Benzothiazole and quinoline derivatives and uses thereof

Abstract

Compounds of Formula (I) or (II) and related compositions and methods for their use as inhibitors of alpha-kinase 1 (ALPK1) are provided.

Description

Technical Field

[0001] This invention relates to benzothiazole and quinoline derivatives having activity as inhibitors of α-protein kinase 1 (ALPK1) and methods for their use in treatment. Background Technology

[0002] α-kinases share little sequence similarity with conventional protein kinases. A total of six α-kinase members have been identified. These include α-protein kinase 1 (ALPK1), ALPK2, ALPK3, elongation factor-2 kinase (eEF2K), and transient receptor potential cation channels M6 and M7 (TRPM6 and TRPM7). See Ryazanov et al., *Curr Biol* 9:R43-45 (1999) and Ryazanov et al., *Proceedings of the National Academy of Sciences of the United States of America* 94:4884-4889 (1997).

[0003] ALPK1 is a cytoplasmic serine-threonine protein kinase that plays a crucial role in the activation of bacterial innate immune responses via TRAF-interacting protein-forkhead-associated domain (TIFA)-dependent pro-inflammatory nuclear factor-κB (NFkB) signaling. See Zimmermann et al., Cell Reports 20:2384-2395 (2017); Milivojevic et al., PLoS Pathog. 13:E1006224-E1006224 (2017); and Zhou et al., Nature 561:122-126 (2018).

[0004] Inappropriate activation of ALPK1 signaling is associated with diseases and conditions related to excessive or inappropriate inflammation. For example, ALPK1 is associated with monosodium urate monohydrate (MSU)-induced inflammation and gout. (Lee et al., Sci.Rep. 6:25740-25740 (2016)). Elevated ALPK1 expression in oral squamous cell carcinoma is also associated with lymph node metastasis and tumor growth. (Chen et al., American Journal of Pathol 189:190-199 (2019)). Furthermore, mutations in ALPK1 are associated with spiroadenoma, spiroadenoma, ROSAH syndrome ("Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Migraine"), and PFAPA syndrome ("Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis"). See, for example, Rashid et al., Nature Communications (2019); Williams et al., Genetics in Medicine 21:2103-2115 (2019); and Sangiorgi et al., Eur. J. Human Genetics (2019). Summary of the Invention

[0005] This disclosure provides compounds of formulas I and II described herein as inhibitors of ALPK1 kinase activity, and sub-examples of formulas I and II, as well as related compositions and methods.

[0006] In some respects, this paper provides compounds of formula (I) having the following structures:

[0007] or its salt,

[0008] Where R 1 R 2 R 3 R 4 R 5 R 6 and R 7 As defined in this article.

[0009] In some embodiments, compounds of formula (I) are represented by formula (IA).

[0010] Where R 1 R 2 R 3 R 4 L 1 R 9 R 10.1 R 10.2 R10.3 and R 10.4 As defined in this article.

[0011] In some embodiments, compounds of formula (I) are represented by formula (IB).

[0012] Where R 1 R 2 R 3 R 4 L 1 R 9 R 10.1 R 10.2 R 10.3 and R 10.4 As defined in this article.

[0013] In some embodiments, compounds of formula (I) are represented by formula (IC).

[0014] Where R 1 R 2 R 3 R 4 , k, R 9 R 10.1 R 10.2 and R 10.3 As defined in this article.

[0015] In some embodiments, compounds of formula (I) are represented by formula (ID).

[0016] Where R 1 R 2 R 3 and R 4 As stated above.

[0017] In some respects, this paper provides compounds of formula (II) having the following structures:

[0018] or its salt,

[0019] Where R 11 R 12 R 13 R 14 R 15 R 16 and R 17 As defined in this article.

[0020] In some embodiments, compounds of formula (II) are represented by formula (II-A) or (II-B).

[0021]

[0022] Where R 11 R 12 R 13 R 14 L 11 R 19 R 20.1 R 20.2 R 20.3 and R 20.4 As defined in this article.

[0023] In some embodiments, compounds of formula (II) are represented by formula (II-C) or (II-D).

[0024]

[0025] Where R 11 R 12 R 13 R 14 L 11 R 19 R 20.1 R 20.2 R 20.3 and R 20.4 As defined in this article.

[0026] In some embodiments, compounds of formula (II) are represented by formula (II-E) or (II-F).

[0027]

[0028] Where R 11 R 12 R 13 R 14 R 20.1 R 20.2 and R 20.3 As defined in this article.

[0029] In the embodiments, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) or (II) as described herein, or a sub-example thereof, or a pharmaceutically acceptable salt thereof.

[0030] In embodiments, this disclosure provides a method for inhibiting ALPK1 kinase activity in the cells or tissues of a subject requiring such treatment, the method comprising administering to the subject a compound of formula (I) or (II) as described herein, or a sub-example thereof.

[0031] In embodiments, this disclosure provides a method for inhibiting or reducing inflammation in target tissues of a subject requiring such treatment, the method comprising administering to the subject a compound of formula (I) or (II) as described herein, or a sub-example thereof.

[0032] In embodiments, this disclosure provides a method for treating a disease, condition, or symptom characterized by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling in a subject requiring such therapy, the method comprising administering to the subject a compound of formula (I) or (II) as described herein, or a sub-example thereof.

[0033] In the embodiments, the disease, condition, or symptom is selected from systemic lupus erythematosus (SLE), sepsis, cancer, spiroadenoma, spiroadenoma, "retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine" ("ROSAH") syndrome and "periodic fever, aphthous stomatitis, pharyngitis and adenitis" ("PFAPA") syndrome.

[0034] In the embodiments, the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma.

[0035] In the embodiments, the disease or condition is selected from ROSAH and PFAPA.

[0036] In this embodiment, the disease or condition is systemic lupus erythematosus (SLE).

[0037] In this embodiment, the disease or symptom is sepsis.

[0038] In the embodiments, the disease or condition is a sweat gland adenoma or aspirin carcinoma.

[0039] In this embodiment, the subject requiring such therapy or treatment is a subject carrying one or more gene mutations in ALPK1. In this embodiment, at least one mutation is an ALPK1 activating mutation. Attached Figure Description

[0040] Figure 1 The bar chart shows IL-8 secretion (pg / ml) in HEK293 cells transiently transfected with an expression vector encoding human ALPK1 (hALPK1), an activating mutation in hALPK1 (T237M or V1092A), or an activating mutation combined with a kinase death mutation in ALPK1 (hALPK1-T237M-D1194S).

[0041] Figure 2In a lupus animal model, as determined by assessment of proteinuria, serum anti-dsDNA antibody levels, and renal histopathology, treatment with PO (potentially administered T007, 50 mg / kg) from 13 to 22 weeks of age via QD showed a statistically significant beneficial effect on systemic lupus erythematosus (SLE) in female MRL / MpJ-faslpr / J mice. Compared with the vector-borne disease control group, mice treated with T007 showed a significant (55%) reduction in urinary protein score at 21 weeks of age (AUC decreased by 34%, p = 0.100).

[0042] Figure 3A In a lupus animal model, renal histopathology (right kidney) showed that treatment with T007 significantly reduced glomerular diameter (38%), crescent score (62%), and protein cast score (70%).

[0043] Figure 3B In the lupus animal model, the total renal score was 34% compared to the vector disease control group.

[0044] Figure 4 In an animal model of sepsis-induced acute kidney injury, compound T007 (20 mg / kg) was administered 2 hours prior to surgery. Survival rates were recorded 24 hours post-surgery and over the following 24 hours. Data showed that the ALPK1 inhibitor improved animal survival rates.

[0045] Figure 5 In an animal model of sepsis-induced acute kidney injury, kidneys were collected 24 hours post-surgery for gene expression analysis via Q-PCR. Results showed that the ALPK1 inhibitor T007 suppressed the expression of pro-inflammatory genes in the kidney, including IL6, TNFα, IL-1β, CCl2, and keratinocyte chemoattractant (KC) chemokines. *p<0.05 compared to CLP-mediators.

[0046] Figure 6 In an animal model of sepsis-induced acute kidney injury, compound T007 (20 mg / kg) was administered 2 hours before surgery. Plasma MCP-1 concentration was measured by ELISA 24 hours post-surgery. Results showed that the ALPK1 inhibitor increased plasma MCP-1 levels. A one-way ANOVA relative to the CLP-mediated drug showed ***p<0.001. Detailed Implementation

[0047] This disclosure provides compounds as ALPK1 inhibitors, compositions comprising the compounds, and methods of using the compounds for treatment.

[0048] As used in this article, the term "ALPK1" can refer interchangeably to isotype 1 (Q96QP1-1) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN) or isotype 2 (Q96QP1-2) of the alternative splice variant.

[0049] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, means a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, or polyunsaturated and may include monovalent, divalent, and polyvalent groups. Alkyl groups may include any number of carbons, such as C10. 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C 1-9 C 1-10 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6 Alkyl groups are uncyclic chains. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, and homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0050] Unsaturated alkyl groups, "alkenyl" or "ynyl", are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, as well as higher homologues and isomers.

[0051] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl groups can include any number of carbon atoms, such as C2, C3, C4, C5, C6, C7, C8, C9 ... 2-3 C 2-4 C 2-5 C 2-6 C 2-7 C 2-8 C 2-9 C 2-10 C3, C 3-4 C 3-5 C 3-6C4, C 4-5 C 4-6 C5, C 5-6 And C6. The alkenyl group can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. In some embodiments, the alkenyl group has one double bond. The alkenyl group can be substituted or unsubstituted.

[0052] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkenyl groups can include any number of carbon atoms, such as C2, C3, C4, C5, C6, C7, C8, C9 ... 2-3 C 2-4 C 2-5 C 2-6 C 2-7 C 2-8 C 2-9 C 2-10 C3, C 3-4 C 3-5 C 3-6 C4, C 4-5 C 4-6 C5, C 5-6 And C6. The alkynyl group can have any suitable number of triple bonds, including but not limited to 1, 2, 3, 4, 5 or more. In some embodiments, the alkynyl group has one triple bond. The alkynyl group can be substituted or unsubstituted.

[0053] As used herein, the term "alkylene" refers to a straight-chain or branched saturated aliphatic group having a specified number of carbon atoms and being attached to at least two other groups, i.e., a divalent hydrocarbon group. The two parts attached to the alkylene group can be attached to the same or different atoms of the alkylene group. For example, a straight-chain alkylene group can be a divalent group of -(CH2)n-, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylene groups can be substituted or unsubstituted. In some embodiments, the alkylene group is substituted with one or two substituents. As non-limiting examples, suitable substituents include halogens and hydroxyl groups.

[0054] The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. In addition to one or more double bonds, the alkenyl group can include more than one double bond and / or one or more triple bonds. In addition to one or more triple bonds, the alkynyl group can include more than one triple bond and / or one or more double bonds.

[0055] As used herein, the term "alkoxy" or "alkoxyl" refers to an alkyl group having an oxygen atom attached to the alkyl group at the attachment point: alkyl-O-. As with alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups can be substituted or unsubstituted.

[0056] As used herein, the term "alkenyloxy" or "alkenyloxyl" refers to an alkenyl group as defined above, having an oxygen atom that connects the alkenyl group to the attachment point: alkenyl-O-. The alkenyloxy group can have any suitable number of carbon atoms, such as C1-6. The alkenyloxy group can be further substituted by the various substituents described herein. The alkenyloxy group can be substituted or unsubstituted.

[0057] As used herein, the term “aminoalkyl” means a straight-chain monovalent hydrocarbon group of one to six carbon atoms or a branched monovalent hydrocarbon group of three to six carbon atoms substituted with -NR'R", wherein R' and R" are independently hydrogen, alkyl, haloalkyl or hydroxyalkyl, each as defined herein, such as aminomethyl, aminoethyl, methylaminomethyl, etc.

[0058] As used herein, the term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by an OH atom. Examples of hydroxyalkyl groups include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 4-hydroxy-butyl.

[0059] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term means a stable straight or branched chain or combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., O, N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. The heteroalkyl group is an uncyclic chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. At most two or three heteroatoms can be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" itself or in combination with another term means a heteroalkyl group comprising at least one double bond. In addition to one or more double bonds, a heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds. Unless otherwise stated, the term "heteroyynyl" itself or in combination with another term means a heteroalkyl group comprising at least one triple bond. In addition to one or more triple bonds, a heteroyynyl group may optionally include more than one triple bond and / or one or more double bonds.

[0060] Similarly, unless otherwise stated, the term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may also occupy one or both at the chain terminus (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As stated above, heteroalkyl as used herein includes those groups attached to the rest of the molecule by a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. In the context of the statement "heteroalkyl," followed by a specific heteroalkyl group such as -NR'R", it should be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are listed for clarity. Therefore, the term "heteroalkyl" herein should not be construed as excluding specific heteroalkyl groups such as -NR'R".

[0061] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" on their own or in combination with other terms refer to the cyclic form of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocyclic alkylene" alone or as part of another substituent refer to divalent groups derived from cycloalkylene and heterocyclic alkylene, respectively.

[0062] As used herein, "saturated or unsaturated" refers to a cyclic system in which two atoms in a group can be bonded to each other by a single, double, or triple bond. A saturated portion is a portion that has only single bonds, while a portion that has multiple bonds (e.g., at least one double bond or at least one triple bond) is called an unsaturated portion.

