reduce HSCT-TMA plasma-mediated endothelial damage in a tissue culture model (Elhadad S, et al., MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab. Clin Exp Immunol (2021) 203(1):96-104).In a pivotal clinical trial of HSCT-TMA, weekly narsoplimab treatment resulted in a 61% response rate based on improvement in laboratory TMA markers and clinical benefit, demonstrating clinically meaningful resolution of HSCT-TMA pathophysiology (Khaled SK, et al.. Narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, for the treatment of adult hematopoietic stem-cell transplantation-associated thrombotic microangiopathy. J Clin Oncol (2022) 40(22):2447-57).

[0425] Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease that results in intrarenal inflammation and kidney damage. IgAN is the most common primary glomerular disease worldwide. In the United States, the annual incidence is approximately 2.5 per 100,000, with an estimated 1 in 1,400 people developing IgAN. As many as 40% of IgAN patients will develop end-stage renal disease (ESRD). Patients typically present with microscopic hematuria with mild to moderate proteinuria and varying degrees of renal failure (Wyatt RJ, et al., NEnglJ Med 36S(25):2402-4, 2013). Clinical markers such as renal dysfunction, persistent hypertension, and severe proteinuria (>1 g / day) are associated with poor prognosis (Goto M et al., Nephrol Dial Transplant 24(10):3068-74, 2009; Berthoux F. et al., J Am Soc Nephrol 22(4):752-61, 2011). Proteinuria is the strongest prognostic factor independent of other risk factors in several large observational and prospective studies (Coppo R. et al., J Nephrol 18(5):503-12, 2005; Reich HN, et al., J Am Soc Nephrol 18(12):3177-83, 2007). If left untreated, it is estimated that 15-20% of subjects will develop ESRD within 10 years of disease onset (D'Amico G., Am J Kidney Dis 36(2):227-37, 2000). The diagnostic hallmark of IgAN is the predominance of IgA deposits in the glomerular mesangium, either alone or in combination with IgG, IgM, or both. In a phase 2 clinical trial for severe IgA nephropathy, weekly administration of narsoplimab was well tolerated; after 3 years of follow-up, patients receiving narsoplimab experienced a slower annual rate of decline in renal function compared with a matched external comparison group (5.2 mL / min / year vs. 8.6 mL / min / year, respectively), and urinary protein excretion was reduced by 38% from baseline in narsoplimab-treated patients.(Lafayette RA, et al., Safety, tolerability and efficacy of narsoplimab, a novel MASP-2 inhibitor for the treatment of IgA nephropathy. Kidney Int Rep (2020) 5(11):2032-41; Lafayette RA, et al., Long-term phase 2 efficacy of the MASP-2 inhibitor narsoplimab for the treatment of severe IgA nephropathy [abstract]. J Am Soc Nephrol (2021) 32(Suppl):B10). Based on this evidence, narsoplimab may be beneficial for the treatment of diseases involving the lectin pathway.

[0426] A major complication of systemic lupus erythematosus (SLE) is nephritis, also known as lupus nephritis, which is classified as a secondary form of glomerulonephritis. Up to 60% of adults with SLE have some form of kidney involvement late in the disease course (Koda-Kimble et al., Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs, 10th Ed., Lippincott Williams & Wilkins: pages 792-9, 2012), with a prevalence of 20-70 per 100,000 in the United States. Lupus nephritis often occurs in patients with other symptoms of active SLE, including fatigue, fever, rash, arthritis, serositis, or central nervous system disease (Pisetsky DS et al., Med Clin North Am 81(1): 113-28, 1997). Some subjects have asymptomatic lupus nephritis; however, laboratory abnormalities such as elevated serum creatinine levels, decreased albumin levels, or urinary protein or sediment at regular follow-up are suggestive of active lupus nephritis.

[0427] Deficiency or blockade of MASP-2 in experimental models also contributes to ischemia-reperfusion injury (e.g., Schwaeble WJ, et al. Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia / reperfusion injury. Proc Natl Acad Sci USA (2011) 108(18): 7523-8; Clark JE, et al., Cardioprotection by an anti-MASP-2 antibody in a murine model of myocardial infarction. Open Heart (2018) 5(1):e000652; Orsini F, et al., Mannan-binding lectin-associated serine protease-2 (MASP-2) critically contributes to post-ischemic brain injury independent of MASP-1. J Neuroinflammation (2016) 13(1):213; and Asgari E, et al. al., Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4. FASEB J (2014) 28(9):3996-4003); myocardial infarction (see, e.g., Clark JE, et al.,. Cardioprotection by an anti-MASP-2 antibody in a murine model of myocardial infarction.Open Heart (2018) 5(1):e000652); stroke (see, e.g., Orsini F, et al., Mannan-binding lectin-associated serine protease-2 (MASP-2) critically contributes to post-ischemic brain injury independent of MASP-1. J Neuroinflammation (2016) 13(1):213); transplantation (see, e.g., Asgari E, et al., Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4. FASEB J (2014) 28(9):3996-4003); kidney disease (see, e.g., Alghadban S, et al., Absence of the Lectin Activation Pathway of Complement Ameliorates Proteinuria-Induced Renal Injury. Front Immunol (2019) 10(2238):2238); rheumatoid arthritis (see, e.g., Banda NK, et al., Deconstructing the lectin pathway in the pathogenesis of experimental inflammatory arthritis: Essential role of the lectin ficolin B and mannose-binding protein-associated serine protease 2. J Immunol (2017) 199(5):1835-45); TMA (see, e.g., Elhadad S, et al., MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by the anti-MASP2 antibody narsoplimab. Clin Exp Immunol (2021) 203(1):96-104); and cytopenia (see, e.g., Belcher JD et al., MASP-2 and MASP-3 inhibitors block complement activation, inflammation, and microvascular stasis in a murine model of vaso-occlusion in sickle cell disease. Transl Res (2022) 249:1-12).

[0428] Methods for inhibiting microglial cell activation for the prevention or treatment of neurodegenerative diseases Microglial cells are resident macrophages in the brain that play a critical role in neuronal differentiation and maturation by regulating the process of axonal pruning and by maintaining central nervous system (CNS) tissue homeostasis through the removal of apoptotic and damaged cells and debris (Parkhurst CN, et al., Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013; 155:1596-609), pathogen clearance, tissue repair, and the release of cytokines and chemokines to attract peripheral immune cells to infected or damaged brain tissue (Fetler L, Neuroscience AS. Brain under surveillance: the microglia patrol. Science 2005; 309:392-3).

[0429] During homeostasis, microglia use their ramified processes to survey the microenvironment in real time for potential signals requiring further action. Mature microglia in the postnatal brain rapidly respond to the extracellular environment with a wide range of surface molecules, including cytokines, chemokines, purines, hormones, and neurotransmitters (Tay, T.L. et al., Microglia across the lifespan: from origin to function in brain development, plasticity, and cognition. J. Physiol. 595, 1929-1945 (2017)). Microglia activation is tightly regulated through receptor-ligand interactions (Hanisch, U.K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387-1394 (2007)). In the adult brain, microglia are highly efficient at removing dead cells and excess cellular material, and microglial phagocytosis shapes adult hippocampal neurogenesis through (Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through Apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483-495 (2010). A growing body of research demonstrates the role of microglia in synapse formation, pruning, and elimination, as well as in regulating synaptic function. Synapse elimination occurs during normal brain development and involves the removal of unnecessary excitatory and inhibitory synaptic connections (Liu, YJ et al. Microglia elimination increases neural circuit connectivity and activity in adult mouse cortex. J. Neurosci. 41, 1274-1287 (2021)).This elimination process is crucial for the formation of mature and efficient neural circuits during normal brain development (Paolicelli, RC et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456-1458 (2011)). Complement cascade proteins, widely expressed in the developing brain, localize to specific subsets of immature synapses and mediate their elimination (Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164-1178 (2007)). Microglia phagocytose complement-labeled synapses via the complement receptor (C3R) pathway, which is essential for accurate synaptic connections. Importantly, disruption of this pruning mechanism causes long-term damage to brain circuits and synaptic connections (Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164-1178 (2007).

[0430] Microglia respond to CNS injury and disease through a complex response commonly referred to as activation. Importantly, microglial activation occurs during brain injury and is associated with neuroinflammation and lesion progression. It is also a hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, vascular dementia, dementia with Lewy bodies (Lewy body disease), and Huntington's disease. Dysregulation of synapse elimination is involved in the development of neurodegenerative diseases (Koffie, RM, Hyman, BT & Spires-Jones, TL Alzheimer's disease: synapses gone cold. Mol. Neurodegener. 6, 63 (2011)). Synapse loss precedes neuron loss and is thought to be a more accurate indicator of cognitive decline in AD (DeTure, MA & Dickson, DW The neuropathological diagnosis of Alzheimer's disease. Mol. Neurodegener. 14, 32 (2019)). In neurodegenerative diseases, reactive microglia, found in the vicinity of protein aggregates such as Aβ plaques, are involved in synapse loss and neuronal damage. Eliminating microglia or attenuating microglial activation in neurodegenerative diseases restored spine number and synaptic integrity, improving functional outcomes (Wilton, DK, Dissing-Olesen, L. & Stevens, B. Neuron-glia signaling in synapses elimination. Annu Rev. Neurosci. 42, 107-127 (2019).Furthermore, it is generally recognized that microglial activation plays a contributory role in and / or initiates neurodegenerative processes (Harry GJ. Microglia in Neurodegenerative Events—An Initiator or a Significant Other? International Journal of Molecular Sciences. 2021; 22(11):5818).

[0431] Microglia constitutively express complement receptors. In the case of SARS-CoV-2-induced encephalitis, inhibition of MASP-2, an effector enzyme of the complement lectin pathway, was demonstrated to reduce microglial activation and brain inflammatory markers (Youssif M Ali, et al., "Inhibition of the Lectin Pathway of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity in a Mouse Model of SARS-CoV-2 Infection," The Journal of Infectious Diseases, 2023). Therefore, overactivation of the lectin pathway is thought to be involved in the initiation of brain inflammation, including various cases of neurodegenerative diseases, and MASP-2 inhibitors may prove useful for treating or preventing such diseases.