[0063] As used herein, “cycloalkyl” refers to a saturated ring combination containing 3 to 10 ring atoms or a specified number of atoms. Cycloalkyl groups can include any number of carbons, such as C10. 3-6 C 4-6 C5-6 、C 3-8 、C 4-8 、C 5-8 、C 6-8When an unsaturated cycloalkyl ring may have one or two double bonds, the cycloalkyl ring may be saturated or unsaturated. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted. In the examples, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In the examples, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such a group may be saturated or unsaturated, but is not aromatic. In the examples, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic or fused bicyclic rings. In embodiments, the bridged monocyclic ring contains a monocyclic cycloalkyl ring, wherein two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group in the form of (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cyclic systems include, but are not limited to, bicyclic [3.1.1]heptane, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, bicyclic [3.2.2]nonane, bicyclic [3.3.1]nonane, and bicyclic [4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused with a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In embodiments, the bridged or fused bicyclic cycloalkyl ring is attached to the parent molecule moiety via any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups that are independently oxo or thiazo groups. In the embodiments, the fused bicyclic cycloalkyl group is a 5 or 6-membered monocyclic cycloalkyl ring fused with a benzene ring, a 5 or 6-membered monocyclic cycloalkyl group, a 5 or 6-membered monocyclic cycloalkenyl group, a 5 or 6-membered monocyclic heterocyclic group, or a 5 or 6-membered monocyclic heteroaryl group, wherein the fused bicyclic cycloalkyl group is optionally substituted by one or two independently oxo or thiazo groups. In the embodiments, the polycyclic cycloalkyl ring system is a ring system fused with (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups (base ring). In the embodiments, the polycyclic cycloalkyl group is attached to the parent molecule moiety through any carbon atom contained within the base ring. In the embodiments, the polycyclic cycloalkyl ring system is a ring system fused with (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) a monocyclic cycloalkyl ring (base ring) fused with two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups.Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenthiazin-1-yl, and perhydrophenoxazin-1-yl.

[0064] In the embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its common meaning. In the embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In the embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such group is unsaturated (i.e., contains at least one cyclic carbon-carbon double bond) but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In the embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic or fused bicyclic. In the embodiments, a bridged monocyclic ring contains a monocyclic cycloalkenyl ring, wherein the two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group in the form of (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyl include, but are not limited to, norbornenyl and bicyclic [2.2.2]oct-2-enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused with a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In embodiments, the bridging or fused bicyclic cycloalkenyl group is attached to the parent molecule portion via any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two independently oxo or thiazo groups. In embodiments, the polycyclic cycloalkenyl ring comprises a ring system fused with (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two independently fused monocyclic cycloalkenyl rings (base rings) selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. In embodiments, the polycyclic cycloalkenyl group is attached to the parent molecule portion via any carbon atom contained within the base ring. In the embodiments, the polycyclic cycloalkenyl ring contains a ring system that is fused with (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups.

[0065] In the embodiments, heterocyclic alkyl groups are heterocyclic groups. As used herein, the terms "heterocyclic group," "heterocyclic," or "heterocyclic alkyl" refer to a saturated or partially saturated heterocyclic group that is monocyclic or polycyclic; having 3 to 16, most preferably 5 to 10, and most preferably 1 or 4 ring atoms; wherein one or more, preferably one to four, and especially one or two ring atoms are heteroatoms selected from oxygen, nitrogen, and sulfur (and thus the remaining ring atoms are carbon). The term heterocyclic group does not include heteroaryl groups. Heterocyclic groups can be attached to the remainder of the molecule by heteroatoms selected from oxygen, nitrogen, and sulfur or carbon atoms. Heterocyclic groups can include fused rings or bridged rings as well as spirocyclic rings. Examples of heterocyclic groups include dihydrofuranyl, dioxolane, dioxane, dithiaalkyl, piperazine, pyrrolidine, dihydropyranyl, oxathionyl, dithiopentane, oxothionylhexane, thiomorpholino, ethylene oxide, acridine, oxacyclobutane, oxacycloheptane, azirionyl, tetrahydrofuranyl, tetrahydrothiophene, pyrrolidine, tetrahydropyranyl, piperidinyl, morpholino, piperazine, azirheptenyl, oxaheptenyl, oxaaziptenyl, oxothionylhexane, thionylheptenyl, azirionylheptenyl, dioxacycloheptane, and diazirionylheptenyl.

[0066] As used herein, “spiroheterocyclic” refers to a specific bicyclic heterocyclic group in which two ring systems are linked by a single carbon atom. For example, the term “spiroheterocyclic” can refer to 6 to 10 spiroheterocyclic groups. Examples include, but are not limited to, 6,9-diazaspiro[4.5]decane, 2-oxa-6,9-diazaspiro[4.5]decane, 2-oxa-6-azaspiro[3.4]octane, 6-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[3.4]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.4]nonane, 1-thia-8-azaspiro[4.5]decane, 1,1-dioxide, 1-oxa-7-azaspiro[4.4]nonane, and 1-oxa-9-azaspiro[5.5]undecane.

[0067] As used in this article, "bridging heterocyclic group" refers to C as defined above. 3-6A cycloalkyl ring or a 3- to 6-membered heterocyclic ring, wherein two non-adjacent ring vertices (“bridgehead atoms”) of the cycloalkyl ring or heterocyclic ring are connected to form an additional ring portion (“bridge”). The bridge contains 1 to 4 ring vertices, excluding the bridgehead atoms. Examples include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 3,9-diazabicyclo[3.3.1]nonane, 2-thia-5-azabicyclo[2.2.1]heptane, 2,2-dioxide, 2-azabicyclo[2.2.1]hept-5-ene, 3-oxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, and 2-oxa-5-azabicyclo[2.2.1]heptane.

[0068] The term "bicyclic heterocyclic group" refers to a heterocyclic group as defined above, in which two ring systems are connected by two adjacent ring vertices (e.g., fused ring systems). A typical "bicyclic heterocyclic group" consists of 6 to 11 ring members with 1 to 4 heteroatom ring vertices selected from N, O, and S (therefore the remaining ring atoms are carbon). Examples include, but are not limited to, benzo[m]dioxacyclopentenyl, benzo[imidazolyl], benzo[isooxazolyl], benzo[furazolyl], benzo[pyranyl], benzo[thiaranyl], benzo[furanyl], benzo[thiazolyl], benzo[thiaphenyl], benzo[triazolyl], benzo[oxazolyl], chromanyl, cycloazinyl, dihydrobenzo[furanyl], dihydroisobenzo[furanyl], dihydrobenzo[thiaphenyl], dihydrobenzo[thiaphenyl], dihydrobenzo[thiaphenyl], dihydroindolyl, indolyl, isochromyl, isodihydroindolyl, isoquinolinyl, isothiazolyl, naphthidyl, pyrazolopyridyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl.

[0069] As used in this article, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine.

[0070] Additionally, terms such as "halogenated alkyl" are intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4) alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0071] As used herein, the term "haloalkoxyl" or "haloalkoxy" refers to an alkoxy group in which some or all of its hydrogen atoms are replaced by halogen atoms. As for alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as C0. 1-6 Alkyl groups can be replaced by one, two, three or more halogens.

[0072] As used herein, the term "aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can include any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. An aryl group can be monocyclic, fused to form a bicyclic or tricyclic group, or linked by bonds to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. An aryl group can be substituted or unsubstituted.

[0073] The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom (such as N, O, or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Other heteroatoms may also be useful, including but not limited to B, Al, Si, and P. Heteroaryl groups may include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heteroaryl groups may include any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have 5 to 9 ring members and 1 to 4 heteroatoms, or 5 to 9 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetraazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), and purines. Heteroaryl groups can also fused with aromatic ring systems (such as benzene rings) to form members including, but not limited to, benzopyrrole (such as indole and isoindole), benzopyridine (such as quinoline and isoquinoline), benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine (such as phthalazine and zoline), benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. The heteroaryl group can be substituted or unsubstituted.

[0074] The term "heteroaryl" also includes fused-ring heteroaryl (i.e., multiple rings fused together, where at least one fused ring is a heteroaryl ring). 5,6-Fused-ring heteroarylene refers to two fused rings, one with 5 members and the other with 6 members, and at least one of the rings is a heteroaryl ring. Similarly, 6,6-Fused-ring heteroarylene refers to two fused rings, one with 6 members and the other with 6 members, and at least one of the rings is a heteroaryl ring. And 6,5-Fused-ring heteroarylene refers to two fused rings, one with 6 members and the other with 5 members, and at least one of the rings is a heteroaryl ring. Heteroaryl groups can be attached to the rest of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzoxazolylbenzimidazolyl, benzofuran, isobenzofuranyl, indoleyl, isoindoleyl, benzothiapheneyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl. Pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and 6-quinolinyl. The substituents in each of the above aryl and heteroaryl ring systems are selected from the group consisting of the following acceptable substituents. "Arylidene" and "heteroarylidene" refer, alone or as part of another substituent, to divalent groups derived from aryl and heteroaryl groups, respectively. Heteroaryl substituents can be -O- bonded to a nitrogen atom in a cyclic heteroatom.

[0075] A fused-ring heterocyclic alkyl-aryl group is an aryl group fused with a heterocyclic alkyl group. A fused-ring heterocyclic alkyl-heteroaryl group is a heteroaryl group fused with a heterocyclic alkyl group. A fused-ring heterocyclic alkyl-heteroalkyl group is a heterocyclic alkyl group fused with a cycloalkyl group. A fused-ring heterocyclic alkyl-heteroalkyl group is a heterocyclic alkyl group fused with another heterocyclic alkyl group. Fused-ring heterocyclic alkyl-aryl, fused-ring heterocyclic alkyl-heteroaryl, fused-ring heterocyclic alkyl-cycloalkyl, or fused-ring heterocyclic alkyl-heteroalkyl can each be independently unsubstituted or substituted with one or more substituents described herein.

[0076] When necessary, any definition herein may be used in combination with any other definition to describe complex structural groups. By convention, the trailing element in any such definition is the element attached to the parent part. For example, the complex group cycloalkoxy means that the cycloalkyl group is attached to the parent molecule via an oxygen group.

[0077] The symbol “” indicates the attachment point between the chemical part and the rest of the molecule or chemical formula.

[0078] The term "oxo" as used in this article refers to an oxygen atom connected to the attachment site via a double bond (=O).

[0079] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both the substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

[0080] Substituents in alkyl and heteroalkyl groups (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more selected from, but not limited to, the following groups: -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR' R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C (NR'R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR" NR"'R"", -CN, -NO2, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", with numerical values ​​ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R, R', R"", R"' and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl ( For example, aryl groups substituted with 1 to 3 halogens, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted alkyl groups, alkoxy or thioalkoxy groups, or aralkyl groups. For example, when the compounds described herein include more than one R group, each R group is chosen independently, and when more than one of these groups is present, so are each R', R", R"' and R"" groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4, 5, 6 or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups comprising a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0081] Similar to the substituents described for alkyl groups, the substituents for aryl and heteroaryl groups are different and selected from, for example: -OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"', -NR-C(NR'R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R"', -NRSO2R', -NR'NR"R"', -ONR'R"', -NR'C(O)NR"NR"'R"', -C N, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", with numerical values ​​ranging from zero to the total number of open valences on the aromatic ring system; and wherein R', R", R"' and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. For example, when the compound described herein includes more than one R group, each R group is selected independently, and when more than one of these groups is present, each R', R"', R"' and R"" group is also selected independently.

[0082] Substituents on the ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring rather than on a specific atom of the ring (often called floating substituents). In this case, the substituent can be attached to any ring atom (following the valence rules), and in the case of fused or spirocyclic rings, the substituent described as associated with a member of the fused or spirocyclic ring (floating substituents on a single ring) can be any substituent on a fused or spirocyclic ring (floating substituents on multiple rings). When the substituent is attached to the ring but not to a specific atom (floating substituent) and the substituent's subscript is an integer greater than one, multiple substituents can be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent can optionally be different. Where the attachment point of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the attachment point can be any atom of the ring, and in the case of fused or spirocyclic rings, it is any atom of any fused or spirocyclic ring, while following the valence rules. In the case where a ring, fused ring, or spirocyclic ring contains one or more cyclic heteroatoms and the ring, fused ring, or spirocyclic ring is shown to have one or more floating substituents (including, but not limited to, attachment sites with the rest of the molecule), the floating substituents may be bonded to the heteroatoms. When, in a structure or formula with floating substituents, the cyclic heteroatom is shown to be bonded to one or more hydrogen atoms (e.g., a cyclic nitrogen with two bonds to the ring atom and a third bond to the hydrogen), the substituent should be understood to substitute for the hydrogen atom when the heteroatom is bonded to the floating substituent, while following the rules of chemical valence.

[0083] Two or more substituents may optionally be linked to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called cyclic substituents are typically (but not necessarily) attached to the cyclic base structure. In one embodiment, the cyclic substituent is attached to an adjacent member of the base structure. For example, two cyclic substituents attached to an adjacent member of the cyclic base structure produce a fused ring structure. In another embodiment, the cyclic substituent is attached to a single member of the base structure. For example, two cyclic substituents attached to a single member of the cyclic base structure produce a spirocyclic structure. In yet another embodiment, the cyclic substituent is attached to a non-adjacent member of the base structure.

[0084] The two substituents on adjacent atoms of the aryl or heteroaryl ring can optionally form the formula -TC(O). p -(CRR') q A -U- ring, wherein T and U are independently -NR-, -O-, -CRR'-, or single bonds, and each p and q is independently an integer from 0 to 3. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH2). rThe substituents of -B- are replaced, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -(CRR'). s -X'-(C"R"R"') d The substituents are substituted, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R" and R"' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0085] As used herein, the term “heteroatom” or “cyclic heteroatom” is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0086] As used in this article, "substituent" refers to a group selected from the following:

[0087] (A) Oxygenated, Halogenated, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, - OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C...). 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0088] (B) Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C... 10 Aryl, C 10 The aryl or phenyl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl) is substituted by at least one substituent selected from the following:

[0089] (i) Oxygenated, Halogenated, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, - OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C...). 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0090] (ii) Alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C... 10 Aryl, C 10The aryl or phenyl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl) is substituted by at least one substituent selected from (i).

[0091] Certain compounds disclosed herein have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and single isomers (e.g., individual enantiomers) are all intended to be covered within the scope of this disclosure. In some embodiments, the compounds of this disclosure are substantially free of other forms of the specific enantiomers, terminal isomers, or diastereomers.

[0092] As used herein, the term “substantially free” means that the amount of another isomer form is 10% or less, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5% or less. In some embodiments, the isomer is a stereoisomer.

[0093] As used herein, the term "isomer" refers to a compound having the same number and type of atoms and therefore the same molecular weight but different in terms of the arrangement or configuration of the atoms.

[0094] As used in this article, "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer form to another.

[0095] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomer forms, all of which are within the scope of this disclosure.

[0096] Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are within the scope of this disclosure.

[0097] The term "analog" or "analogue" is used according to its common meaning in chemistry and biology, and refers to a compound that is structurally similar to another compound (i.e., the so-called "reference" compound) but has a different composition. For example, one atom may be replaced by an atom of a different element, or one functional group may be replaced by another in the presence of a particular functional group, or one functional group may be replaced by another, or the reference compound may have one or more chiral centers with absolute stereochemistry. Therefore, an analog is a compound that is functionally or physically similar to or equivalent to a reference compound but not structurally or geographically similar to or equivalent to it.

[0098] As used herein, the terms “a” or “an” mean one or more. Additionally, the phrase “substituted [n]” as used herein means that a particular group can be substituted by one or more of any or all specified substituents. For example, when a group such as an alkyl or heteroaryl is substituted by an “unsubstituted C1-C” substituent… 20 When alkyl or unsubstituted 2 to 20 heteroalkyl groups are substituted, the group may contain one or more unsubstituted C1-C1 groups. 20 Alkyl and / or one or more unsubstituted 2 to 20 heteroalkyl groups.

[0099] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, when a group can be substituted by one or more of a plurality of substituents, these substitutions are chosen to conform to the principles of chemical bonding, resulting in compounds that are inherently unstable and / or known to those skilled in the art to be unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions). For example, according to the principles of chemical bonding known to those skilled in the art, heterocyclic alkyl or heteroaryl groups are attached to the remainder of the molecule via cyclic heteroatoms, thereby avoiding inherently unstable compounds.

[0100] The term "leaving group" is used according to its ordinary meaning in chemistry and refers to the portion (e.g., atom, functional group, molecule) that separates from the molecule after a chemical reaction involving the atom or chemical part to which the leaving group is attached (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction). It is also referred to herein as the "leaving group reactive portion" and the complementary reactive portion (i.e., the chemical portion that reacts with the leaving group reactive portion) to form a new bond between the residual portion of the leaving group reactive portion and the complementary reactive portion. Thus, the leaving group reactive portion and the complementary reactive portion form a complementary reactive group pair. Non-limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl groups), halogens (e.g., Br), perfluoroalkyl sulfonates (e.g., trifluoromethanesulfonates), toluenesulfonates, toluenesulfonates, water, alcohols, nitrates, phosphates, thioethers, amines, ammonia, fluorides, carboxylates, phenolates, boric acids, borate esters, and alkoxides. In embodiments, two molecules having leaving groups are brought into contact, and the leaving groups are separated from the corresponding molecules during reaction and / or bond formation (e.g., conjugation, aldol condensation, Clayson condensation, Steer reaction). In embodiments, the leaving groups are bioconjugated reactive moieties. In embodiments, at least two leaving groups (e.g., R...) are brought into contact. 1 and R 13 Contact is achieved by bringing the leaving groups close enough to react, interact, or physically contact. In the examples, the leaving groups are designed to facilitate the reaction.

[0101] The term "protecting group" is used according to its common meaning in organic chemistry and refers to a portion covalently bonded to a heteroatom, heterocyclic alkyl group, or heteroaryl group to prevent the reactivity of the heteroatom, heterocyclic alkyl group, or heteroaryl group during one or more chemical reactions prior to the removal of the protecting group. Typically, the protecting group is bonded to a heteroatom (e.g., O) during a portion of a multipart synthesis where it is undesirable for the heteroatom to react with a reagent (e.g., chemical reduction). After protection, the protecting group can be removed (e.g., by adjusting the pH). In the examples, the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS)). In the examples, the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), and toluenesulfonyl (Ts).

[0102] The term "solution" is used in accor and refers to a liquid mixture in which a minor component (e.g., a solute or compound) is uniformly distributed in a major component (e.g., a solvent).

[0103] As used herein, the term "organic solvent" is used according to its common meaning in chemistry and refers to solvents containing carbon. Non-limiting examples of organic solvents include acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, tert-butanol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, diethylene glycol dimethyl ether (diethylene glycol, dimethyl ether), 1,2-dimethoxyethane (dimethyl glycol dimethyl ether, DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, Ethyl acetate, ethylene glycol, glycerol, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphoric triamine, triamide (HMPT), hexane, methanol, methyl tert-butyl ether (MTBE), dichloromethane, N-methyl-2-pyrrolidone (NMP), nitromethane, pentane, petroleum ether, 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, o-xylene, m-xylene, or p-xylene. In the examples, the organic solvent is or includes chloroform, dichloromethane, methanol, ethanol, tetrahydrofuran, or dioxane.

[0104] As used herein, the term "salt" refers to an acid or base salt of a compound used in the methods of this disclosure. Illustrative examples of acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts.

[0105] As used herein, the terms “bind” and “bound” are used according to their simple and common meaning and refer to association between atoms or molecules. Association can be direct or indirect. For example, bonded atoms or molecules can be direct, such as through covalent bonds or joints (e.g., first joints or second joints), or indirect, such as through non-covalent bonds (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (π effect), hydrophobic interactions, etc.).

[0106] As used herein, the term "capable of binding" refers to a portion (e.g., a compound as described herein) capable of measurably binding to a target (e.g., NF-κB, Toll-like receptor protein). In embodiments in which the portion is capable of binding to the target, the portion is capable of binding to a K+ concentration of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM. d Bonding.

[0107] The term "pharmaceutically acceptable salt" refers to salts comprising active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hepatoside, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid), and those derived from relatively non-toxic organic acids (such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.). Also included are salts of amino acids, such as arginine salts, and salts of organic acids (such as glucuronic acid or galacturonic acid) (see, for example, Berge, SM et al., "Pharmaceutical Salts," *Journal of Pharmaceutical Science*, 1977, 66, 1-19). Certain specific compounds of this disclosure contain basic and acidic functional groups, which allow the compounds to be converted into basic or acid addition salts.

[0108] Therefore, the compounds of this disclosure can exist as salts, such as salts formed with pharmaceutically acceptable acids. This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids (such as glutamic acid), as well as quaternary ammonium salts (e.g., iodomethane, iodoethane, etc.). These salts can be prepared by methods known to those skilled in the art.

[0109] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, these salts are otherwise equivalent to the parent form of the compound.

[0110] Certain compounds of this disclosure may exist in both unsolvable and solvable forms (including hydrated forms). Generally, solvable forms are equivalent to unsolvable forms and are covered within the scope of this disclosure. Certain compounds of this disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the intended use of this disclosure and are intended to be within the scope of this disclosure.

[0111] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of the active agent to a subject and absorption by the subject, and can be included in the compositions of this disclosure without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, aqueous saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose), amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, and / or aromatic substances, etc., which do not react harmfully with the compounds of this disclosure. Those skilled in the art will recognize that other pharmaceutical excipients may be used in this disclosure.

[0112] The term "formulation" is intended to include an active compound and an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without another carrier, is surrounded and bound to the carrier. Similarly, this includes capsules and tablets. Tablets, powders, capsules, pills, capsules, and tablets are available as solid dosage forms suitable for oral administration.

[0113] As used herein, the term "about" means a range of values ​​that include a specified value and that will be reasonably considered by those skilled in the art to be reasonably similar to the specified value. In embodiments, "about" means within the standard deviation using a measurement generally acceptable in the art. In embodiments, "about" means a range extending to + / - 10% of the specified value. In embodiments, "about" includes the specified value.

[0114] The term “EC” used in this article 50 "Or "half-maximal effective concentration" refers to the concentration of a molecule (e.g., a drug, small molecule, antibody, antagonist, or specific inhibitor) that, after a specified exposure time, induces a response between half that of the baseline response (e.g., no treatment or effect) and the maximum response. In the examples, EC 50 It is the concentration of 50% of the molecules (e.g., antibodies, chimeric antigen receptors, or bispecific antibodies) that produce the maximum possible effect of the molecule.

[0115] The term "IC" as used in this article 50 "or 'half-maximal inhibitory concentration'" refers to the concentration of a molecule (e.g., a drug, small molecule, antibody, antagonist, or specific inhibitor) that, after a specified exposure time, inhibits half of the response between the baseline response (e.g., no inhibition) and the maximal response. In the examples, IC50... 50 It is the concentration of molecules that produce the maximum possible inhibition of that molecule (e.g., drugs, small molecules, antibodies, antagonists, or specific inhibitors).

[0116] "Inhibitor" refers to a compound that reduces activity when compared to a control (such as a compound that is not present or has a known inactive compound) (e.g., the compound described herein).

[0117] As defined herein, the terms “activation,” “activate,” “activating,” “activator,” etc., relating to protein-inhibitor interactions, mean positively influencing (e.g., increasing) the activity or function of a protein relative to the absence of an activator. In the embodiments, activation means positively influencing (e.g., increasing) the concentration or level of a protein relative to the absence of an activator. These terms may refer to activation in a disease, or activation, sensitization, or upregulation of signal transduction or enzyme activity, or a reduction in the amount of protein. Thus, activation may include at least partially, partially, or entirely increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signal transduction or enzyme activity, or the amount of disease-related protein (e.g., a reduction in protein relative to a non-disease control in a disease). Activation may include at least partially, partially, or entirely increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signal transduction or enzyme activity, or the amount of protein.

[0118] The terms "agonist," "activator," and "upregulator" refer to substances that can detectably increase the expression or activity of a given gene or protein. Agonists can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control without an agonist. In some cases, the expression or activity is 1.5, 2, 3, 4, 5, 10, or higher than that without an agonist.

[0119] As defined herein, the terms “inhibition,” “inhibit,” and “inhibiting” in relation to protein-inhibitor interactions mean negatively affecting (e.g., reducing) the activity or function of a protein relative to the absence of an inhibitor. In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level of a protein relative to the absence of an inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptoms. In embodiments, inhibition refers to a reduction in the activity of a specific protein target. Therefore, inhibition includes at least partially, partially, or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of protein. In embodiments, inhibition refers to a reduction in target protein activity resulting from a direct interaction (e.g., the binding of an inhibitor to a target protein). In embodiments, inhibition refers to a reduction in target protein activity resulting from an indirect interaction (e.g., the binding of an inhibitor to a protein that activates the target protein, thereby preventing target protein activation).

[0120] The terms “inhibitor,” “blocker,” “antagonist,” or “downregulator” are used interchangeably to refer to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control without an antagonist. In some cases, expression or activity is 1.5, 2, 3, 4, 5, 10, or less of the expression or activity without an antagonist.

[0121] In the context of a substance or its activity or function relating to a disease (e.g., protein-related diseases, cancers (e.g., cancer, inflammatory diseases, autoimmune diseases, or infectious diseases)), the term "related" or "associated with" means that the disease (e.g., cancer, inflammatory diseases, autoimmune diseases, or infectious diseases) is caused by (all or part) of a substance or its activity or function, or that the symptoms of the disease are caused by (all or part) of a substance or its activity or function. As used herein, a substance described as relating to a disease, if it is a pathogen, may be a target for treating the disease.

[0122] In this disclosure, the terms “comprises,” “comprising,” “containing,” and “having” may have the meanings given to them under U.S. patent law and may mean “includes,” “including,” etc. “consisting essentially of” or “consists essentially” also have the meanings given under U.S. patent law, and the term is open-ended, allowing for the existence of more than those listed, provided that the essential or novel features of the listed are not altered by the presence of more than those listed, but excluding prior art embodiments.

[0123] compound

[0124] This article provides, in particular, compounds having the structure of formula (I) or formula (II) or salts thereof (e.g., pharmaceutically acceptable salts).