[0432] The lectin pathway has also been shown to critically contribute to inflammatory pathology after traumatic brain injury (TBI), with the highest degree of protection achieved in the absence of MASP-2, an effector enzyme of the lectin pathway, highlighting the potential therapeutic utility of therapeutics targeting MASP-2 in TBI (Mercurio D, et al., Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role. Acta Neuropathol Commun. 2020 Oct 28;8(1):174).

[0433] Thus, in some embodiments, the method comprises inhibiting microglial activation in a subject suffering from or at risk of developing a neurodegenerative disease or disorder, comprising administering to the subject a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and the embodiment in an amount sufficient to inhibit microglial activation in the subject. In some embodiments, the methods may further comprise determining that the subject is suffering from or at risk of developing a neurodegenerative disease or disorder prior to administering to the subject a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and embodiments. In some embodiments, the method comprises treating a subject suffering from or at risk of developing a neurodegenerative disease or disorder selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, vascular dementia, dementia with Lewy bodies (Lewy body disease), Huntington's disease, and Long COVID with a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to treat or prevent the neurodegenerative disease in the subject.

[0434] VI. Composition, dosage, dosage The compounds described herein (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments) can be administered in a manner compatible with the dosage formulation, and in an amount that is prophylactically or therapeutically effective or suitable. The amount administered will vary depending on various factors, including, for example, the individual's age, weight, physical activity, and diet, as well as the desired effect. In certain embodiments, the size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the compound in a particular individual.

[0435] However, it will be understood that the specific dose level and frequency of administration for any particular subject may vary by physician and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, age, body weight, genetic characteristics, general health, sex, diet, mode and timing of administration, excretion rate, drug combination, severity of the particular condition, and the host being treated.

[0436] In certain embodiments, the dosage may be in solid, semi-solid, liquid, or gaseous form. In certain embodiments, unit dosage forms are preferred for ease of administration and uniformity of dosage.

[0437] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a single dosage for humans and other mammals, each unit containing a predetermined amount of active agent calculated to provide a desired onset, tolerability, efficacy, and / or therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., an ampoule). Additionally, more concentrated dosage forms may be prepared, which may result in more dilute unit dosage forms.

[0438] The compounds described herein (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts, and embodiments thereof) can be administered to a subject in need of prevention or treatment using methods known in the art, such as by oral administration or by injection. Injection may be, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular. As described herein, parenteral formulations can be prepared in unit dosage forms.

[0439] The pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt, and embodiment thereof) formulated with one or more pharmaceutically acceptable carriers or excipients. As used herein, the term "pharmaceutically acceptable carrier" means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Pharmaceutical compositions for this use can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), bucally, or as an oral or nasal spray.

[0440] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfumes.

[0441] Injectable preparations include, for example, sterile injectable aqueous or oleaginous suspensions formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, USP Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0442] To prolong the effect of compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or their stereoisomers, tautomers, or pharmaceutically acceptable salts, and embodiments, it may be desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which in turn may depend, for example, on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms can be achieved by dissolving or suspending the compound in an oil vehicle.

[0443] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar or high molecular weight polyethylene glycols and the like.

[0444] The active compound can also be in microencapsulated form, containing one or more of the above-mentioned excipients.Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation field.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms can also contain, as is customary, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents.

[0445] Dosage forms for topical or transdermal administration of the compounds disclosed herein (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and embodiments thereof) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. For example, the active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and any needed preservatives or buffers, as may be required.

[0446] Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0447] According to the therapeutic methods of the present disclosure, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, according to any one of the foregoing embodiments, in an amount and for a time necessary to achieve the desired result. As is well understood in the medical field, a therapeutically effective amount of a compound of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt, and embodiment thereof, will be present at a reasonable benefit / risk ratio applicable to any medical treatment.

[0448] In general, compounds (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts, and embodiments thereof) are administered in a therapeutically effective amount via any of the usual and acceptable modes known in the art, either alone or in combination with one or more other therapeutic agents. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.

[0449] Generally, satisfactory results have been shown to be obtained systemically at a daily dose of about 0.03 to 2.5 mg / kg body weight. Suggested daily doses for larger mammals, such as humans, range from about 0.5 mg to about 250 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, about 10, about 20, about 30, about 40, or about 50 mg, conveniently administered, for example, in divided doses or delayed doses up to four times daily. Suitable unit dosage forms for oral administration contain about 1 to 60 mg of the active ingredient.

[0450] In certain embodiments, a therapeutic amount or dose of a compound (e.g., a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and embodiments) may range from about 0.1 mg / kg to about 500 mg / kg, or from about 1 mg / kg to about 50 mg / kg. Generally, treatment regimens according to the present application involve administration of about 10 mg to about 1000 mg of compound per day, in single or multiple doses, to a subject in need of such treatment. The therapeutic amount or dose will also vary depending on the route of administration and possible co-administration with other agents.

[0451] When the condition of the subject improves, if necessary, the compound, composition or combination of the present disclosure can be administered in a maintenance dose.After that, when the symptom is alleviated to a desired level, the dosage or administration frequency, or both, can be reduced according to the function of the symptom to the level at which the improved condition is maintained, or treatment can be terminated.However, when the disease symptom recurs, the subject may need to be treated intermittently for a long period of time.

[0452] It will be understood, however, that the total daily usage of the compounds (e.g., compounds of structures (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C), or stereoisomers, tautomers, or pharmaceutically acceptable salts, and embodiments thereof) will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory amount for any particular subject will vary depending upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific compound employed; the duration of treatment; drugs combined with or used concomitantly with the specific compound employed; and similar factors well known in the medical arts.

[0453] The present disclosure provides: (a) a first agent comprising a compound of structure (I), (IA), (IB), (IC), (ID), (IE), (II), (II-A), (II-B), (II-C), (II-D), (III), (III-A), (III-B), and (III-C) as disclosed herein, in free form or a pharmaceutically acceptable salt form, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and an embodiment thereof; (b) at least one coagent; Also provided is a pharmaceutical combination, e.g., a kit, comprising:

[0454] The kit may include instructions for its administration.

[0455] Methods for preparing such dosage forms are known to those skilled in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)). Dosage forms typically contain a conventional pharmaceutical carrier or excipient and may further contain other medicinal agents, carriers, adjuvants, diluents, tissue penetration enhancers, solubilizers, etc. Appropriate excipients can be tailored for particular dosage forms and administration routes by methods well known in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)). [Example]

[0456] The following examples are offered by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially similar results.

[0457] General methods The compounds described herein, including their salts, can be prepared using known organic synthesis techniques, or can be synthesized by any of a number of possible synthetic routes, such as those illustrated in the Examples.

[0458] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with the starting materials or reactants, intermediates, or products at the temperature at which the reaction is carried out, for example, temperatures that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, suitable solvents for a particular reaction step can be selected by those skilled in the art.

[0459] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups.The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art.The chemical properties of protecting groups are described, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0460] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0461] The specific synthetic methods used in the examples provide general guidance regarding the preparation of the disclosed compounds, and those skilled in the art will recognize that, using their general knowledge of organic chemistry, the preparation methods can be modified or optimized to prepare a variety of compounds within the scope of the present disclosure.

[0462] Starting materials, reagents, and intermediates whose synthesis is not described herein are either commercially available, known in the literature, or can be prepared by methods known to those skilled in the art.

[0463] Those skilled in the art will recognize that the processes described herein are not the only means by which the disclosed compounds may be synthesized, and that a wide repertoire of synthetic organic reactions is available that may be employed in synthesizing the disclosed compounds. Those skilled in the art will know how to select and carry out appropriate synthetic routes.Suitable synthetic methods for the starting materials, intermediates, and products are described in Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry, Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991), and other references.

[0464] Unless otherwise noted, chromatography refers to flash chromatography performed on silica gel. "Amine column" refers to flash chromatography performed on a Redisep Rf Gold® high performance amine column. HPLC purification refers to high performance liquid chromatography performed by one of two methods.

[0465] HPLC Method 1: UV / ELS detector (254 nm and 280 nm) and ThermoFisher Hypersil GOLD™ Agilent (21.2 × 250 mm) 5 μm C 18 The column was coupled to a Gilson preparative reverse-phase HPLC system; the eluent consisted of a mixture of water and acetonitrile (containing 0.05% trifluoroacetic acid); the flow rate was typically 20 mL / min with a linear gradient of 2 to 90% acetonitrile in water over 45 min; the injection volume ranged from 1 to 3 mL with a maximum of 20 mg of sample per load.

[0466] HPLC Method 2: UV / MS detector (254 nm and 280 nm) and XBridge Prep (19 × 50 mm) C 18 A Waters™ preparative reverse-phase HPLC system was coupled with a 10 μM OBD column; the eluent consisted of a mixture of water and acetonitrile (containing 0.05% trifluoroacetic acid); the flow rate was typically 50 mL / min with a linear gradient of 5 to 95% acetonitrile in water over 8 min; the injection volume ranged from 0.2 to 1 mL with a maximum of 20 mg of sample per load.

[0467] abbreviation μ Micro ℃ Celsius ACN Acetonitrile anhyd aq water-based Ar Argon ATM atmosphere ave average Boc tert-butoxycarbonyl calc Calculated value concd concentration cmp no compound number DCC N,N'-dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM dichloromethane DIEA N,N-Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF Dimethylformamide DMSO dimethyl sulfoxide ES Electrospray Et Ethyl Et2O diethyl ether EtOAc ethyl acetate Example of a working example g grams h time HATU Hexafluorophosphate N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide HPLC High Performance Liquid Chromatography HOAc acetic acid L liters m millimeter M molar concentration MeCN acetonitrile MeOH Methanol min mL milliliter mmol millimole mol mole; molecular (as in mol wt) MS mass spectrometry N Normal NHS N-hydroxysuccinimide NMR nuclear magnetic resonance o Ortho p Para Ph phenyl prep preparative psi pounds per square inch RT: room temperature (e.g., approximately 20–23°C) sat saturation temp temperature tert third grade TFA trifluoroacetic acid THF tetrahydrofuran vac (or vacuum)

[0468] Example 1 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (Compound 1) The compound on TIFF2025541737000079.tif20128 was synthesized according to the detailed procedure found on pages 19-21 of patent US2004 / 0006065A.

[0469] TIFF2025541737000080.tif20128 Project 1 tert-Butyl (S)-3-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylate (2.00 g, 5.19 mmol) was dissolved in DCM (10 mL) and treated with TFA (4.80 mL, 62.3 mmol). After stirring at 20° C. for 18 hours, 0.5 mL of TFA was added to the above mixture and the reaction mixture was stirred for an additional 5 hours. 0.2 mL of TFA was added and the reaction was stirred for 16 hours. The mixture was concentrated and the crude material was used without further purification.

[0470] TIFF2025541737000081.tif15128 Project 2tert-Butyl (5-cyano-6-methylpyridin-2-yl)carbamate (10 g, 43 mmol) and Pd / C (0.23 g, 10% wt, 0.21 mmol) in glacial acetic acid were stirred in a Parr hydrogenation apparatus at 60 psi for 48 hours. The reaction was filtered through Celite®, and the eluate was evaporated in vacuo. The residue was dissolved in chloroform, basified to pH 13 with 10% aqueous NaOH, and then extracted three times with chloroform. The solution was concentrated and purified by column chromatography (6-10% DCM / 7M NH3-MeOH) to give the product, tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (2.89 g, 14% yield).

[0471] TIFF2025541737000082.tif22136 Project 3 (S)-3-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo-[1,2-a]pyrimidine-6-carboxylic acid (370 mg, 1.12 mmol) was dissolved in DCM (17 mL) and DMF (1.5 mL) and treated with N-hydroxysuccinimide (155 mg, 1.35 mmol) and DCC (278 mg, 1.35 mmol). After stirring for 1 h, tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (400 mg, 1.69 mmol) was added. After stirring for an additional 15 h, the reaction was filtered through a medium-sized fritted funnel and concentrated. The residue was purified by column chromatography (60-100% EtOAc-heptane, then 10-30% MeOH-DCM) to give (S)-(6-(((6-((tert-butoxycarbonyl)amino)-2-methylpyridin-3-yl)methyl)carbamoyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamate (520 mg, 84% yield).

[0472] TIFF2025541737000083.tif20129 Project 4Benzyl (S)-(6-(((6-((tert-butoxycarbonyl)amino)-2-methylpyridin-3-yl)methyl)carbamoyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamate (2 g, 3.646 mmol) was dissolved in MeOH (20 mL) and EtOAc (20 mL). The mixture was purged with Ar, and Pd / C (194.0 mg, 10% wt, 182.3 μmol) was added. The reaction vessel was placed under vacuum and filled with H three times and stirred under 1 atm of H for 2.5 days. The reaction mixture was filtered through a syringe filter and concentrated to give tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (1.30 g, 3.14 mmol, 86% yield).

[0473] TIFF2025541737000084.tif23137 Project 5 To a solution of tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (200 mg, 483 μmol) and 3,5-dimethylbenzaldehyde (129 mg, 130 μL, 965 μmol) in DCE (8 mL) was added HOAc (166 μL, 2.90 mmol). After stirring for 30 min, sodium triacetoxyborohydride (307 mg, 1.45 mmol) was added. After stirring at 20 °C for 2 h, the reaction mixture was diluted with DCM, washed with saturated NaHCO, brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc-heptane and 0-30% MeOH-DCM) to give tert-butyl (S)-(5-((3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (220 mg, 85% yield).

[0474] TIFF2025541737000085.tif18137 Project 6 To a solution of tert-butyl (S)-(5-((3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (220 mg, 413 μmol) in DCM (13 mL) was added TFA (1.88 g, 1.27 mL, 16.5 mmol). After stirring at 20° C. for 18 h, the reaction mixture was concentrated. The residue was purified by column chromatography (amine column, 0-50% MeOH-DCM), and final purification by column chromatography (0-50% MeOH-DCM) gave (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (114 mg, 64% yield).

[0475] Example 2 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((3-methoxy-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 2) TIFF2025541737000086.tif20128 Project 1 (S)-tert-Butyl 3-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylate (2.00 g, 5.19 mmol) was dissolved in DCM (10 mL) and treated with TFA (5.92 g, 4.00 mL, 51.9 mmol). After stirring at 20° C. for 18 h, the reaction mixture was concentrated. The crude material was used without further purification.

[0476] TIFF2025541737000087.tif15128 Project 2A mixture of tert-butyl (5-cyano-6-methylpyridin-2-yl)carbamate (5.14 g, 22.0 mmol) and Pd / C (234 mg, 10% wt, 220 μmol) in glacial acetic acid was stirred in a Parr hydrogenation apparatus at 60 psi for 48 hours. The reaction was filtered through Celite® and evaporated in vacuo. The residue was dissolved in DCM and made basic with saturated NaHCO3. The organic material was extracted twice with DCM, and the combined organics were concentrated to give a brown oil. The material was purified by column chromatography (amine column, 10% DCM / MeOH) to give tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (2.81 g, 36% yield) as a white, oily solid.

[0477] TIFF2025541737000088.tif22136 Project 3 (S)-3-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo-[1,2-a]pyrimidine-6-carboxylic acid (1.8 g, 5.5 mmol) was dissolved in 80 mL of DCM and 5 mL of DMF and treated with N-hydroxysuccinimide (0.69 g, 6.0 mmol) and DCC (1.2 g, 6.0 mmol). After stirring for 1 hour, tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (1.53 g, 6.45 mmol) was added. After stirring for 15 hours, the reaction was filtered through a medium-sized fritted funnel and concentrated. The residue was purified by column chromatography (60–100% EtOAc-heptane and 10–30% MeOH-DCM) to give (S)-(6-(((6-((tert-butoxycarbonyl)amino)-2-methylpyridin-3-yl)methyl)carbamoyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamate (1.0 g, 33% yield).

[0478] TIFF2025541737000089.tif21136 Project 4Benzyl (S)-(6-(((6-((tert-butoxycarbonyl)amino)-2-methyl-pyridin-3-yl)methyl)carbamoyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-3-yl)carbamate (1000 mg, 1.823 mmol) was dissolved in MeOH (11 mL) and EtOAc (11 mL). The mixture was purged with Ar and Pd / C (96 mg, 10% wt, 91.14 μmol) was added. The reaction vessel was placed under vacuum and filled with H three times, then stirred under 1 atm of H overnight. The reaction mixture was filtered through a syringe filter and concentrated to give tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (697 mg, 92% yield).

[0479] TIFF2025541737000090.tif23137 Project 5 To a solution of tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (198 mg, 478 μmol) and 3-methoxy-5-methylbenzaldehyde (143 mg, 135 μL, 955 μmol) in DCE (8 mL) was added HOAc (164 μL, 2.87 mmol). After stirring for 30 min, sodium triacetoxyborohydride (304 mg, 1.43 mmol) was added. After stirring at 20 °C for 2 h, the reaction mixture was diluted with DCM, washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc-heptane and 0-50% MeOH-DCM) to give tert-butyl (S)-(5-((3-((3-methoxy-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (210 mg, 80% yield).

[0480] TIFF2025541737000091.tif20137 Project 6 To a solution of tert-butyl (S)-(5-((3-((3-methoxy-5-methyl-benzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)-methyl)-6-methylpyridin-2-yl)carbamate (210 mg, 383 μmol) in DCM (10 mL) was added 0.3 mL of TFA. After stirring at 20° C. for 18 h, the reaction mixture was concentrated. The residue was purified by preparative HPLC method 2 followed by column chromatography (amine column, 0–50% MeOH-DCM) to give (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((3-methoxy-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (95 mg, 55% yield).

[0481] Example 3 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((2-fluoro-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 3) TIFF2025541737000092.tif22136 Project 1To a solution of tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (208 mg, 502 μmol, prepared according to Example 1) and 2-fluoro-5-methylbenzaldehyde (139 mg, 0.13 mL, 1.00 mmol) in DCE (8 mL) was added HOAc (172 μL, 3.01 mmol). After stirring for 30 min, sodium triacetoxyborohydride (319 mg, 1.51 mmol) was added. After stirring at 20° C. for 2 h, the reaction mixture was diluted with DCM, washed with saturated NaHCO, brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc-heptane, then 0-30% MeOH-DCM) to give tert-butyl (S)-(5-((3-((2-fluoro-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (204 mg, 76% yield).

[0482] TIFF2025541737000093.tif16137 Project 2 To a solution of tert-butyl (S)-(5-((3-((2-fluoro-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methyl-pyridin-2-yl)carbamate (204 mg, 380 μmol) in DCM (10 mL) was added 0.3 mL of TFA. After stirring at 20° C. for 18 h, the reaction mixture was concentrated. The residue was purified by preparative HPLC method 2, and final purification by column chromatography (amine column, 0–50% MeOH-DCM) gave (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((2-fluoro-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (65 mg, 39% yield).

[0483] Example 4 Preparation of (S)-N-((6-aminopyridin-3-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 4) TIFF2025541737000094.tif25128 Project 1 (S)-tert-Butyl 3-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylate (500 mg, 1.30 mmol) was dissolved in MeOH (30 mL) and purged with Ar. Pd / C (13.8 mg, 10% wt, 13.0 μmol) was added, and the flask was then evacuated and filled with H three times. After stirring at 20 °C for 2 h, the mixture was filtered and concentrated to give tert-butyl (S)-3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (326 mg, 100% yield).

[0484] TIFF2025541737000095.tif30128 Project 2 To a solution of (S)-tert-butyl 3-amino-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylate (326 mg, 1.30 mmol) and 3,5-dimethylbenzaldehyde (348 mg, 349 μL, 2.59 mmol) in DCE (15 mL) was added HOAc (446 μL, 7.78 mmol). After stirring for 30 min, sodium triacetoxyborohydride (825 mg, 3.89 mmol) was added. After stirring at 20 °C for 1 h, the mixture was diluted with DCM, washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% EtOAc-heptane) to give tert-butyl (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo-[1,2-a]pyrimidine-6-carboxylate (447 mg, 93% yield).