[0125] In one respect, the compound has the following structure:

[0126] or its salt,

[0127] in:

[0128] R 1For hydrogen, halogen, -CX3, -CHX2, -CH2X, -OCX3, -OCH2X, -OCHX2, -OR 1A substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted 2- to 6-membered heteroalkyl groups, or substituted or unsubstituted C3-C6 cycloalkyl groups;

[0129] R 2 It is hydrogen or halogen;

[0130] Each R 3 and R 4 Independent of halogen, -OR 3A Or unsubstituted C1-C6 alkyl groups;

[0131] R 5 For hydrogen, -NR 5B R 5C -(CH2) n5 NR 5B R 5C -C(O)NR 5B R 5C -O(CH2) m5 OR 5A -C(O)OR 5A -OR 5A -CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 Aryl or substituted or unsubstituted 5 to 6-membered heteroaryl groups;

[0132] R 6 For hydrogen, -NR 6B R 6C -(CH2) n6 NR 6B R 6C -C(O)NR 6B R 6C -O(CH2) m6 OR 6A -C(O)OR 6A -OR 6A -CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 Aryl or substituted or unsubstituted 5 to 6-membered heteroaryl groups;

[0133] R 7 For hydrogen, -NR 7B R 7C-(CH2) n7 NR 7B R 7C -C(O)NR 7B R 7C -O(CH2) m7 OR 7A -C(O)OR 7A -OR 7A -CN, substituted or unsubstituted C1-C7 alkyl, substituted or unsubstituted 2- to 7-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 Aryl or substituted or unsubstituted 5 to 6-membered heteroaryl groups;

[0134] X can be -F, -Cl, -Br, or -I independently;

[0135] Each n5, n6, and n7 is an independent integer from 1 to 4;

[0136] Each m5, m6, and m7 is an independent integer from 1 to 4; and

[0137] Each R 1A R 3A R 5A R 5B R 5C R 6A R 6B R 6C R 7A R 7B and R 7C Independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2- to 4-membered heteroalkyl, or R 5B and R 5C Together with the atoms attached thereto, they are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; R 6B and R 6C Together with the atoms attached thereto, they are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; or R 7B and R 7C The atoms attached thereto are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

[0138] In some embodiments, R 2 It is hydrogen or halogen. In some embodiments, R 2 It is hydrogen. In some embodiments, R is... 2 It can be -F, -Cl, or Br.

[0139] In some embodiments, each R 3 and R 4 Independently, it is a halogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 3 It is a halogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 4 It is a halogen or an unsubstituted C1-C4 alkyl group. In some embodiments, each R 3 and R 4 Independently -F, -Cl, or methyl. In some embodiments, R 3 It is -F, -Cl, or methyl. In some embodiments, R 4 It can be -F, -Cl, or methyl.

[0140] In some embodiments, R 6 and R 7 It is hydrogen. In some embodiments, R is... 5B and R 5C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups. In some embodiments, R 6 and R 7 It is hydrogen; and R 5B and R 5C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

[0141] In some embodiments, the compound has the following structure:

[0142]

[0143] in:

[0144] L 1 For bonds, -C(O)- or -(CH2) n5 ;

[0145] R 9 It is hydrogen, -(CH2) m OH, -(CH2) m (C6H5), -C(O)NR 9B R 9C substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted 2- to 6-membered heteroalkyl groups;

[0146] Each R 10.1 R 10.2 R 10.3 and R 10.4 Independently hydrogen, -OR 10A -C(O)OR 10A -NR 10B R 10C -(CH2) mOH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl or substituted or unsubstituted C3-C6 cycloalkyl, or R 10.1 R 10.2 R 10.3 and R 10.4 One or more of them may be optionally connected to each other or to atoms of the piperazine ring to form substituted or unsubstituted heterocyclic alkyl groups;

[0147] Each m is an independent integer from 1 to 4; and

[0148] Each R 9B R 9C R 10A R 10B and R 10C It is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted 5- to 6-membered heterocyclic alkyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

[0149] In equation (IA), R 1 R 2 R 3 and R 4 As stated above.

[0150] In some embodiments, L 1 For bonds, -C(O)-, methylene, or ethylene. In some embodiments, L 1 As a key. In some embodiments, L 1 For -C(O)-. In some embodiments, L 1 Methylene. In some embodiments, L 1 It is ethylene.

[0151] In some embodiments, R 9 It is hydrogen, unsubstituted C1-C4 alkyl or -C(O)NR 9B R 9C R 9B and R 9C Independently, it is hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted 2- to 4-membered heteroalkyl group, a substituted or unsubstituted 5- to 6-membered heterocyclic alkyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group. In some embodiments, R 9B and R 9C It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

[0152] In some embodiments, L 1 For bonds, -C(O)-, methylene or ethylene; and R 9 It is hydrogen, unsubstituted C1-C4 alkyl or -C(O)NR 9BR 9C .

[0153] In some embodiments, L 1 As a key. In some embodiments, R 9 For hydrogen, methyl, ethyl, propyl, -C(O)NH2, In some embodiments, L 1 As the key; and R 9 For hydrogen, methyl, ethyl, propyl, -C(O)NH2,

[0154] In some embodiments, each R 10.1 R 10.2 R 10.3 and R 10.4 Independently, it is a hydrogenated, oxidized, or unsubstituted C1-C4 alkyl group, -C(O)OH, or -CH2OH. In some embodiments, R 10.1 It is a hydrogenated, oxidized, or unsubstituted C1-C4 alkyl group, -C(O)OH, or -CH2OH. In some embodiments, R 10.2 Independently, it is a hydrogenated, oxidized, or unsubstituted C1-C4 alkyl group, -C(O)OH, or -CH2OH. In some embodiments, R 10.3 Independently, it is a hydrogenated, oxidized, or unsubstituted C1-C4 alkyl group, -C(O)OH, or -CH2OH. In some embodiments, R 10.4 It is independently hydrogen, oxo- or unsubstituted C1-C4 alkyl, -C(O)OH or -CH2OH.

[0155] In some embodiments, L 1 As the key; and R 10.1 R 10.2 R 10.3 and R 10.4 It is hydrogen. In some embodiments, the compound is:

[0156] R 1 R 2 R 3 and R 4 As stated above.

[0157] In some embodiments, R 1 It can be hydrogen, halogen, unsubstituted C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, -OCX3, -OCH2X, -OCHX2 or -OR 1A And R 1A It is hydrogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 1It can be hydrogen, methyl, ethyl, -C≡CH, -C≡CH-CH3, -OH, -OCH3, -OCHF2, -OCH2F, -OCF3, -F, -Cl, or -Br. In the examples, R 2 It is hydrogen. In the examples, R is... 2 It can be -F, -Cl, or -Br.

[0158] In some embodiments, R 9 It is hydrogen, unsubstituted C1-C4 alkyl or -C(O)NR 9B R 9C In some embodiments, R 9 It can be hydrogen, methyl, ethyl, propyl or -C(O)NH2.

[0159] For example, the compound of formula (IA-1) is:

[0160]

[0161]

[0162] In some embodiments, the compound is

[0163]

[0164] In some embodiments, in equation (IA-1a), each R 3 and R 4 Independently -F, -Cl, -Br, or methyl. In some embodiments, the compound of formula (IA-1a) is

[0165]

[0166] In some embodiments, L 1 For key; R 9 It is hydrogen; and R 10.1 R 10.2 R 10.3 and R 10.4 At least one of them is not hydrogen. In some embodiments, L 1 As the key; and R 10.1 R 10.2 R 10.3 and R 10.4 One of them is not hydrogen.

[0167] In some embodiments, R 10.1 or R 10.3 methyl. In some embodiments, R 10.2 or R 10.4 methyl. In some embodiments, R 10.1 or R 10.3For oxidation. In some embodiments, R... 10.2 or R 10.4 For oxidation. In some embodiments, R... 10.1 or R 10.3 It is -C(O)OH. In some embodiments, R 10.2 or R 10.4 It is -C(O)OH. In some embodiments, R 10.1 or R 10.3 For -CH2OH. In some embodiments, R 10.2 or R 10.4 It is -CH2OH. For example, the compound of formula (IA) is:

[0168]

[0169] In some embodiments, L 1 For -C(O)- and R 9 It is hydrogen. In some embodiments, the compound is:

[0170] R 1 R 2 R 3 and R 4 As described above. For example, compound (IA-2) is

[0171] In some embodiments, R 10.1 R 10.2 R 10.3 and R 10.4 One or more of them are linked to each other or to atoms of the piperazine ring to form substituted or unsubstituted heterocyclic alkyl groups. For example, R 10.1 R 10.2 R 10.3 and R 10.4 One or more of the following are connected to each other or to atoms of the piperazine ring to form substituted or unsubstituted 2,5-diazabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 3,9-diazabicyclo[3.3.1]nonane, 2-thia-5-azabicyclo[2.2.1]heptane, 2,2-dioxide, 2-azabicyclo[2.2.1]hept-5-ene, 3-oxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, and 2-oxa-5-azabicyclo[2.2.1]heptane.

[0172] In some embodiments, R 10.1 or R10.3 Atoms attached to the piperazine ring form a 4- to 6-membered heterocyclic alkyl group including a nitrogen atom of the piperazine ring. In some embodiments, R 10.1 or R 10.3 Atoms attached to the piperazine ring to form R 5 For example, the compound is

[0173] In some embodiments, R 5 and R 7 It is hydrogen. In some embodiments, R is... 6B and R 6C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups. In some embodiments, R 5 and R 7 It is hydrogen; and R 6B and R 6C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

[0174] In some embodiments, L 1 It is methylene or ethylene. In some embodiments, the compound has the following structure:

[0175]

[0176] R 1 R 2 R 3 R 4 R 9 R 10.1 R 10.2 R 10.3 and R 10.4 As stated above.

[0177] In some embodiments, R 10.1 R 10.2 R 10.3 and R 10.4 It is hydrogen. In some embodiments, R is... 9 It is hydrogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 9 It is hydrogen. In some embodiments, R is... 9 It is an unsubstituted C1-C4 alkyl group. In the examples, R 9 -C(O)NR 9B R 9C For example, compounds of formula (IA-3) or (IA-4) are

[0178]

[0179]

[0180] In some embodiments, the compound has the following structure:

[0181] R 1 R 2 R 3 R 4 L 1 R 9 R 10.1 R 10.2 R 10.3 and R 10.4 As stated above.

[0182] In some embodiments, R 9 It is hydrogen. In some embodiments, R is... 9 R 10.1 R 10.2 R 10.3 and R 10.4 It is hydrogen. In some embodiments, the compound has the following structure:

[0183] R 1 R 2 R 3 and R 4 As described above. For example, compound (IB-1) is

[0184] In some embodiments, in formula (IB), R 9 For methyl, ethyl, propyl, -C(O)NH2,

[0185] In some embodiments, R 5 and R 6 It is hydrogen. In some embodiments, R is... 7B and R 7C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups. In some embodiments, R 5 and R 6 It is hydrogen; and R 7B and R 7C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

[0186] In some embodiments, the compound has the following structure:

[0187] R 1 R 2 R 3 R 4L 1 R 9 R 10.1 R 10.2 R 10.3 and R 10.4 As stated above.

[0188] In some embodiments, R 6 and R 7 It is hydrogen, and R 5 It is a substituted or unsubstituted heterocyclic alkyl group (e.g., piperidinyl, pyrrolidinyl, or morpholinyl) or a substituted or unsubstituted heteroaryl group (e.g., pyridinyl or pyrimidinyl). In some embodiments, R 6 and R 7 For hydrogen, R 5 For -NR 5B R 5C And R 5B and R 5C Together with the atoms attached thereto, they are linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

[0189] In some embodiments, the compound has the following structure:

[0190] in:

[0191] k is 1 or 2;

[0192] Each R 10.1 R 10.2 and R 10.3 Independently hydrogen, -OR 10A -C(O)OR 10A -NR 10B R 10C -(CH2) m OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl or substituted or unsubstituted C3-C6 cycloalkyl, or R 10.1 R 10.2 and R 10.3 One or more of them may be connected to each other or to atoms of a heterocycle to form a substituted or unsubstituted heterocyclic alkyl group;

[0193] m is an integer from 1 to 4; and

[0194] Each R 10A R 10B and R 10C It is independently hydrogen or an unsubstituted C1-C6 alkyl group.

[0195] In formula (IC), R 1 R 2 R3 and R 4 As stated above.

[0196] In some embodiments, each R 10.1 R 10.2 and R 10.3 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 10.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 10.2 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 10.3 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 10.1 It is hydrogen. In some embodiments, R is... 10.2 It is hydrogen. In some embodiments, R is... 10.3 It is hydrogen.

[0197] In some embodiments, R 10.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 10.2 and R 10.3 It is hydrogen. In some embodiments, R is... 10.2 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 10.1 and R 10.3 It is hydrogen. In some embodiments, R is... 10.3 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 10.1 and R 10.3 It is hydrogen.

[0198] In some embodiments, the compound has the following structure:

[0199]

[0200] R 1 R 2 R 3 R 4 and R 10.1 As stated above.

[0201] In some embodiments, R 1For -OCH3. In some embodiments, R 10.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. For example, compounds of formula (IC-1) or (IC-2) are...

[0202]

[0203] In some embodiments, R 6 and R 7 It is hydrogen, and R 5 The morpholino group may be substituted or unsubstituted. In some embodiments, R 6 and R 7 For hydrogen, R 5 For -NR 5B R 5C And R 5B and R 5C Together with the atoms attached to it, they form substituted or unsubstituted morpholino groups.

[0204] In some embodiments, the compound has the following structure:

[0205] R 1 R 2 R 3 and R 4 As stated above.

[0206] In some embodiments, R 9 It is hydrogen. For example, the compound is...

[0207] In some embodiments, R 6 and R 7 It is hydrogen, and R 5 The morpholino group may be substituted or unsubstituted. In some embodiments, R 5 It is an unsubstituted morpholino group. In some embodiments, R 6 and R 7 For hydrogen, R 5 For -NR 5B R 5C And R 5B and R 5C Together with the atoms attached thereto, they form substituted or unsubstituted morpholino groups. In some embodiments, R 5B and R 5C Together with the atoms attached to it, they connect to form an unsubstituted morpholino group. For example, the compound is...

[0208]

[0209] In some embodiments, R 6 and R 7 It is hydrogen, and R 5 The aryl group may be substituted or unsubstituted. In some embodiments, R 5 The phenyl group can be substituted or unsubstituted. For example, the compound is...

[0210] In some embodiments, R 6 and R 7 It is hydrogen, and R 5 -O(CH2) m OH or -NHR 5C R 5C -(CH2) m OH, -(CH2) m NH2、-(CH2) m NHCH3 and -(CH2) m N(CH3)2, and each m is an independent integer from 1 to 4. In some embodiments, m is 1 or 2. In some embodiments, R 5 for For example, the compound is

[0211] In some embodiments, R 5 R 6 and R 7 It is hydrogen and R 1 It is cyclopropyl or -Br. For example, the compound is...

[0212] When R 2 R 5 R 6 and R 7 It is hydrogen and R 3 and R 4 When it is -F, then R 1 Not -OCH3. In some embodiments, when R 5 R 6 and R 7 It is hydrogen and R 3 and R 4 When it is -F, then R 1 Not -OCH3.

[0213] In some embodiments, the compound or sub-example of formula (I) is

[0214]

[0215]

[0216] In some embodiments, the compound is

[0217] In one respect, the compound has the following structure:

[0218] or its salt,

[0219] in:

[0220] W is -CR 18 = or -N=;

[0221] R 11 For hydrogen, halogen, -CX'3, -CHX'2, -CH2X', -OCX'3, -OCH2X', -OCHX'2, -OR 11A Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted 2- to 6-membered heteroalkyl groups, and substituted or unsubstituted C3-C6 cycloalkyl groups;

[0222] Each R 12 R 13 and R 14 Independently hydrogen, halogen, -OR 12A Or unsubstituted C1-C6 alkyl groups;

[0223] R 15 For hydrogen, -NR 15B R 15C -(CH2) n15 NR 15B R 15C -C(O)NR 15B R 15C -O(CH2) m15 OR 15A -OR 15A Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted 2- to 6-membered heteroalkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted 5- to 6-membered heterocycloalkyl groups, substituted or unsubstituted C6-C6 cycloalkyl groups. 12 Aryl or substituted or unsubstituted 5 to 6-membered heteroaryl groups;

[0224] R 16 For hydrogen, -NR 16B R 16C -(CH2) n16 NR 16B R 16C -C(O)NR 16B R 16C -O(CH2) m16 OR 16A -OR16A Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted 2- to 6-membered heteroalkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted 5- to 6-membered heterocycloalkyl groups, substituted or unsubstituted C6-C6 cycloalkyl groups. 12 Aryl or substituted or unsubstituted 5 to 6-membered heteroaryl groups;

[0225] R 17 For hydrogen, -NR 17B R 17C -(CH2) n17 NR 17B R 17C -C(O)NR 17B R 17C -O(CH2) m17 OR 17A -OR 17A Substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted 2- to 6-membered heteroalkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted 5- to 6-membered heterocycloalkyl groups, substituted or unsubstituted C6-C6 cycloalkyl groups. 12 Aryl or substituted or unsubstituted 5 to 6-membered heteroaryl groups;

[0226] R 18 It is hydrogen or an unsubstituted C1-C6 alkyl group;

[0227] X' can be -F, -Cl, -Br, or -I independently;

[0228] Each n15, n16, and n17 is an independent integer from 1 to 4;

[0229] Each m15, m16, and m17 is an independent integer from 1 to 4;

[0230] Each R 11A R 12A R 15A R 15B R 15C R 16A R 16B R 16C R 17A R 17B and R 17C Independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2- to 4-membered heteroalkyl, or R 15B and R 15C Together with the atoms attached thereto, they are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; R 16B and R 16CTogether with the atoms attached thereto, they are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; or R 17B and R 17C The atoms attached thereto are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

[0231] In some embodiments, W is -N=. In some embodiments, W is -CR. 18 =. In some embodiments, R 18 It can be hydrogen or methyl.

[0232] In some embodiments, R 11 It can be hydrogen, halogen, unsubstituted C2-C4 alkynyl, unsubstituted C1-C4 alkyl, unsubstituted C3-C6 alkyl, -OCX'3, -OCH2X', -OCHX'2 or -OR 11A And R 11A It is hydrogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 11 It is hydrogen. In some embodiments, R is... 11 It is -OCH3. In some embodiments, R 11 It is -Br.

[0233] In some embodiments, R 12 For hydrogen, halogen or -OR 12A In some embodiments, R 12 It is hydrogen. In some embodiments, R is... 12 It is -F, -Cl, or Br. In some embodiments, R 12 For -OR 12A And R 12A It is hydrogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 12A methyl. In some embodiments, R 12 It is -OCH3.

[0234] In some embodiments, each R 13 and R 14 Independently hydrogen, halogen, or unsubstituted C1-C4 alkyl. In some embodiments, R 13 It is hydrogen, halogen, or unsubstituted C1-C4 alkyl. In some embodiments, R 14 It is hydrogen, halogen, or unsubstituted C1-C4 alkyl. In some embodiments, each R 13 and R 14 Independently hydrogen, -F, -Cl, or methyl. In some embodiments, R 14 It is hydrogen, -F, -Cl, or methyl. In some embodiments, R 14It is hydrogen, -F, -Cl, or methyl. In some embodiments, R 13 and R 14 It is -F.

[0235] In some embodiments, R 16 and R 17 It is hydrogen. In some embodiments, R is... 15B and R 15C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups. In some embodiments, R 16 and R 17 It is hydrogen; and R 15B and R 15C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

[0236] In some embodiments, the compound has the following structure:

[0237]

[0238] in:

[0239] L 11 For bond or -(CH2) n15 ;

[0240] R 19 It is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl;

[0241] Each R 20.1 R 20.2 R 20.3 and R 20.4 Independently hydrogen, -OR 20A -C(O)OR 20A -NR 20B R 20C -(CH2) m' OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl or substituted or unsubstituted C3-C6 cycloalkyl, or R 20.1 R 20.2 R 20.3 and R 20.4 One or more of them may be optionally connected to each other or to atoms of the piperazine ring to form substituted or unsubstituted heterocyclic alkyl groups;

[0242] q is an integer from 0 to 8.

[0243] Each m' is an independent integer from 1 to 4; and

[0244] Each R 19A R 20A R20B and R 20C It is hydrogen independently, or a substituted or unsubstituted C1-C6 alkyl group.

[0245] In equation (II-A) or (II-B), R 11 R 12 R 13 R 14 and R 18 As stated above.

[0246] In some embodiments, R 15 and R 17 It is hydrogen. In some embodiments, R is... 16B and R 16C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups. In some embodiments, R 15 and R 17 It is hydrogen; and R 16B and R 16C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

[0247] In some embodiments, the compound has the following structure:

[0248]

[0249] R 11 R 12 R 13 R 14 L 11 R 18 R 19 R 20.1 R 20.2 R 20.3 and R 20.4 As stated above.

[0250] In some embodiments, R 15 and R 16 It is hydrogen. In some embodiments, R is... 17B and R 17C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups. In some embodiments, R 15 and R 16 It is hydrogen; and R 17B and R 17C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

[0251] In some embodiments, the compound has the following structure:

[0252]

[0253] R 11 R 12 R 13 R 14 L 11 R 18 R 19 R 20.1 R 20.2 R 20.3 and R 20.4 As stated above.

[0254] In some embodiments, L 11 For example, the bond is used. In some embodiments, the compound has the following structure:

[0255]

[0256]

[0257] R 11 R 12 R 13 R 14 R 18 R 19 R 20.1 R 20.2 R 20.3 and R 20.4 As stated above.

[0258] In some embodiments, R 19 It is hydrogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 19 It is hydrogen. In some embodiments, R is... 19 It is methyl or ethyl. In some embodiments, R 19 It is a methyl group.

[0259] In some embodiments, R 11 -OCH 3 In some embodiments, R 12 It is hydrogen, -F, or -OCH3. In some embodiments, R 13 and R 14 For -F. In some embodiments, R 20.1 R 20.2 R 20.3 and R 20.4 It is hydrogen. In some embodiments, R is... 19 It can be hydrogen or methyl. For example, compounds of formula (II-A-1) are...

[0260]

[0261] Compound of formula (II-B-1) is The compound of formula (II-C-1) is

[0262] In some embodiments, L 11 The methylene group is present. In some embodiments, the compound has the following structure:

[0263]

[0264]

[0265] R 11 R 12 R 13 R 14 R 18 R 19 R 20.1 R 20.2 R 20.3 and R 20.4 As stated above.

[0266] In some embodiments, R 11 -OCH 3 In some embodiments, R 12 It is hydrogen. In some embodiments, R is... 13 and R 14 For -F. In some embodiments, R 20.1 R 20.2 R 20.3 and R 20.4 It is hydrogen. In some embodiments, R is... 18 and R 19 It is hydrogen. For example, compounds of formula (II-C-2) are...

[0267] In some embodiments, R 20.1 R 20.2 R 20.3 and R 20.4 It is hydrogen.

[0268] In some embodiments, R 16 and R 17 It is hydrogen, and R 15 It is a substituted or unsubstituted heterocyclic alkyl group (e.g., piperidinyl, pyrrolidinyl, or morpholinyl) or a substituted or unsubstituted heteroaryl group (e.g., pyridinyl or pyrimidinyl). In some embodiments, R 16 and R 17 For hydrogen, R 15 For -NR 15B R15C And R 15B and R 15C Together with the atoms attached thereto, they are linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

[0269] In some embodiments, the compound has the following structure:

[0270]

[0271] in:

[0272] k' is 1 or 2;

[0273] Each R 20.1 R 20.2 and R 20.3 Independently hydrogen, oxy, -OR 20A -C(O)OR 20A -NR 20B R 20C -(CH2) m' OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl or substituted or unsubstituted C3-C6 cycloalkyl, or R 20.1 R 20.2 and R 20.3 One or more of them may be connected to each other or to atoms of a heterocycle to form a substituted or unsubstituted heterocyclic alkyl group;

[0274] Each m' is an independent integer from 1 to 4; and

[0275] Each R 20A R 20B and R 20C It is independently hydrogen or an unsubstituted C1-C6 alkyl group.

[0276] In formula (II-E) or (II-F), R 11 R 12 R 13 R 14 R 18 R 20.1 R 20.2 and R 20.3 As stated above.

[0277] In some embodiments, R 20.1 R 20.2 and R 20.3 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 20.1Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 20.2 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 20.3 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH. In some embodiments, R 20.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 20.2 and R 20.3 It is hydrogen. In some embodiments, R is... 20.2 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 20.1 and R 20.3 It is hydrogen. In some embodiments, R is... 20.3 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 20.1 and R 20.2 It is hydrogen.

[0278] In some embodiments, R 20.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 20.2 and R 20.3 It is hydrogen. In some embodiments, R is... 20.2 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 20.2 and R 20.3 It is hydrogen.

[0279] In some embodiments, R 20.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, -OH, or -(CH2)OH, and R 20.2 and R 20.3 It is hydrogen.

[0280] In some embodiments, the compound has the following structure:

[0281]

[0282] R 11 R 12 R 12 R 14 R 18and R 20.1 As stated above.

[0283] In some embodiments, R 11 It is -OCH3 and R 11 It is hydrogen. In some embodiments, R is... 20.1 It can be hydrogen or -OH independently. For example, compounds of formula (II-F-1) are...

[0284] In some embodiments, the compound or sub-example of formula (II) is:

[0285]

[0286]

[0287] In some embodiments, the compounds are selected from the examples provided herein.

[0288] Preparation of Formula I compounds and exemplary compounds

[0289] Analysis details

[0290] NMR Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz) spectrometer with or without tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported from TMS to low magnetic field in ppm, and spectral splitting modes are specified as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unresolved or overlapping signal (m), and broad signal (br). Deuterated solvents are given in parentheses and have chemical shifts as shown in the NMR spectral data for dimethyl sulfoxide (δ 2.50 ppm), chloroform (δ 7.26 ppm), methanol (δ 3.31 ppm), or other solvents.