[0485] TIFF2025541737000096.tif23128 Project 3 tert-Butyl (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxylate (447 mg, 1.21 mmol) was dissolved in DCM (6 mL) and treated with TFA (3.03 g, 2.05 mL, 26.6 mmol). After 8 h, 0.2 mL of TFA was added and the reaction was stirred overnight. The mixture was concentrated to give crude (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (370 mg, 98%), which was carried on to the next step without further purification.

[0486] TIFF2025541737000097.tif22136 Project 4 To a solution of (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (61 mg, 0.19 mmol) in DMF (3 mL) was added HATU (0.15 g, 0.39 mmol) and DIEA (75 mg, 0.10 mL, 0.58 mmol). After stirring for 10 min, 5-(aminomethyl)pyridin-2-amine (29 mg, 0.23 mmol) was added. After stirring at 20 °C for 18 h, the reaction mixture was concentrated, and the residue was purified by column chromatography (amine column, 0-100% MeOH-DCM). Further purification by column chromatography (0–50% MeOH-DCM), preparative HPLC method 2, and final purification by column chromatography (amine column, 0–50% MeOH-DCM) gave (S)—N-((6-aminopyridin-3-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (82 mg, 100% yield).

[0487] Example 5 Preparation of (S)-N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 5) TIFF2025541737000098.tif27136 Project 1 To a solution of (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (33 mg, 0.11 mmol, prepared according to Example 4) in DMF (1.5 mL) was added HATU (80 mg, 0.21 mmol) and DIEA (41 mg, 55 μL, 0.32 mmol). After stirring for 10 minutes, (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine (26 mg, 0.13 mmol) was added. After stirring at 20 °C for 18 hours, the reaction was concentrated, and the residue was purified by column chromatography (0-100% EtOAc-heptane, then 15% MeOH-DCM). The residue was repurified by preparative HPLC method 2 to give (S)—N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide trifluoroacetic acid (23.3 mg, 44% yield).

[0488] Example 6 Preparation of (S)-N-((1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-A]pyrimidine-6-carboxamide (Compound 6) TIFF2025541737000099.tif23128 Projects 1-3 : The title compound was prepared by following steps 1-3 of Example 4, except that the acid was purified by column chromatography (MeOH-DCM) to give (S)-3-((3,5 dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (92% yield).

[0489] TIFF2025541737000100.tif23137 Project 4 A 20 mL scintillation vial was charged with (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (47 mg, 0.15 mmol), (1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (26 mg, 0.18 mmol), and DMF, followed by HATU (63 mg, 0.17 mmol) and DIEA (39 mg, 52 μL, 0.30 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The crude material was purified twice by column chromatography (0–50% MeOH-DCM) to give (S)—N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (23.2 mg, 26% yield).

[0490] Example 7 Preparation of (S)-3-((3,5-dimethylbenzyl)amino)-N-((6-methyl-1H-pyrrolo[3,2-C]pyridin-2-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-A]pyrimidine-6-carboxamide, trifluoroacetate (compound 7) TIFF2025541737000101.tif23128 Projects 1-3 : The title compound was prepared according to steps 1-3 of Example 6.

[0491] TIFF2025541737000102.tif23136 Project 4A 20 mL scintillation vial was charged with (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (47 mg, 0.15 mmol), (6-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methanamine (29 mg, 0.18 mmol), prepared according to the procedure disclosed in WO 2019 / 231935, and DMF followed by DIEA (39 mg, 52 μL, 0.30 mmol) and HATU (63 mg, 0.17 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The crude material was purified by column chromatography (amine column, 0-100% MeOH-DCM) and repurified by column chromatography (0-50% MeOH-DCM). Final purification by preparative HPLC method 2 then afforded (S)-3-((3,5-dimethylbenzyl)amino)-N-((6-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate (34.3 mg, 40% yield).

[0492] Example 8 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((3-cyano-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 8) TIFF2025541737000103.tif20128 Project 2tert-Butyl (S)-3-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8-tetra-hydropyrrolo[1,2-a]pyrimidine-6-carboxylate (2.00 g, 5.19 mmol) was dissolved in DCM and treated with TFA (5.92 g, 4.00 mL, 51.9 mmol) and triisopropylsilane (822 mg, 5.19 mmol). The mixture was stirred at room temperature overnight. The crude material was concentrated twice to give a brown oil. The material was then triturated with EtO and filtered to give the product as an off-white solid (1.71 g, 100% yield).

[0493] TIFF2025541737000104.tif21128 Project 3~4 : The title compound was prepared according to steps 3-4 of Example 1.

[0494] TIFF2025541737000105.tif23137 Project 3 To a solution of tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (70 mg, 0.17 mmol, prepared according to Example 1) and 3-formyl-5-methylbenzonitrile (49 mg, 0.34 mmol) in 2 mL of 1,2-dichloroethane was added HOAc (58 μL, 1.0 mmol). After 30 min, sodium triacetoxyborohydride (0.11 g, 0.51 mmol) was added. The solution was stirred at room temperature for 2 h. The mixture was diluted with saturated NaHCO solution and extracted three times with DCM. The combined organics were washed with brine, dried over NaSO, filtered, and concentrated to give the pure product (92 mg, 100% yield).

[0495] TIFF2025541737000106.tif23137 Project 4tert-Butyl (S)-(5-((3-((3-cyano-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (92 mg, 0.17 mmol) was dissolved in DCM and treated with TFA (0.19 g, 0.13 mL, 1.7 mmol). The reaction was stirred at room temperature for 72 hours. The crude material was concentrated and basified with EtN. The product was purified by chromatography (amine column, 0-100% EtOAc-heptane, then 0-100% MeOH-DCM), then rechromatographed (0-100% MeOH-DCM) and lyophilized to give (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((3-cyano-5-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide as a white fluffy powder (43.8 mg, 58% yield).

[0496] The following compounds were prepared according to the procedure described above using the appropriate aldehyde, except that the final product was treated with a small amount of TFA to give the TFA salt. TIFF2025541737000107.tif29136

[0497] Example 9 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((2-methoxy-3-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate (compound 10) TIFF2025541737000108.tif23130 Project 1To a solution of tert-butyl (S)-(5-((3-amino-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)(tert-butoxy-carbonyl)carbamate (80 mg, 0.16 mmol, prepared according to Example 8) and 2-methoxy-3-methylbenzaldehyde (47 mg, 44 μL, 0.31 mmol) in 2 mL of 1,2-dichloroethane was added HOAc (53 μL, 0.93 mmol). After 1 h, sodium triacetoxyborohydride (99 mg, 0.47 mmol) was added. The solution was stirred at room temperature overnight. The mixture was diluted with saturated NaHCO3 solution and extracted three times with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The semi-pure material was purified by column chromatography (0–100% MeOH-DCM) to give tert-butyl (S)-(tert-butoxycarbonyl)(5-((3-((2-methoxy-3-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate as a colorless oil (69 mg, 68% yield).

[0498] TIFF2025541737000109.tif21137 Project 2 : (S)-tert-Butyl (5-((3-((2-methoxy-3-methylbenzyl)-amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (0.10 g, 0.16 mmol) was dissolved in HCl in MeOH (0.29 g, 2.7 mL, 3 molar, 8.0 mmol) and stirred at room temperature for 2 days. The material was concentrated in vacuo and purified by preparative HPLC method 2 to give (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-3-((2-methoxy-3-methylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate (35.7 mg, 40% yield).

[0499] The following compounds were prepared according to the procedure described above using the appropriate aldehyde and amine starting materials, except that in the final step they were concentrated after the reaction. TIFF2025541737000110.tif29146

[0500] Example 10 Preparation of (S)-N-((6-amino-2-methylpyridin-3-yl)methyl)-3-(((2,2-difluorobenzo[D][1,3]dioxol-5-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-A]pyrimidine-6-carboxamide, trifluoroacetate (compound 12) TIFF2025541737000111.tif21128 Projects 1-5 : The title compound was prepared according to steps 1-5 of Example 9 using the appropriate amine starting material.

[0501] TIFF2025541737000112.tif16134 Project 6 tert-Butyl (S)-(tert-butoxycarbonyl)(5-((3-(((2,2-difluorobenzo-[d][1,3]dioxol-5-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)methyl)-6-methylpyridin-2-yl)carbamate (0.11 g, 0.16 mmol) was dissolved in DCM and cooled to 0° C. The mixture was treated with TFA (0.12 mL, 1.6 mmol), allowed to warm to room temperature, and stirred overnight. The crude material was concentrated to dryness twice and lyophilized for 72 hours to give (S)—N-((6-amino-2-methylpyridin-3-yl)methyl)-3-(((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate (54 mg, 56% yield).

[0502] The following compounds were prepared according to the procedures described above using the appropriate aldehyde and amine starting materials. TIFF2025541737000113.tif43146

[0503] Example 11 Preparation of (S)-N-((S)-1-(6-aminopyridin-3-yl)ethyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 15) TIFF2025541737000114.tif23137 Project 4 A 20 mL scintillation vial was charged with (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (47 mg, 0.15 mmol, prepared according to Example 4), (S)-5-(1-aminoethyl)pyridin-2-amine (25 mg, 0.18 mmol), and DMF, followed by HATU (63 mg, 0.17 mmol) and DIEA (39 mg, 52 μL, 0.30 mmol). The mixture was stirred at room temperature overnight. The crude material was concentrated and purified by column chromatography (amine column, 0-100% MeOH-DCM) to give (S)—N-((S)-1-(6-aminopyridin-3-yl)ethyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (27 mg, 42% yield).

[0504] The following compounds were prepared according to the procedures described above using the appropriate amine starting materials. TIFF2025541737000115.tif22146

[0505] Example 12 Preparation of (S)-N-((5-chloropyridin-3-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate (compound 17) TIFF2025541737000116.tif20136 Project 1 A 20 mL scintillation vial was charged with (S)-3-((3,5-dimethyl-benzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (47 mg, 0.15 mmol, prepared according to Example 4), (5-chloropyridin-3-yl)methanamine (26 mg, 0.18 mmol), and DMF, followed by HATU (63 mg, 0.17 mmol) and DIEA (39 mg, 52 μL, 0.30 mmol). The reaction mixture was stirred overnight at room temperature. (5-chloropyridin-3-yl)methanamine (26 mg, 0.18 mmol) and HATU (63 mg, 0.17 mmol) were added to the mixture, and stirring was continued overnight. The crude material was concentrated and purified by column chromatography (amine column, 100% EtOAc). Semi-pure fractions were collected and re-purified by column chromatography and then by preparative HPLC method 2 to give (S)—N-((5-chloropyridin-3-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate as a white solid (14 mg, 17% yield).