[0291] LC-MS: System Shimadzu20A-2010MS

[0292] Tested: SPD-M20A

[0293] Column: MERCK, RP-18e 25-2mm;

[0294] Wavelength: UV 220nm, 254nm;

[0295] Column temperature: 50℃; MS ionization: ESI

[0296] Mobile phase: 1.5 mL / 4 LTFA aqueous solution (solvent A) and 0.75 mL / 4 LTFA acetonitrile solution (solvent B), using an elution gradient of 5% to 95% over 0.7 min (solvent B), and maintained at 95% for 0.4 min at a flow rate of 1.5 mL / min;

[0297] Rapid column chromatography system

[0298] System: CombiFlash Rf+

[0299] Pillar: Santai Technologies, Inc.

[0300] Samples are usually adsorbed onto the precipitate.

[0301] Preparation on an HPLC system

[0302] System: Trilusion LC 4.0

[0303] Testing: Gilson 159UV-VIS

[0304] Condition 1: Column: Phenomenex Gemini-NX 80*40mm*3um

[0305] Eluent A: Water (0.05% NH3H2O ​​+ 10mM NH4HCO3)

[0306] Elution Buffer B: CH3CN

[0307] Start B: 20% to 45%, End B: 80% to 20%, Gradient Time (minutes): 8

[0308] Condition 2: Column: Ultimate C18 10μm 250mm*50mm;

[0309] Eluent A: Water (0.04% NH3H2O ​​+ 10mM NH4HCO3).

[0310] Eluent B: CH3CN 50% to 80%; Gradient time (minutes): 8

[0311] All raw materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds disclosed herein are commercially available or can be produced by organic synthesis methods known to those skilled in the art.

[0312] The following is a list of chemical abbreviations:

[0313]

[0314]

[0315] All raw materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds disclosed herein are commercially available or can be produced by organic synthesis methods known to those skilled in the art.

[0316] synthesis

[0317] General Method A

[0318] At room temperature, HATU / HBTU / PyBOP (1.2 to 2 equivalents) and TEA / DIEA (2 to 3 equivalents) were added to a solution of carboxylic acid (1 equivalent) and amine (1 to 2 equivalents) in DMF (0.1 M). The mixture was stirred under N2 at room temperature to 100°C for 4 to 16 hours. The resulting suspension was diluted with EtOAc and washed with brine, then dried (Na2SO4), filtered, and evaporated to dryness. The resulting residue was purified by grinding / preparative TLC / FCC / preparative HPLC to obtain the product.

[0319] Example 1: 4-(3,5-difluoro-4-((8-methoxyquinoline-2-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0320]

[0321] To a solution of compound 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,6-difluorobenzoic acid (3.34 g, 9.770 mmol) and 8-methoxyquinoline-2-amine (1.7 g, 9.770 mmol) in DMF (40 mL), HATU (4.46 g, 11.72 mmol) and DIEA (2.52 g, 19.54 mmol, 3.2 mL) were added. The mixture was stirred overnight at 90 °C. The reaction mixture was washed with H₂O (80 mL), the aqueous layer was extracted with EA (80 mL × 2), the combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (PE:EA 3:1). The desired compound (1.79 g, yield: 36.79%) was given as a pale yellow solid. MS (ESI) m / z (M+H) + =499.

[0322] General Method B

[0323] Carboxylic acid (1 equivalent), EDCI (2 to 2.5 equivalents), with or without HOBt (2 equivalents), and DIEA / pyridine / DMAP (3 equivalents) were dissolved in THF or DMF (0.1 M) and stirred at room temperature to 80°C for 15 to 30 minutes. Then, an amine (1 equivalent) was added in a single addition, and the reaction mixture was stirred at room temperature to 70°C for 2 to 16 hours. Once the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by grinding / preparative TLC / FCC / preparative HPLC to obtain the product.

[0324] Example 2: 2,6-Difluoro-4-(4-hydroxypiperidin-1-yl)-N-(4-methoxybenzo[d]thiazolyl)benzamide

[0325]

[0326] A mixture of 2,6-difluoro-4-(4-hydroxypiperidin-1-yl)benzoic acid (200.0 mg, 777.5 μmol), 4-methoxybenzo[d]thiazol-2-amine (140.1 mg, 777.5 μmol), and EDCI (298.1 mg, 1.56 mmol) in Py (5 mL) was stirred at 80 °C for 12 hours. The mixture was then concentrated directly under vacuum. The crude product was purified by preparative HPLC (HCl). The desired compound (63 mg, yield: 19.32%) was given as a yellow solid.

[0327] 1 H NMR(400MHz,DMSO-d6)δ12.77(br s,1H),7.56(d,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),6.72(d,J=12.8Hz,2H),3.92(s, 3H),3.75-3.68(m,2H),3.17(s,2H),3.14-3.05(m,2H),2.07(s,1H),1.83-1.74(m,2H),1.45-1.33(m,2H). MS(ESI)m / z(M+H) + =420.1

[0328] General Method C

[0329] SOCl2 (1 equivalent) and DMF (3 equivalents) were added to a solution of carboxylic acid (1 equivalent) in DCM (0.01 to 0.1 M). The reaction mixture was stirred at 0 °C for 0.5 h. Then Py (5 equivalents) and an amine (1 equivalent) were added. The reaction mixture was stirred at 25 °C for 24 h. Once the reaction was determined to be complete by LCMS analysis, the reaction was quenched with 1 M HCl (aqueous solution). The mixture was diluted with EtOAc and washed with brine, then dried (Na2SO4), filtered, and evaporated. The resulting residue was purified by grinding / preparative TLC / FCC / preparative HPLC to obtain the product.

[0330] Example 3: Preparation of tert-butyl 4-(3,5-difluoro-4-((4-methoxybenzo[d]thiazolyl-2-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid

[0331]

[0332] At 0 °C, SOCl2 (521.0 mg, 4.38 mmol, 317.9 μL) was added dropwise to a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (1.50 g, 4.38 mmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 1 hour. Py (1.64 g, 20.79 mmol, 1.68 mL) was added, and the mixture was stirred at 25 °C for 0.5 hours. 4-Methoxy-1,3-benzothiazol-2-amine (674.4 mg, 3.74 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with H2O (10 mL), and the organic layer was separated. The organic layer was washed with HCl (10 mL × 2), saturated NaHCO3 (10 mL), and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1, 1 / 1). The desired compound (1.2 g, yield: 57.20%) was given as a white solid.

[0333] General methods for removing BOC

[0334] The Boc compound was dissolved in HCl / MeOH, and the reaction mixture was stirred at room temperature for 1 to 2 hours. The solution was concentrated to dryness to obtain the final compound.

[0335] Example 4: Preparation of 2,6-difluoro-N-(4-methoxybenzo[d]thiazolyl)-4-(piperazin-1-yl)benzamide

[0336]

[0337] At 15 °C, HCl / MeOH (4 M, 6 mL) was added to a solution of 200.0 mg (397 μmol) of 4-(3,5-difluoro-4-((4-methoxybenzo[d]thiazo-2-yl)carbamoyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (DCM) in 2 mL. The mixture was stirred at 15 °C for 1 hour. After direct concentration under vacuum, the residue was purified by preparative HPLC (HCl). The desired compound (88.2 mg, yield: 55.2%) was given as a yellow solid.

[0338] 1 H NMR(400MHz,DMSO-d6)δ12.94(br s,1H),9.40(br s,2H),7.56(d,J=7.94Hz,1H),7.32-7.26(m,1H),7.29(t,J=8.05Hz,1H),7.02(d,J=8.16Hz,1H),6.84(br d,J=12.35Hz,2H),3.92(s,3H),3.67-3.55(m,4H),3.18(br s,4H). MS(ESI)m / z(M+Na) + =427.0.

[0339] Example 5: Preparation of 2-fluoro-N-(4-methoxybenzo[d]thiazolyl-2-yl)-6-methyl-4-(piperazin-1-yl)benzamide

[0340]

[0341] A solution of 4-bromo-2-fluoro-N-(4-methoxybenzo[d]thiazolyl)-6-methylbenzamide (150.0 mg, 0.38 mmol), piperazine-1-carboxylic acid tert-butyl ester (71 mg, 0.38 mmol), x-phos (36.0 mg, 0.2 mmol), Pd2(dba)3 (39.0 mg, 0.1 mmol), and Cs2CO3 (247.0 mg, 0.76 mmol) in toluene (5 mL) was stirred overnight at 110 °C. Once TLC analysis was completed, the resulting suspension was diluted with EtOAc and washed with brine, then dried (Na2SO4), filtered, and evaporated to dryness. The residue was purified by grinding, FCC, or preparative TLC to obtain the product.

[0342] Table 1: Compounds (Formula I) and determination results of benzothiazole derivatives

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] Table 2: Compounds (Formula II) and determination results of quinoline derivatives

[0358]

[0359]

[0360]

[0361] How to use

[0362] ALPK1 is a cytoplasmic serine-threonine protein kinase that plays a crucial role in activating the innate immune response. ALPK1 binds to the bacterial pathogen-associated molecular pattern metabolite (PAMP), ADP-D-glycerol-β-D-mannohepose (ADP-heptaose). ALPK1-ADP-heptaose binding occurs through a direct interaction with the N-terminal domain of ALPK1. This interaction stimulates the kinase activity of ALPK1 and its phosphorylation, as well as the activation of the TRAF-interacting protein (TIFA) with a fork-head-associated domain. In turn, TIFA activation triggers pro-inflammatory NF-κB signaling, including the expression and / or secretion of pro-inflammatory cytokines and chemokines. Therefore, the compounds disclosed herein are generally intended as inhibitors of ALPK1 kinase activity and downstream activation of NF-κB pro-inflammatory signaling.

[0363] This disclosure provides the use of compounds of formula (I) or (II) or sub-examples thereof, as described herein, for inhibiting ALPK1 kinase activity and reducing inflammation in target tissues. The method also covers the use of compounds of formula (I) or (II) or sub-examples thereof, as described herein, for treating diseases, conditions, or symptoms characterized by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling. In the examples, the disease, condition, or symptom is selected from systemic lupus erythematosus (SLE), sepsis, cancer, spiroadenoma, spiroadenoma, retinal dystrophy, optic edema, splenomegaly, anhidrosis, and migraine (“ROSAH”) syndrome, and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (“PFAPA”) syndrome. In the examples, the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma. In the examples, the cancer is oral squamous cell carcinoma.

[0364] In embodiments, this disclosure provides a method for inhibiting ALPK1 kinase activity in cells or target tissues by contacting mammalian cells or target tissues with a compound of formula (I) or (II) or a sub-example described herein. In embodiments, the method comprises administering to a subject a pharmaceutical composition comprising a compound of formula (I) or (II) or a sub-example described herein in an amount that effectively inhibits ALPK1 kinase activity in the subject's target cells or tissues. In embodiments, the method comprises reducing inflammation in the target tissues of a subject requiring such therapy by administering to a subject a compound of formula (I) or (II) or a sub-example described herein or a pharmaceutical composition comprising thereto.

[0365] In embodiments, this disclosure provides a method for treating a subject with a disease or condition characterized by excessive or inappropriate activation of ALPK1 kinase activity, the method comprising administering to the subject a compound of formula (I) or (II) or a sub-example described herein. In embodiments, the disease or condition is selected from systemic lupus erythematosus (SLE), sepsis, cancer, spiroadenoma, spiroadenoma, ROSAH syndrome, and PFAPA syndrome.

[0366] In the embodiments, the disease or condition is hidradenoma or spirochete carcinoma, and the methods involve administering a compound of formula (I) or (II) or a sub-example described herein to a subject requiring such treatment. In the embodiments, the subject requiring treatment is a subject diagnosed with hidradenoma or spirochete carcinoma and carrying one or more gene mutations in ALPK1. In the embodiments, at least one gene mutation is an activating mutation. In the embodiments, the gene mutation in ALPK1 is p.V1092A, as described by Rashid et al. in *Nature Communications* (2019).

[0367] In an embodiment, the disease or condition is ROSAH, and the method comprises administering a compound of formula (I) or (II) or a sub-embodiment described herein to a subject requiring such treatment. In an embodiment, the subject requiring treatment is a subject diagnosed with ROSAH and carrying one or more gene mutations in ALPK1. In an embodiment, at least one gene mutation is an activating mutation. In an embodiment, the gene mutation in the ALPK1 gene is c.710C>T, p.T237M, as described in Williams et al., *Genetics in Medicine* 21:2103-2115 (2019).

[0368] In an embodiment, the disease or condition is PFAPA, and the method comprises administering a compound of formula (I) or (II) or a sub-embodiment described herein to a subject requiring such treatment. In an embodiment, the subject requiring treatment is a subject diagnosed with or having clinical symptoms of PFAPA and carrying one or more gene mutations in ALPK1. In an embodiment, at least one gene mutation is an activating mutation. In an embodiment, the gene mutation in the ALPK1 gene is 2770T>C, p.(S924P), as described by Sangiorgi et al. in the European Journal of Human Genetics (2019).

[0369] In this embodiment, the disease or condition is a cancer selected from lung cancer, colon cancer, and oral squamous cell carcinoma. In this embodiment, the cancer is oral squamous cell carcinoma. In this embodiment, the subject requiring treatment is a subject diagnosed with cancer, wherein the cancer cells carry at least one activating mutation in ALPK1, or wherein the cancer cells express ALPK1 mRNA or protein at an elevated level compared to the subject's non-cancer cells.