[0506] Example 13 Preparation of (S)-N-((3-chloro-1H-pyrrolo[2,3-B]pyridin-5-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-A]pyrimidine-6-carboxamide, trifluoroacetate (compound 18) TIFF2025541737000117.tif22136 Project 4A 20 mL scintillation vial was charged with (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (47 mg, 0.15 mmol, prepared according to Example 4), (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine, ditrifluoroacetate (74 mg, 0.18 mmol), and DMF, followed by DIEA (78 mg, 0.10 mL, 0.60 mmol) and HATU (63 mg, 0.17 mmol). The resulting mixture was stirred overnight at room temperature. The crude material was purified by column chromatography (amine column, 0-100% MeOH-DCM) and repurified by column chromatography (0-50% MeOH-DCM). The corresponding mixture was purified by preparative HPLC method 2 to give (S)—N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, trifluoroacetate (34.8 mg, 39% yield).

[0507] Example 14 Preparation of (S)-3-((3,5-dimethylbenzyl)amino)-N-((2-methylpyridin-4-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (compound 19) TIFF2025541737000118.tif23134 Project 4To a solution of (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetra-hydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (46 mg, 0.15 mmol, prepared according to Example 4) in DMF (2.5 mL) was added HATU (0.11 g, 0.29 mmol) and DIEA (57 mg, 77 μL, 0.44 mmol). After stirring for 10 minutes, 4-(aminomethyl)-2-methylpyridine (22 mg, 0.18 mmol) was added. After stirring at 20 °C for 18 h, the reaction mixture was concentrated, and the residue was purified by column chromatography (amine column, 0–100% MeOH-DCM) and additional column chromatography (0–50% MeOH-DCM) to give (S)-3-((3,5-dimethylbenzyl)amino)-N-((2-methylpyridin-4-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (34.6 mg, 56% yield).

[0508] Example 15 Preparation of (S)-3-((3,5-dimethylbenzyl)amino)-N-(imidazo[1,5-α]pyridin-6-ylmethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide (compound 20) TIFF2025541737000119.tif23134 Project 1To a solution of (S)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (41 mg, 0.13 mmol, prepared according to Example 4) in DMF (2.0 mL) was added HATU (0.10 g, 0.26 mmol) and DIEA (85 mg, 0.11 mL, 0.65 mmol). After stirring for 10 minutes, {imidazo[1,5-a]pyridin-6-yl}methanamine dihydrochloride (35 mg, 0.16 mmol) was added. After stirring at 20 °C for 18 h, the reaction mixture was concentrated, and the residue was purified by column chromatography (amine column, 0–100% MeOH-DCM) followed by additional column chromatography (0–50% MeOH-DCM) to give (S)-3-((3,5-dimethylbenzyl)amino)-N-(imidazo[1,5-a]pyridin-6-ylmethyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide (23.1 mg, 40% yield).

[0509] Example 16 Preparation of (S)-N-((5,6-dihydro-4H-thieno[2,3-C]pyrrol-2-yl)methyl)-3-((3,5-dimethylbenzyl)amino)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-A]pyrimidine-6-carboxamide, trifluoroacetate (compound 21) TIFF2025541737000120.tif10128 Project 1A brown mixture of 5-(tert-butoxycarbonyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylic acid (5.0 g, 18.6 mmol) in THF (42 mL) was placed under nitrogen and cooled to 0 °C. A solution of borane tetrahydrofuran complex (6.9 g, 80 mL, 1 molar, 80 mmol) was added dropwise. The reaction was stirred at 0 °C for 5 minutes and stirred for 16 hours while warming to room temperature. The reaction was quenched with anhydrous methanol at 0 °C and then stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure. The crude product was dissolved in CHCl and adsorbed onto silica gel. Purification by chromatography (0-100% EtOAc-hexanes) afforded tert-butyl 2-(hydroxymethyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate (3.58 g, 75% yield) as a pale yellow solid.

[0510] TIFF2025541737000121.tif10128 Project 2 A suspension of tert-butyl 2-(hydroxymethyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate (3.58 g, 14.00 mmol) in THF (35 mL) was placed under nitrogen and treated with diphenylphosphoryl azide (5.8 g, 4.5 mL, 21 mmol) at room temperature. After cooling to 0 °C, 1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 g, 3.2 mL, 21 mmol) was added. The reaction flask was sealed and allowed to warm to room temperature for approximately 5 minutes. The resulting solution was heated at 65 °C for 16 hours. The reaction was quenched with water and extracted three times with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The crude product was dissolved in CHCl and adsorbed onto silica gel. Purification by column chromatography (0-40% EtOAc-heptane) afforded tert-butyl 2-(azidomethyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate (3.82 g, 97% yield) as a white solid.

[0511] TIFF2025541737000122.tif11128 Project 3A solution of tert-butyl 2-(azidomethyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-carboxylate (3.82 g, 13.6 mmol) in THF (48 mL) was placed under nitrogen and treated with water (5.4 g, 5.4 mL, 0.30 mol), followed by the addition of triphenylphosphine (5.37 g, 20.46 mmol) at room...

Claims

1. Structure (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 is a substituted aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl, or Cy 1 is R 5 or R 6 and the carbon to which they are attached, a substituted or unsubstituted C fused to a substituted or unsubstituted 5- to 10-membered heteroaryl 3 ~C 6 forms a cycloalkyl, or a substituted or unsubstituted phenyl; Cy 2 is a substituted aryl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or hydrogen; R 2 is hydrogen, substituted or unsubstituted C 1 ~C 3 alkyl, or substituted or unsubstituted cycloalkyl; R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 ~C 3 alkyl, or substituted or unsubstituted cycloalkyl, or R 3 and R 4 together with the carbon to which they are attached, form a substituted or unsubstituted C 3 ~C 6 Cycloalkyl or substituted or unsubstituted C 5 ~C 6 forming a cycloalkenyl; R 5 and R 6 are independently hydrogen, C 1 ~C 3 Alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, or C 3 ~C 6 is cycloalkyl; R 7 is hydrogen, halogen, substituted or unsubstituted C 1 ~C 3 Alkyl, and substituted or unsubstituted C 3 ~C 6 cycloalkyl; L is hydrogen or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently the same or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted straight-chain or branched C 1 ~C 3 alkyl or R 8a and R 8b together with the carbon to which they are attached, form a substituted or unsubstituted C 3 ~C 6 forming a cycloalkyl; and n is 1, 2, or 3; Here, the C 3 ~C 6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and One or more hydrogen atoms in structure (I) may be replaced with deuterium atoms; provided that the compound of structure (I) has the structure: where R A is benzyl, phenethyl, or 3-CF 3 -benzyl, The compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

2. R 2 2. The compound of claim 1, wherein is hydrogen.

3. R 2 2. The compound of claim 1, wherein is methyl or ethyl.

4. R 3 and R 4 4. The compound of claim 1, wherein is hydrogen.

5. R 5 5. The compound of claim 1, wherein is hydrogen.

6. R 7 are hydrogen, deuterium, and C 1 ~C 3 Alkyl, or C 1 ~C 3 6. The compound of any one of claims 1 to 5, which is haloalkyl.

7. R 7 7. The compound of any one of claims 1 to 6, wherein is hydrogen.

8. Structure (IA):

8. The compound of any one of claims 1 to 7, having the formula:

9. structure: or a combination thereof.

10. R 6 10. The compound of any one of claims 1 to 9, wherein is hydrogen.

11. R 6 10. The compound of any one of claims 1 to 9, wherein is methyl.

12. Structure (IB): wherein m is 1 or 2; The compound of any one of claims 1 to 7.

13. 13. The compound of claim 12, wherein m is 1.

14. structure:

14. The compound of any one of claims 1 to 7, 12, or 13, having:

15. Cy 1 is substituted C 6 ~C 10 15. The compound of any one of claims 1 to 14, which is aryl.

16. Cy 1 is hydrogen, C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , C(=NOH)NH 2 , C(=NH)NHC(=O)NHC(=O)N(CH 3 )R 17 , C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl 6 ~C 10 is aryl, where R 8 , R 9 , R 10 , R 11 , and R 12 independently in each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The one or more substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the one or more substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 But CH 2 OC(=O)CH 3 C optionally substituted with 6 ~C 10 aryl or 5-10 membered heteroaryl; 16. The compound of any one of claims 1 to 15.

17. Cy 1 But -C(=NH)NH 2 , chloro, fluoro, -CHF 2 , -NH 2 , -CF 3 , -CH 2 NH 2 , -CH(CH 3 )NH 2 , and 17. The compound of any one of claims 1 to 16, which is phenyl substituted with at least one substituent selected from the group consisting of:

18. Cy 1 but, 12. The compound of any one of claims 1 to 11, selected from the group consisting of:

19. Cy 1 but, 15. The compound of any one of claims 1 to 7 or 12 to 14, selected from the group consisting of:

20. Cy 1 but 20. The compound of any one of claims 1-7, 12-14, or 19, wherein:

21. Cy 1 15. The compound of any one of claims 1-14, wherein is substituted or unsubstituted 5-10 membered heteroaryl.

22. Cy 1 The substituted 5- to 10-membered heteroaryl is selected from the group consisting of hydrogen, C 1～6 Deuterated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH 3 )R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 or a 5- to 10-membered heteroaryl substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; or, when the heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 a cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a heteroaryl; where R 9 , R 10 , R 11 , and R 12 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; The one or more substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the one or more substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 But CH 2 OC(=O)CH 3 C optionally substituted with 6 ~C 10 aryl or 5-10 membered heteroaryl; 22. The compound of claim 21.

23. Cy 1 23. The compound of any one of claims 21-22, wherein the 5-10 membered heteroaryl is pyridinyl, pyrrolopyridinyl, imidazopyridinyl, thienopyridinyl, benzimidazolyl, isoindolinyl, thiophenyl, or benzothiazolyl.

24. Cy 1 24. The compound of any one of claims 1-14 or 21-23, wherein is substituted or unsubstituted pyridinyl.

25. Cy 1 but, 12. The compound of any one of claims 1-11, having a structure selected from the group consisting of:

26. Cy 1 but 26. The compound of any one of claims 1 to 11 or 25, wherein

27. Cy 1 but 27. The compound of any one of claims 1-11, 25, or 26, wherein:

28. Cy 1 but 15. The compound of any one of claims 1 to 7 or 12 to 14, wherein

29. Cy 1 but 29. The compound of any one of claims 1-7, 12-14, or 28, wherein:

30. Cy 1 but 30. The compound of any one of claims 1-7, 12-14, 28, or 29, wherein:

31. R 1a However, hydrogen, deuterium, C 1～6 Alkyl, and C 1～6 31. The compound of any one of claims 25 to 30, wherein the compound is selected from the group consisting of deuterated alkyls.

32. R 1a are hydrogen, methyl, ethyl, and CD 3 32. The compound of any one of claims 25 to 31, selected from the group consisting of:

33. R 1a 33. The compound of any one of claims 25-32, wherein is hydrogen.

34. R 1b , R 1c , R 1d , and R 1e are independently hydrogen, deuterium, and C 1～6 Alkyl, C 1～6 Deuterated alkyl, halogen, aminyl alkyl, amino, C 1～3 Alkoxy, and C 1～6 34. The compound of any one of claims 25-33, selected from the group consisting of haloalkyl.

35. R 1b , R 1c , R 1d , and R 1e are independently hydrogen, methyl, ethyl, CD 3 35. The compound of any one of claims 25-34, wherein the aryl group is selected from the group consisting of , amino, aminylmethyl, F, Cl, Br, and methoxy.

36. Cy 1 but, 28. The compound of any one of claims 1-11 or 25-27, selected from the group consisting of:

37. Cy 1 but, 37. The compound of any one of claims 1-11, 25, or 36, selected from the group consisting of:

38. Cy 1 but, 37. The compound of any one of claims 1-11, 25, or 36, selected from the group consisting of:

39. Cy 1 but, 37. The compound of any one of claims 1-11, 25-27, or 36, selected from the group consisting of:

40. Cy 1 but, 31. The compound of any one of claims 1-7, 12-14, or 28-30, selected from the group consisting of:

41. Cy 1 but 41. The compound of any one of claims 1-7, 12-14, 28-30, or 40, wherein:

42. Structure (IC):

42. The compound of any one of claims 1-7, 12-14, 28-30, 40, or 41, having the formula:

43. Structure (ID): and where R 1b is hydrogen or methyl, and R 6 is hydrogen or methyl; 40. The compound of any one of claims 1-11, 25-27, 36, or 39.

44. Structure (IE): and where R 1a is hydrogen or C 1 ~C 3 alkyl, and R 6 is hydrogen or methyl; 38. The compound of any one of claims 1-11, 25, 36, or 37.

45. L is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or -CH 2 CH 2 CH 2 45. The compound of any one of claims 1 to 44, wherein:

46. L is -CH 2 45. The compound of any one of claims 1 to 44, wherein:

47. Cy 2 is substituted C 6 ~C 10 47. The compound of any one of claims 1 to 46, which is aryl.

48. Cy 2 But hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl 6 ~C 10 aryl or C 6 ~C 10 When an aryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is C 6 ~C 10 fused to an aryl, where R 9 , R 10 , R 11 , and R 12 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The one or more substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the one or more substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 48. The compound of any one of claims 1 to 47.

49. Cy 2 but, having a structure selected from the group consisting of where R 2a , R 2b , R 2c , R 2d , and R 2e are independently hydrogen, C 1 ~C 3 Alkyl, halogen, C 1 ~C 3 Alkyloxy, C 3 ~C 6 Cycloalkyloxy, CN, cyanoalkyl, COOH, CONH 2 , hydroxyalkyl, C 1 ~C 3 Alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C 1 ~C 3 Alkylsulfonyl, C 2 ~C 6 Alkynyl, C 1 ~C 3 selected from the group consisting of acyl, a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and a 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O; or R 2a , R 2b , R 2c , R 2d , and R 2e When any two of the carbon atoms are bonded to adjacent carbon atoms and taken together with the carbon atoms to which they are bonded, a substituted or unsubstituted C fused to a phenyl is 5 ~C 6 forming a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of cycloalkyl, or N, S, and O, and the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl; 49. The compound of any one of claims 1 to 48.

50. Cy 2 is phenyl substituted with one or more substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

51. Cy 2 is phenyl substituted on two adjacent carbon atoms of the phenyl such that, together with the carbon atoms to which the substituents are attached, they form a phenyl-fused dioxane, a phenyl-fused furan, or a phenyl-fused difluorodioxolane.

52. Cy 2 but, 52. The compound of any one of claims 1 to 51, selected from the group consisting of:

53. Cy 2 is substituted or unsubstituted C 3 ~C 6 cycloalkyl, wherein the substituted C 3 ~C 6 Cycloalkyl is hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 substituted with 1 to 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl; where R 9 and R 10 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The 1 to 5 substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the 1 to 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 47. The compound of any one of claims 1 to 46.

54. Cy 2 is substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, COOH, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, and combinations thereof; 5 ~C 6 54. The compound of any one of claims 1-46 or 53, which is cycloalkyl.

55. Cy 2 but 55. The compound of any one of claims 1-46, 53, or 54, wherein:

56. Cy 2 is a substituted or unsubstituted 5- to 10-membered heteroaryl, wherein the substituted 5- to 10-membered heteroaryl is selected from the group consisting of hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or when heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 a cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a heteroaryl; where R 9 and R 10 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The 1 to 4 substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the 1 to 4 substituents are selected from halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 47. The compound of any one of claims 1 to 46.

57. Cy 2 57. The compound of any one of claims 1-46 or 56, wherein the 5-10 membered heteroaryl is pyrazole.

58. Cy 2 58. The compound of any one of claims 1-46, 56, or 57, wherein the 5- to 10-membered heteroaryl, wherein is substituted with one or more substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, and combinations thereof.

59. Cy 2 but 59. The compound of any one of claims 1-46 or 56-58, wherein

60. 60. The compound of any one of claims 1-59, wherein one or more hydrogen atoms are replaced with one or more deuterium atoms.

61. The compound of any one of claims 1 to 60, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

62. Structure (II): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 teeth selected from the group consisting of Cy 2 is hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, Amino C 1～6 Alkyl, C 1～6 Alkyloxy, cyano, cyanomethyl, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 phenyl substituted with 1 to 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or the phenyl is substituted at two adjacent carbon atoms and the substituents, together with the carbon atoms to which they are attached, form a C fused to the phenyl; 5 ~C 6 C fused to the phenyl to form a cycloalkyl or 5- to 6-membered heterocycle 5 ~C 6 Each cycloalkyl or 5- to 6-membered heterocycle is C 1～6 Alkyl, C 3～6 Cycloalkyl, C 1～6 Haloalkyl, C 3～6 optionally substituted with 1 to 8 substituents independently selected from the group consisting of halocycloalkyl, and halogen; where R 9 and R 10 independently in each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The 1 to 5 substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the 1 to 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently in each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; R 6 is hydrogen, C 1～3 Alkyl, or C 1～3 is haloalkyl, R 7 are hydrogen, deuterium, and C 1～6 Alkyl, C 3～6 Cycloalkyl, C 1～6 Haloalkyl, C 3～6 halocycloalkyl, or halogen; L is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or -CH 2 CH 2 CH 2 -and one or more hydrogen atoms may be replaced by one or more deuterium atoms; The compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

63. R 6 63. The compound of claim 62, wherein is hydrogen or methyl.

64. R 7 64. The compound of claim 62 or 63, wherein is hydrogen.

65. Cy 1 but, 65. The compound of any one of claims 62-64, selected from the group consisting of:

66. Structure (II-A): and where R 1b are hydrogen, methyl, ethyl, and CD 3 and R 6 is hydrogen or methyl; 66. The compound of any one of claims 62 to 65.

67. Structure (II-B): and where R 1a is hydrogen or C 1 ~C 3 alkyl, and R 6 is hydrogen or methyl; 66. The compound of any one of claims 62 to 65.

68. Structure (II-C): and where R 1a is hydrogen or C 1 ~C 3 alkyl, and R 6 is hydrogen or methyl; 66. The compound of any one of claims 62 to 65.

69. Structure (II-D): where R 6 is hydrogen or methyl; 66. The compound of any one of claims 62 to 65.

70. Cy 2 but, having a structure selected from the group consisting of where R 2a , R 2b , R 2c , R 2d , and R 2e are independently hydrogen, C 1 ~C 3 Alkyl, halogen, C 1 ~C 3 Alkyloxy, C 3 ~C 6 Cycloalkyloxy, CN, cyanoalkyl, COOH, CONH 2 , hydroxyalkyl, C 1 ~C 3 Alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C 1 ~C 3 Alkylsulfonyl, C 2 ~C 6 Alkynyl, C 1 ~C 3 selected from the group consisting of acyl, a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and a 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O; or R 2a , R 2b , R 2c , R 2d , and R 2e If any two of these are bonded to adjacent carbon atoms, then together with the carbon atoms to which they are bonded, they form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 cycloalkyl or the substituted or unsubstituted 5- to 6-membered heterocyclic ring is fused to a phenyl; 70. The compound of any one of claims 62 to 69.