[0370] In embodiments, this disclosure further provides a method for identifying a disease, condition, or symptom for treatment with a compound of formula (I) or (II) or a sub-example described herein, the method comprising determining, in comparison with reference cells or tissues not involved in the disease, condition, or symptom, one or more of an activating mutation in ALPK1 and overexpression of ALPK1 mRNA or protein in cells or tissues involved in the disease, condition, or symptom, from a biological sample from a subject diagnosed with the disease, condition, or symptom. In an embodiment, the activating mutation in ALPK1 is 2770T>C, p.(S924P).

[0371] In the context of the methods described herein, the term "treatment" can refer to the improvement or stabilization of one or more symptoms associated with the treated disease, condition, or symptom. The term "treatment" can also encompass the management of a disease, condition, or symptom, referring to a beneficial effect obtained by the subject from the therapy without resulting in a cure for the underlying disease, condition, or symptom.

[0372] In embodiments in which a therapeutically effective amount of the composition is administered to a subject, the therapeutically effective amount is an amount sufficient to achieve the desired therapeutic outcome, such as improvement or stabilization of one or more symptoms of the disease, condition, or symptom being treated, or, in the context of prevention, an amount sufficient to prevent recurrence, development, progression, or onset of one or more symptoms of the disease, condition, or symptom.

[0373] In this embodiment, the therapeutically effective amount is the amount required to achieve a therapeutic effect that is at least equivalent to that of a standard therapy. An example of a standard therapy is an FDA-approved medicine for treating the same disease, condition, or symptom.

[0374] In the context of any of the methods described herein, the subject is preferably a human, but may be a non-human mammal, preferably a non-human primate. In other embodiments, the non-human mammal may be, for example, a dog, cat, rodent (e.g., mouse, rat, rabbit), horse, cow, sheep, goat, or any other non-human mammal.

[0375] In this embodiment, human subjects are selected from adult, pediatric, or elderly patients, terms that are understood by a practicing physician, such as those defined by the U.S. Food and Drug Administration.

[0376] Pharmaceutical Composition

[0377] In embodiments, this disclosure also provides a pharmaceutical composition for use in the methods described herein, comprising a compound of formula (I) or (II) or a sub-example described herein, and a carrier or excipient. In embodiments, the pharmaceutical composition is formulated for delivery via oral or rectal route. In embodiments, the pharmaceutical composition is formulated as an oral dosage form in the form of tablets or capsules. In embodiments, the pharmaceutical composition is formulated as a rectal dosage form in the form of an ointment, suppository, or enema. In embodiments, the pharmaceutical composition is formulated as a parenteral dosage form. In embodiments, the parenteral dosage form is suitable for administration via intravenous, intra-arterial, or intramuscular routes, for example, by injecting an aqueous liquid.

[0378] In the embodiments, this disclosure provides a composition comprising a compound of formula (I) or (II) or a sub-example described herein, and one or more excipients or carriers, preferably pharmaceutically acceptable excipients or carriers. As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, carriers, and / or dosage forms that are suitable for contact with tissues in humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio. Excipients used to prepare pharmaceutical compositions are generally those known to be safe and non-toxic when administered to humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, sterile liquids, water, buffered saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), oils, detergents, suspending agents, carbohydrates (e.g., glucose, lactose, sucrose, or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, and suitable mixtures of any of the foregoing substances. The specific excipients used in the composition will depend on a variety of factors, including the chemical stability and solubility of the formulated compound and the intended route of application.

[0379] Pharmaceutical compositions may be supplied in bulk or in unit dosage forms. It is particularly advantageous to formulate pharmaceutical compositions into unit dosage forms that are easy to administer and provide uniform dosing. The term "unit dosage form" refers to a physically discrete unit suitable for use as a single dose in a subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect when used with the desired drug carrier. Unit dosage forms may be ampoules, vials, suppositories, sugar-coated pills, tablets, capsules, IV bags, or a single pump on an aerosol inhaler.

[0380] In therapeutic applications, dosage may vary depending on the chemical and physical properties of the active compound and the clinical characteristics of the subject, including, for example, age, weight, and comorbidities. Generally, the dosage should be a therapeutically effective amount. An effective amount of a pharmaceutical composition is the amount that provides an objectively identifiable improvement noticeable to a clinician or other qualified observer. For example, relief of symptoms of a disease, ailment, or condition.

[0381] Pharmaceutical compositions may be in any suitable form (e.g., liquid, aerosol, solution, inhaler, nebulizer, spray; or solid, powder, ointment, paste, cream, lotion, gel, patch, etc.) for administration via any desired route (e.g., pulmonary, inhalation, intranasal, oral, sublingual, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, transdermal, transmucosal, rectal, etc.). In the examples, the pharmaceutical compositions are in the form of orally acceptable dosage forms, including but not limited to capsules, tablets, sublingual forms, sugar tablets, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions, or solutions. Capsules may contain excipients, such as inert fillers and / or diluents, including starch (e.g., corn, potato, or cassava starch), sugar, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flour, gelatin, gum, etc. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, may also be added.

[0382] In the embodiments, the pharmaceutical composition is in the form of a tablet. The tablet may contain a unit dose of the compound described herein, along with an inert diluent or carrier, such as a sugar or sugar alcohol, for example lactose, sucrose, sorbitol, or mannitol. The tablet may further contain a non-sugar-derived diluent (such as sodium carbonate, calcium phosphate, calcium carbonate), or cellulose or its derivatives (such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose) and starch (such as corn starch). The tablet may further contain a binder and granulating agent (such as polyvinylpyrrolidone), a disintegrant (such as a swelling crosslinking polymer, such as crosslinked carboxymethyl cellulose), a lubricant (such as stearate), a preservative (such as parabens), an antioxidant (such as butylated hydroxytoluene), a buffer (such as a phosphate or citrate buffer), and an effervescent agent (such as a citrate / bicarbonate mixture). The tablet may be a coated tablet. The coating may be a protective film coating (such as a wax or varnish) or a coating designed to control the release of the active compound, such as delayed release (releasing the active substance after a predetermined lag time following ingestion) or release at a specific location in the gastrointestinal tract. The latter can, for example, use enteric coating (such as under the brand name) To achieve this (through sales of those).

[0383] Tablet formulations can be prepared by conventional compression, wet granulation, or dry granulation methods, using pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or stabilizers, including but not limited to magnesium stearate, stearic acid, talc, sodium dodecyl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, alginate, gum arabic, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch, and powdered sugar. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetearyl alcohol, polysilicate emulsion wax, sorbitol ester, colloidal silica, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine.

[0384] In the embodiments, the pharmaceutical composition is in the form of hard or soft gelatin capsules. According to this formulation, the compounds disclosed herein can be in solid, semi-solid, or liquid form.

[0385] In the examples, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for parenteral administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrasheath, intralesional, and intracranial injection or infusion techniques.

[0386] In the embodiments, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for administration by direct injection or by addition to a sterile infusion fluid for intravenous infusion, and comprises a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, or one or more vegetable oils. Solutions or suspensions can be prepared in water using a cosolvent or surfactant. Examples of suitable surfactants include polyethylene glycol (PEG) fatty acids and PEG fatty acid monoesters and diesters, PEG glycerides, alcohol-oil transesterification products, polyglycerol fatty acids, propylene glycol fatty acid esters, sterols and sterol derivatives, polyethylene glycol sorbitol fatty acid esters, polyethylene glycol alkyl ethers, sugars and their derivatives, polyethylene glycol alkylphenols, polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, sorbitol fatty acid esters, ionic surfactants, fat-soluble vitamins and their salts, water-soluble vitamins and their amphiphilic derivatives, amino acids and their salts, and organic acids and their esters and anhydrides. The dispersion can also be prepared, for example, in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.

[0387] This disclosure also provides packaging and kits comprising pharmaceutical compositions used in the methods described herein. The kit may comprise one or more containers selected from the group consisting of vials, vials, ampoules, blister packs, and syringes. The kit may further include one or more instructions for use, one or more syringes, one or more applicators, or sterile solutions suitable for reconstituted compounds or compositions described herein.

[0388] Unless otherwise specified, all percentages and ratios used herein are by weight.

[0389] The invention is further described and illustrated by the following non-limiting examples.

[0390] Example

[0391] In the embodiments, the compound of formula (I) or (II) or the sub-examples described herein are inhibitors of ALPK1, such as in an in vitro ALPK1 kinase assay or in an assay designed to measure ALPK1 pathway activation (e.g., NFkB transcriptional activation or IL-8 secretion). Typically, the computer program XL fit is used for data analysis, including nonlinear regression analysis. The half-maximal inhibitory concentration (IC50) is used as a measure of the effectiveness of the compound in the assay. The IC50 value is determined using the following logical equation: Y = min + (max - min) / (1 + (X / IC50)) 50 (^-slope), where Y is the value at compound concentration X. Concentration-response curve fitting was performed using GraphPad Prism version 6.00 software.

[0392] Bioassays and Data

[0393] In the embodiments, the compound of formula (I) or (II) is an inhibitor of ALPK1, as measured, for example, in an in vitro ALPK1 kinase assay, or in an assay designed to indirectly measure ALPK1 kinase activity, such as activation via the ALPK1 pathway through downstream targets in the assay pathway (e.g., NFkB transcriptional activation or IL-8 secretion). Typically, the computer program XL fit is used for data analysis, including nonlinear regression analysis. The half-maximal inhibitory concentration (IC50) is used as a measure of the compound's effectiveness in the assay. The IC50 value is determined using the following logistic equation: Y = min + (max - min) / (1 + (X / IC50^-slope)), where Y is the value at compound concentration X. Concentration-response curve fitting is performed using GraphPad Prism version 6.00 software.

[0394] ALPK1 in vitro kinase assay

[0395] ALPK1 kinase activity was measured in vitro using ADP-heptaose as the ligand and activator of its kinase activity, and TIFA protein as the phosphorylation substrate for ALPK1. Homogeneous time-resolved fluorescence (HTRF) was used to measure protein-protein interactions between HA-labeled TIFA proteins as an indicator of TIFA phosphorylation due to the oligomerization of phosphorylated TIFA proteins.

[0396] In short, cultured in antibiotics (pen / strep, G418) supplemented with 10% fetal bovine serum (FBS, Hyclone) TM HEK293 cells in Dalberg modified Eagle medium (DMEM) were used in a dose-response study in 384-well assay plates. Each well contained 0.1 mg TIFA, ALPK1 (final concentration in the reaction mixture was 2 nM), and kinase buffer (100 mM HEPES pH 7.4, 4 mM DTT, 40 mM MgCl2, 20 mM disodium β-glycerophosphate, 0.4 mM Na3VO4, 0.16 mg / mL). Titration of the test compounds was prepared in dimethyl sulfoxide (DMSO). The reaction was initiated by the addition of ATP and ADP-heptanose.

[0397] For HTRF, refer to the manufacturer's instructions (PerkinElmer). TM CisBio TM The sample was incubated with a Tb-labeled anti-HA antibody to capture HA-labeled proteins, and the fluorescence signal was quantified (TecanInfinite F NANO+). The HTRF signal was calculated as the HTRF ratio (the ratio of fluorescence measured at 665 nm and 620 nm) × 10⁴ (thus using the signal at 620 nm as an internal standard).

[0398] In this assay, all compounds showed a dose-dependent decrease in TIFA phosphorylation. IC50 values ​​were determined using GraphPadPrism version 6.00 with a 3- or 4-parameter logic equation. Reference compound A027 was used as a positive control for each plate. This compound had an IC50 of approximately 50 nanomolars (nM) in this assay. The IC50 values ​​of the tested compounds ranged from 1 to 2000 nM and are shown below. Table 1 (Compound of Formula I) and Table 2 In (compound of formula II).

[0399] NFκB gene reporter alkaline phosphatase assay

[0400] The inhibition of ALPK1-dependent NF-κB reporter gene activation was measured using an alkaline phosphatase reporter assay system. Briefly, HEK293 cells (referred to herein as “G9 cells”) stably expressing the NF-κB reporter gene were maintained in DMEM as described above. For the assay, cells were seeded at a density of 10,000 cells / well in 96-well Freestyle plates. TM Cells were in 293 expression medium (Thermo Fisher Scientific) and allowed to attach overnight. Cells were pretreated with serially diluted compounds for 30 min, followed by stimulation with D-glycero-D-manno-6-fluoro-heptaose-1β-S-ADP. This compound is an analog of ADP-heptaose and exhibits increased in vitro stability and a similar ability to activate ALPK1 kinase activity. NFkB gene activation was detected using the chromogenic substrate p-nitrophenyl phosphate (pNPP) according to the manufacturer's protocol (pNPP phosphatase assay, Beyotime Biotechnology). In this assay, all compounds showed a dose-dependent decrease in NFkB promoter-driven gene expression. IC50 values ​​ranged from 0.5 to 15 μM and are shown in [Figure / Table / Insert Table ... Table 1 (Compound of Formula I) and Table 2 In (compound of formula II).

[0401] Inhibition of activated ALPK1

[0402] Activating mutations in ALPK1 are associated with diseases and conditions such as cancer, spiroadenoma, spirocarcinoma, ROSAH syndrome, and PFAPA syndrome. We conducted further experiments to evaluate the ability of representative compounds to inhibit ALPK1 in the context of two activating mutations, T237M and V1092A. In our preliminary experiments, we determined that IL-8 protein secretion was elevated in cells transiently transfected with human ALPK1 expression vectors containing each of these activating mutations. Therefore, we used IL-8 secretion as an indicator of ALPK1 inhibition in cells expressing these mutations.