71. Cy 2 is phenyl substituted with one or more substituents independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

72. Cy 2 but, 72. The compound of any one of claims 62-71, selected from the group consisting of:

73. L is -CH 2 - or -CH(CH 3 73. The compound of any one of claims 62-72, wherein:

74. Structure (III): or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, During the ceremony, Cy 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted 5-10 membered heteroaryl; Cy 2 is a substituted aryl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, or substituted or unsubstituted 5-10 membered heteroaryl; R 2 is hydrogen, substituted or unsubstituted C 1 ~C 3 alkyl, or substituted or unsubstituted cycloalkyl; R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 ~C 3 alkyl, or substituted or unsubstituted cycloalkyl, or R 3 and R 4 together with the carbon to which they are attached, form a substituted or unsubstituted C 3 ~C 6 forms a cycloalkyl or a substituted or unsubstituted 5- to 6-membered cycloalkenyl; R 7 is hydrogen, halogen, substituted or unsubstituted C 1 ~C 3 Alkyl, and substituted or unsubstituted C 3 ~C 6 cycloalkyl; L is absent or -(CR 8a R 8b ) n -, where each -(CR 8a R 8b )- are independently the same or different; R 8a and R 8b are each independently hydrogen, substituted or unsubstituted C 1 ~C 3 alkyl or R 8a and R 8b together with the carbon to which they are attached, form a substituted or unsubstituted C 3 ~C 6 Forming a cycloalkyl; m is 1 or 2; and n is 1, 2, or 3; Here, the C 3 ~C 6 cycloalkyl consists of monocyclic or bicyclic ring systems, including fused or bridged ring systems; The 5- to 10-membered heteroaryl consists of a monocyclic or bicyclic ring system containing at least one aromatic ring and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and one or more hydrogen atoms may be replaced by deuterium atoms; The compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

75. 75. The compound of claim 74, wherein m is 1.

76. R 2 76. The compound of claim 74 or 75, wherein is hydrogen.

77. R 3 77. The compound of any one of claims 74-76, wherein is hydrogen.

78. R 4 78. The compound of any one of claims 74-77, wherein is hydrogen.

79. R 7 79. The compound of any one of claims 74-78, wherein is hydrogen.

80. Structure (III-A):

80. The compound of any one of claims 74-79, having the formula:

81. structure: or a combination thereof.

82. L is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or -CH 2 CH 2 CH 2 82. The compound of any one of claims 74 to 81, wherein:

83. L is -CH 2 83. The compound of any one of claims 74 to 82, wherein:

84. Cy 1 But hydrogen, C(NH)NH 2 , C(=NH)NHC(=O)OR 8 , C(=NOC(=O)R 8 )NH 2 , C(=NOC(=O)OR 8 )NH 2 , C(=NOH)NH 2 , C(=NH)NHC(=O)NHC(=O)N(CH 3 )R 13 , C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, halogen, C 1 ~C 6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 phenyl substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or when phenyl is substituted on two adjacent atoms, the two substituents are connected together with the atoms to which they are attached to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl; where R 8 , R 9 , R 10 , R 11 , and R 12 independently at each occurrence: hydrogen, deuterium, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, Hydroxyl, C 1 ~C 6 Alkoxy, aryl, arylalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; R 13 But CH 2 OC(=O)CH 3 C optionally substituted with 6 ~C 10 aryl or 5- to 10-membered heteroaryl; Any of the one or more substituents is substituted C 1 ~C 6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4-10 membered heterocyclyl, the one or more substituents are halo, CN, OR e , S.R. e , C(O)R e , C(O)NR e R f , C(O)OR e ,OC(O)R e , OC(O)NR e R f , N.R. e R f , N.R. e C(O)R f , N.R. e C(O)NR f R g , N.R. e C(O)OR f , C(=NR e )NR f R g , N.R. e C(=NR f )NR g R h , S(O)R e , S(O)NR e R f , S(O) 2 R e , N.R. e S(O) 2 R f , S(O) 2 NR e R f and oxo, wherein R e , R f , R g , and R h independently at each occurrence: hydrogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, Hydroxyl, C 1 ~C 6 Alkoxy, aryl, arylalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 84. The compound of any one of claims 74 to 83.

85. Cy 1 but and where R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1～6 Alkyl, C 1～6 is selected from the group consisting of deuterated alkyl, amino, and aminyl alkyl; or R 1a , R 1b , R 1c , and R 1d When any two of 1a , R 1b , R 1c , and R 1d Two of the carbon atoms to which they are attached are joined together to form a substituted or unsubstituted C 5 ~C 6 forming a substituted or unsubstituted 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of cycloalkyl, or N, S, and O, and the substituted or unsubstituted 5- to 6-membered heterocyclic ring is fused to a phenyl; 85. The compound of any one of claims 74 to 84.

86. Cy 1 but, 86. The compound of any one of claims 74-85, selected from the group consisting of:

87. Cy 1 87. The compound of any one of claims 74-86, wherein is phenyl substituted with amino.

88. Cy 1 but, 88. The compound of any one of claims 74-87, selected from the group consisting of:

89. Cy 1 is a substituted or unsubstituted 5- to 10-membered heteroaryl, wherein the substituted 5- to 10-membered heteroaryl is selected from the group consisting of hydrogen, C 1～6 Deuterated alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NH)NHC(=O)NHC(=O)N(CH 3 )R 17 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or when a 5- to 10-membered heteroaryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a 5- to 10-membered heteroaryl; where R 9 , R 10 , R 11 , and R 12 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; The one or more substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the one or more substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; and R 17 But CH 2 OC(=O)CH 3 C optionally substituted with 6 ~C 10 aryl or 5-10 membered heteroaryl; 84. The compound of any one of claims 74 to 83.

90. Cy 1 90. The compound of any one of claims 74-83 or 89, wherein is substituted or unsubstituted pyridinyl.

91. Cy 1 but, 91. The compound of any one of claims 74-83 or 89-90, having a structure selected from the group consisting of:

92. R 1a , R 1b , and R 1c are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 92. The compound of claim 91, wherein the compound is selected from the group consisting of deuterated alkyl, amino, aminyl alkyl, alkoxy, and halogen.

93. Cy 1 93. The compound of any one of claims 74-83 or 89-92, wherein is pyridinyl substituted with amino.

94. Cy 1 but, 94. The compound of any one of claims 74-83 or 89-93, selected from the group consisting of:

95. Cy 1 but 95. The compound of any one of claims 74-83 or 89-94, wherein

96. Structure (III-B):

96. The compound of any one of claims 74-83 or 89-95, having the formula:

97. Cy 2 is substituted or unsubstituted C 3 ~C 6 cycloalkyl, wherein the substituted C 3 ~C 6 Cycloalkyl is hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 C substituted with 1 to 5 substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl 3 ~C 6 is cycloalkyl, where R 9 and R 10 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The 1 to 5 substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the 1 to 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 97. The compound of any one of claims 74 to 96.

98. Cy 2 But hydrogen, C 1 ~C 3 Alkyl, halogen, C 1 ~C 3 Alkyloxy, C 3 ~C 6 Cycloalkyloxy, CN, cyanoalkyl, COOH, CONH 2 , hydroxyalkyl, C 1 ~C 3 C substituted with one or more substituents independently selected from the group consisting of alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and combinations thereof. 5 ~C 6 98. The compound of any one of claims 74-97, which is cycloalkyl.

99. Cy 2 but 99. The compound of any one of claims 74 to 98, wherein

100. Cy 2 is a substituted or unsubstituted 5- to 10-membered heteroaryl, wherein the substituted 5- to 10-membered heteroaryl is selected from the group consisting of hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl, or when the 5- to 10-membered heteroaryl is substituted on adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 a cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a heteroaryl; where R 9 and R 10 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The 1 to 5 substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the 1 to 5 substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 97. The compound of any one of claims 74 to 96.

101. Cy 2 But hydrogen, C 1 ~C 3 Alkyl, halogen, C 1 ~C 3 Alkyloxy, C 3 ~C 6 Cycloalkyloxy, CN, cyanoalkyl, COOH, CONH 2 , hydroxyalkyl, C 1 ~C 3 101. The compound of any one of claims 74-96 or 100, which is a 5-10 membered heteroaryl substituted with one or more substituents independently selected from the group consisting of alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, and combinations thereof.

102. Cy 2 is a 5-10 membered heteroaryl substituted on two adjacent carbon atoms of the heteroaryl such that, together with the carbon atoms to which the substituents are attached, they form a heteroaryl-fused dioxane, a heteroaryl-fused furan, or a heteroaryl-fused difluorodioxolane.

103. Cy 2 is substituted or unsubstituted pyrazolyl.

104. Cy 2 but 104. The compound of any one of claims 74-96 or 100-103, wherein

105. Cy 2 But hydrogen, C 2～6 Alkenyl, C 2～6 Alkynyl, halogen, C 1～6 Haloalkyl, aminylalkyl, hydroxyalkyl, cyano, OR 9 , S.R. 9 , C(O)R 9 , C(O)NR 9 R 10 , C(O)OR 9 ,OC(O)R 9 ,OC(O)OR 9 , OC(O)NR 9 R 10 , N.R. 9 R 10 , N(R 9 )C(O)R 10 , N(R 9 )C(O)NR 10 R 11 , N(R 9 )C(O)OR 10 , C(=NR 9 )NR 10 R 11 , C(=NOR 9 )NR 10 R 11 , C(=NOC(O)R 9 )NR 10 R 11 , C(=NR 9 )N(R 10 )C(O)OR 11 , N(R 9 )C(=NR 10 )NR 11 R 12 , S(O)R 9 , S(O)NR 9 R 10 , S(O) 2 R 9 , N(R 9 )S(O) 2 R 10 , S(O) 2 NR 9 R 10 , oxo, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 6～10 Aryl, substituted or unsubstituted C 6～10 Aryl alkyl, substituted or unsubstituted C 6～10 Aryloxy, substituted or unsubstituted C 6～10 arylalkoxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 3～10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and substituted or unsubstituted 4- to 10-membered heterocyclyl 6 ~C 10 aryl or C 6 ~C 10 When an aryl is substituted on two adjacent atoms, the two substituents, together with the atoms to which they are attached, are connected to form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is C 6 ~C 10 fused to an aryl, where R 9 , R 10 , R 11 , and R 12 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, and heteroaryl; The one or more substituents are substituted C 1～6 Alkyl, substituted C 6～10 Aryl, substituted C 6～10 Aryl alkyl, substituted C 6～10 Aryloxy, substituted C 6～10 Arylalkoxy, substituted 5-10 membered heteroaryl, substituted C 3～10 When cycloalkyl or substituted 4- to 10-membered heterocyclyl, the one or more substituents are halogen, CN, OR 13 , S.R. 13 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 R 14 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15 , N.R. 13 C(O)OR 14 , C(=NR 13 )NR 14 R 15 , N.R. 13 C(=NR 14 )NR 15 R 16 , S(O)R 13 , S(O)NR 13 R 14 , S(O) 2 R 13 , N.R. 13 S(O) 2 R 14 , S(O) 2 NR 13 R 14 and oxo, R 13 , R 14 , R 15 , and R 16 independently at each occurrence: hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, Hydroxyl, C 1～6 Alkoxy, aryl, arylalkyl, C 1～6 Haloalkyl, C 1～6 Haloalkoxy, C 1～6 selected from the group consisting of hydroxyalkyl, cycloalkyl, heterocyclyl, and heteroaryl; 97. The compound of any one of claims 74 to 96.

106. Cy 2 but, having a structure selected from the group consisting of where R 2a , R 2b , R 2c , R 2d , and R 2e are independently hydrogen, C 1 ~C 3 Alkyl, halogen, C 1 ~C 3 Alkyloxy, C 3 ~C 6 Cycloalkyloxy, CN, cyanoalkyl, COOH, CONH 2 , hydroxyalkyl, C 1 ~C 3 Alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C 1 ~C 3 Alkylsulfonyl, C 2 ~C 6 Alkynyl, C 1 ~C 3 selected from the group consisting of acyl, a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and a 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O; or R 2a , R 2b , R 2c , R 2d , and R 2e If any two of these are bonded to adjacent carbon atoms, then together with the carbon atoms to which they are bonded, they form a substituted or unsubstituted C 5 ~C 6 cycloalkyl, or a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O, and said substituted or unsubstituted C 5 ~C 6 cycloalkyl or the substituted or unsubstituted 5- or 6-membered heterocyclic ring is fused to a phenyl; 106. The compound of any one of claims 74-96 or 105.

107. Cy 2 is phenyl independently substituted with one or more substituents selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, pyrazole, cyclopropoxy, morpholinyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and combinations thereof.

108. Cy 2 is phenyl substituted with 1 to 5 methyl groups.

109. Cy 2 but, 109. The compound of any one of claims 74-96 or 105-108, selected from the group consisting of:

110. Cy 2 but, 110. The compound of any one of claims 74-96 or 105-109, selected from the group consisting of:

111. Structure (III-C):

107. The compound of any one of claims 74-96 or 105-106, having the formula:

112. R 2a , R 2b , R 2c , R 2d , and R 2e are independently hydrogen, C 1 ~C 3 Alkyl, halogen, C 1 ~C 3 Alkyloxy, C 3 ~C 6 Cycloalkyloxy, CN, cyanoalkyl, COOH, CONH 2 , hydroxyalkyl, C 1 ~C 3 Alkyloxycarbonyl, haloalkyl, haloalkyloxy, aryl, C 1 ~C 3 Alkylsulfonyl, C 2 ~C 6 Alkynyl, C 1 ~C 3 112. The compound of claim 111, wherein the compound is selected from the group consisting of acyl, a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, S, and O, and a 5- or 6-membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, S, and O.

113. R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, methoxy, ethoxy, CN, cyanomethyl, COOH, methoxycarbonyl, ethoxycarbonyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, pyrazole, cyclopropoxy, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and morpholinyl.

114. R 2a , R 2b , R 2c , R 2d , and R 2e are independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, methoxy, CN, cyanomethyl, trifluoromethyl, phenyl, methanesulfonyl, ethynyl, hydroxymethyl, acetyl, and difluoromethyl.

115. R 2a and R 2b , R 2b and R 2c , R 2c and R 2d , or R 2d and R 2e But R 2a , R 2b , R 2c , R 2d , and R 2e is taken together with the carbon atom to which it is attached to form a phenyl-fused dioxane, a phenyl-fused furan, or a phenyl-fused difluorodioxolane.

116. The compound of any one of claims 74-115, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of:

117. 117. The compound of any one of claims 1-116, wherein the pharmaceutically acceptable salts are trifluoroacetic acid, hydrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, and gluconic acid.

118. 117. The compound of any one of claims 1-116, wherein the pharmaceutically acceptable salt is trifluoroacetic acid, hydrogen chloride, and acetic acid.

119. 119. A pharmaceutical composition comprising the compound of any one of claims 1-118, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

120. A method for inhibiting MASP-2 in a subject, comprising administering to the subject a compound described in any one of claims 1 to 118, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount effective to inhibit MASP-2.

121. A method for inhibiting MASP-2 in a subject, comprising administering to the subject the pharmaceutical composition described in claim 119.

122. A compound according to any one of claims 1 to 118, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in treating a disease treatable by inhibiting MASP-2.

123. Use of a compound according to any one of claims 1 to 118, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease treatable by inhibiting MASP-2.

124. A method for treating or preventing a disease or disorder treatable by inhibiting MASP-2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in any one of claims 1 to 118, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

125. The method of claim 124, wherein the compound is administered in an amount sufficient to inhibit MASP-2-dependent complement activation in the subject.

126. 125. The method of claim 124, wherein the subject has been diagnosed as needing treatment for a lectin complement-associated disease or disorder.

127. 125. The method of claim 124, wherein said disease or disorder is thrombotic microangiopathy (TMA), a renal condition, an inflammatory response resulting from tissue or organ transplantation, ischemia-reperfusion injury, complications associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, a neurodegenerative disease, an ocular disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno-occlusive disease, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome, fluid overload, or a combination thereof.

128. 125. The method of claim 124, wherein the disease or disorder is thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic syndrome (aHUS), factor H-independent atypical hemolytic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplant, TMA associated with hematopoietic stem cell transplantation, or a combination thereof.

129. 125. The method of claim 124, wherein the disease or disorder is graft-versus-host disease.

130. 125. The method of claim 124, wherein the disease or disorder is diffuse alveolar hemorrhage (DAH).

131. 125. The method of claim 124, wherein the disease or disorder is veno-occlusive disease (VOD).

132. 125. The method of claim 124, wherein the disease or disorder is a renal disease.

133. 133. The method of claim 132, wherein the renal disease is mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangial capillary glomerulonephritis), acute post-infectious glomerulonephritis (post-streptococcal glomerulonephritis), C3 glomerulopathy, cryoglobulinemic glomerulonephritis, microimmune necrotizing crescentic glomerulonephritis, lupus nephritis, Henoch-Schönlein purpura nephritis, IgA nephropathy, or a combination thereof.

134. 125. The method of claim 124, wherein the disease or disorder is renal fibrosis, proteinuria, or a combination thereof.

135. 125. The method of claim 124, wherein said disease or disorder is an inflammatory response resulting from tissue or solid organ transplantation.

136. 125. The method of claim 124, wherein the disease or disorder is ischemia-reperfusion injury (I / R).

137. 125. The method of claim 124, wherein the disease or disorder is a complication associated with non-obese diabetes, type 1 diabetes, type 2 (adult-onset) diabetes, or a combination thereof.

138. 125. The method of claim 124, wherein the disease or disorder is a cardiovascular disease or disorder.

139. 125. The method of claim 124, wherein the disease or disorder is an inflammatory gastrointestinal disorder.

140. 125. The method of claim 124, wherein the disease or disorder is a pulmonary disorder.

141. The method of claim 124, wherein the disease or disorder is an ex vivo exposure-induced inflammatory response.

142. 125. The method of claim 124, further comprising treating a subject undergoing an extracorporeal circulation procedure.

143. 125. The method of claim 124, wherein the disease or disorder is inflammatory arthritis, non-inflammatory arthritis, a musculoskeletal disorder, or a combination thereof.

144. 125. The method of claim 124, wherein the disease or disorder is a skin disease.

145. 125. The method of claim 124, wherein the disease or disorder is a peripheral nervous system (PNS) disorder or injury, a central nervous system (CNS) disorder or injury, or a combination thereof.

146. 125. The method of claim 124, wherein the disease or disorder is sepsis or a condition resulting from sepsis.

147. 125. The method of claim 124, wherein the disease or disorder is a genitourinary disorder.

148. 125. The method of claim 124, wherein the disease or disorder is an inflammatory response in a subject being treated with a chemotherapeutic agent, radiation therapy, or a combination thereof.

149. 125. The method of claim 124, wherein the disease or disorder is an angiogenesis-dependent cancer.

150. 125. The method of claim 124, wherein the disease or disorder is an angiogenesis-dependent benign tumor.

151. 125. The method of claim 124, wherein the disease or disorder is an endocrine disorder.

152. 125. The method of claim 124, wherein the disease or disorder is an ocular disease or disorder.

153. 125. The method of claim 124, wherein the disease or disorder is an ocular neovascular disease or disorder.

154. 125. The method of claim 124, wherein the disease or disorder is disseminated intravascular coagulation (DIC), a complement-mediated coagulopathy, or a combination thereof.

155. 125. The method of claim 124, wherein said disease or disorder is acute radiation syndrome, dense deposit disease, Degos disease, refractory antiphospholipid syndrome (CAPS), Behcet's disease, cryoglobulinemia, paroxysmal nocturnal hemoglobinuria ("PNH"), cold agglutinin disease, or a combination thereof.

156. 125. The method of claim 124, wherein the disease or disorder is atypical hemolytic uremic syndrome (aHUS).

157. 125. The method of claim 124, wherein the disease or disorder is hematopoietic stem cell transplantation-associated TMA.

158. 125. The method of claim 124, wherein the disease or disorder is immunoglobulin A nephropathy (IgAN).

159. 125. The method of claim 124, wherein the disease or disorder is lupus nephritis (LN).

160. 125. The method of claim 124, wherein said disease or disorder is COVID-19 induced acute respiratory distress syndrome (ARDS) or COVID-19 induced pneumonia.

161. 125. The method of claim 124, wherein said disease or disorder is a neurodegenerative disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, vascular dementia, dementia with Lewy bodies (Lewy body disease), Huntington's disease, and long COVID.

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