[0403] First, in preliminary experiments, we determined that IL-8 secretion was significantly increased in cells transiently expressing either of two activating mutations, T237M or V1092A. HEK293 cells were cultured as described above and then transiently transfected with an empty vector or an expression vector encoding (i) human ALPK1 (hALPK1), (ii) hALPK1 with the T237M activating mutation (hALPK1-T237M), (iii) hALPK1 with the V1092A activating mutation (hALPK1-V1092A), or (iv) a kinase-dead ALPK1 mutant (hALPK1-T237M-D1194S). This was done according to the manufacturer's protocol (Lipofectamine). TM Transfection was performed using 3000 (Thermo Fisher Scientific). Transfected cells were selected and seeded into 96-well plates, treated with serially diluted test compounds for 6.5 hours. After treatment, cell viability was measured using a luminescent cell viability assay (CCL assay or cell counting-Lite assay from Vazyme Biotech Co., Ltd.), and cell-free supernatant was collected and IL-8 protein was analyzed by IL-8 ELISA as described above. Figure 1 The figure shows IL-8 secretion in each test group. As shown, very little IL-8 was detected in cells transfected with any empty vector, hALPK1, or kinase-dead hALPK1 mutant. In contrast, both activating mutations in hALPK1 induced significant IL-8 secretion.

[0404] Next, we tested a group of representative compounds to inhibit IL-8 secretion in cells expressing each of the activated ALPK1 mutants T237M and V1092A. Table 3 This demonstrates the inhibition of IL-8 secretion in cells transfected with T237M. Table 4 The inhibition of IL-8 secretion in cells transfected with the V1092A mutant is shown. For the T237M mutant study, we generated a HEK293 cell line (“A2”) stably expressing the T237M hALPK1 mutant. A2 cells were cultured for a total of 40 hours in the presence of the test compound. Fresh medium and the compound were added at 24 hours. 16 hours after the second addition of the compound, cell viability and IL-8 secretion were measured using the CCL assay and IL-8 ELISA as described above. Table 3 The half-maximal inhibitory concentration (IC50) of IL-8 secretion in A2 cells relative to IL-8 secretion from wild-type HEK293 cells is shown, making knockdown to IL-8 levels from wild-type cells considered as 100% inhibition.

[0405] Table 3The half-maximal inhibitory concentration (IC50) of IL-8 secretion in cells expressing the T237M mutant.

[0406] Compound ID IC50(uM) T007 0.06831 T017 1.474 T019 0.6676 T047 0.6349 T054 0.2254 T060 2.1400 T064 1.6890

[0407] for Table 4 The V1092A mutant study shown was performed by transiently transfecting HEK293 cells with the hALPK1-V1092A or hALPK1 (wild-type) expression vector, followed by treatment with the test compound for 24 hours. Fresh culture medium and the compound were added at 18 hours. Six hours after the second addition of the compound, cell viability and IL-8 secretion were measured using the CCL assay and IL-8 ELISA as described above. Table 4 shows the half-maximal inhibitory concentration (IC50) of IL-8 secretion relative to wild-type HEK293 cells.

[0408] Table 4 The half-maximal inhibitory concentration (IC50) of IL-8 secretion in cells expressing the V1092A mutant.

[0409] Compound ID IC50(uM) T007 0.4093 T017 5.034 T019 3.167 T047 1.806 T054 0.226 T060 5.385

[0410] Treatment efficacy studies in SLE animal models

[0411] The ability of ALPK1 inhibitors to treat systemic lupus erythematosus (SLE) was evaluated using a mouse model of this condition. Female MRL / MpJ-faslpr / J mice were treated with the test compound (T007) for 9 weeks. At approximately 13 weeks of age (day 0 of the study), the female mice were randomly assigned to two treatment groups of 10 mice each and began daily (QD) oral (PO) treatment with either the medium (5% PEG400, 95% methylcellulose [MC]) or the test compound T007 (50 mg / kg). Animals were euthanized at 22 weeks of age for necropsy and tissue collection. Figure 2 As shown, T007 demonstrated a statistically significant beneficial effect on SLE, as determined by assessments of proteinuria, serum anti-dsDNA antibody levels, and renal histopathology. Compared to the untreated (carrier) group, the treated group showed a significant (55%) reduction in urinary protein scores at 21 weeks of age (AUC decreased by 34%, p = 0.100). Figure 3A As shown, renal histopathology (right kidney) indicates that treatment with T007 significantly reduced glomerular diameter (38%), crescent score (62%), and protein cast score (70%). Figure 3B The total renal score (34%) in the treated group is shown compared to the untreated (mediator) group.

[0412] Therapeutic effects of sepsis-induced acute kidney injury animal model

[0413] Multimicrobial sepsis induced by cecal ligation and puncture (CLP) is the most commonly used model because it closely resembles the progression and characteristics of human sepsis. We used this model system to evaluate the role of compound T007 in sepsis. Briefly, the cecum of SD rats was ligated with sterile silk sutures, then punctured twice with a needle, gently squeezed to expel a small amount of feces, and the abdominal incision was closed. The test compound T007 (20 mg / kg) was administered 2 hours prior to surgery. Survival was recorded 24 hours post-surgery, plasma was collected for MCP-1 analysis, and kidneys were collected for gene expression analysis via Q-PCR. Figure 4 The test compound was shown to improve the survival rate of mice. Figure 5 The test compound was shown to inhibit the expression of pro-inflammatory genes in the kidney. Specifically, inhibition of gene expression of IL6, TNFα, IL-1β, CCl2, and KC was observed. Figure 6 The results showed that plasma MCP-1 concentrations, as measured by ELISA, were also improved in the treatment group.

[0414] equivalent

[0415] Those skilled in the art will recognize or be able to identify many equivalents of the specific embodiments of the invention described herein using only conventional experiments. These equivalents are intended to be covered by the following claims.

[0416] All references cited in this article are incorporated herein by reference in their entirety and for all purposes, to the extent that each individual publication or patent or patent application is specifically and individually cited in its entirety for all purposes.

[0417] This invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention will become apparent to those skilled in the art from the foregoing description and drawings, in addition to those described herein. These modifications are intended to fall within the scope of the appended claims.

Claims

1. A compound having the following structure: （I）， in: R 1 For hydrogen, halogen, -CX3, -CHX2, -CH2X, -OCX3, -OCH2X, -OCHX2, -OR 1A Unsubstituted C1-C6 alkyl or unsubstituted C2-C6 alkynyl; R 2 It is hydrogen or halogen; Each R 3 and R 4 It is independently a halogen or an unsubstituted C1-C6 alkyl group; R 5 For -NR 5B R 5C -(CH2) n5 NR 5B R 5C -C(O)NR 5B R 5C -O(CH2) m5 OR 5A C6-C that is either substituted with -COOH or unsubstituted 12 Aryl; R 6 and R 7 For H; or, R 6 For -NR 6B R 6C ;R 5 and R 7 For H; or, R 7 For -NR 7B R 7C ;R 5 and R 6 For H; X can be -F, -Cl, -Br, or -I independently; Each n5 is an independent integer from 1 to 4; Each m5 is an independent integer from 1 to 4; Each R 1A R 5A R 5B and R 5C Independently hydrogen or substituted or unsubstituted C1-C4 alkyl, wherein substitution refers to substitution by -OH or -N(C1-C6 alkyl)2, or, R 5B and R 5C Together with the atoms attached thereto, they are optionally linked to form substituted or unsubstituted 5- to 6-membered heterocyclic alkyl groups or unsubstituted 5- to 6-membered heteroaryl groups; R 6B and R 6C The atoms attached thereto are optionally linked to form an unsubstituted 5- to 6-membered heterocyclic alkyl group; or R 7B and R 7C The atoms attached thereto are optionally linked to form an unsubstituted 5- or 6-membered heterocyclic alkyl group; wherein the substitution refers to substitution by C1-C6 alkyl, -OH, -NH2, -C(O)NH2, oxo, -C(O)O-(C1-C6 alkyl), -N(C1-C6 alkyl)2, OH-substituted C1-C6 alkyl, or phenyl-substituted C1-C6 alkyl, or two or more substituents are optionally linked to form a heterocyclic alkyl group; wherein the phenyl group in the "phenyl-substituted C1-C6 alkyl group" is optionally further substituted with F; Or its salt.

2. The compound according to claim 1, wherein: R 6 and R 7 It is hydrogen; and, R 5B and R 5C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

3. The compound according to claim 2, having the following structure: (I-A), in: L 1 For bonds, -C(O)- or -(CH2) n5 ; R 9 It is hydrogen, -(CH2) m OH, -(CH2) m (C6H5) or unsubstituted C1-C6 alkyl; Each R 10.1 R 10.2 R 10.3 and R 10.4 Independently hydrogen, -OR 10A -C(O)OR 10A -NR 10B R 10C -(CH2) m OH or unsubstituted C1-C6 alkyl, or R 10.1 R 10.2 R 10.3 and R 10.4 One or more of them are optionally connected to each other or to atoms of the piperazine ring to form an unsubstituted heterocyclic alkyl group; Each m is an independent integer from 1 to 4; and, Each R 10A R 10B and R 10C It is independently hydrogen or an unsubstituted C1-C4 alkyl group.

4. The compound according to claim 3, wherein: L 1 For bonds, -C(O)-, methylene or ethylene; and, R 9 It is hydrogen or an unsubstituted C1-C4 alkyl group.

5. The compound according to claim 3, wherein: L 1 As the key; and, R 9 For hydrogen, methyl, ethyl, propyl, or .

6. The compound according to claim 5, each R 10.1 R 10.2 R 10.3 and R 10.4 It is independently hydrogen, oxo- or unsubstituted C1-C4 alkyl, -C(O)OH or -CH2OH.

7. The compound according to claim 3, having the following structure: (I-A-1)。 8. The compound according to claim 7, wherein R 1 It can be hydrogen, halogen, unsubstituted C1-C4 alkyl, unsubstituted C2-C6 ynyl, -OCX3, -OCH2X, -OCHX2 or -OR 1A And R 1A It is hydrogen or an unsubstituted C1-C4 alkyl group.

9. The compound according to claim 8, wherein R 1 For hydrogen, methyl, ethyl, , , -OH, -OCH3, -OCHF2, -OCH2F, -OCF3, -F, -Cl or -Br.

10. The compound according to claim 9, wherein R 2 It can be hydrogen, -F, -Cl, or -Br.

11. The compound according to claim 7, wherein the compound is: , , , , , , , , , , , , , , , , , , , or .

12. The compound according to claim 7, having the following structure: (I-A-1a)。 13. The compound according to claim 12, each R 3 and R 4 It can be -F, -Cl, -Br or methyl independently.

14. The compound according to claim 12, wherein the compound is: , or .

15. The compound according to claim 3, wherein R 5 for .

16. The compound according to claim 1, having the following structure: (I-B), in: L 1 For key; R 9 R 10.1 R 10.2 R 10.3 and R 10.4 It is hydrogen.

17. The compound according to claim 1, having the following structure: (I-C), in: k is 1 or 2; Each R 10.1 R 10.2 and R 10.3 Independently hydrogen, -OR 10A -C(O)OR 10A or -NR 10B R 10C ; Each R 10A R 10B and R 10C It is independently hydrogen or an unsubstituted C1-C6 alkyl group.

18. The compound of claim 17, wherein each R 10.1 R 10.2 and R 10.3 It can be hydrogen, -C(O)OH, -C(O)OCH3, -NH2 or -OH independently.

19. The compound according to claim 18, wherein R 10.1 Independently, it is hydrogen, -C(O)OH, -C(O)OCH3, -NH2, or -OH, and R 10.2 and R 10.3 It is hydrogen.

20. The compound according to claim 1, having the following structure: (I-D)。 21. The compound according to claim 1, wherein: R 6 and R 7 It is hydrogen. R 5 -O(CH2) m OH, -NHR 5C , morpholino, pyridinyl or phenyl substituted with -COOH or unsubstituted; R 5C -(CH2) m OH and -(CH2) m N(CH3)2; and, Each m is an independent integer from 1 to 4.

22. The compound according to claim 21, wherein: R 5 for , , , , , , or .

23. The compound according to any one of claims 2 to 22, wherein R 1 It can be hydrogen, halogen, unsubstituted C1-C4 alkyl, -OCX3, -OCH2X, -OCHX2 or -OR 1A And R 1A It is hydrogen or an unsubstituted C1-C4 alkyl group.

24. The compound according to claim 23, wherein R 1 For hydrogen, methyl, ethyl, , , -OH, -OCH3, -OCHF2, -OCH2F, -OCF3, -F, -Cl or -Br.

25. The compound according to claim 24, wherein R 1 It is -OCH3.

26. The compound according to claim 22, wherein R 1 It can be -OCH3 or -Br.

27. The compound of claim 26, wherein each R 3 and R 4 It is independently a halogen or an unsubstituted C1-C4 alkyl group.

28. The compound of claim 27, wherein each R 3 and R 4 It can be -F, -Cl, or methyl independently.

29. The compound according to claim 1, wherein the compound is selected from any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

30. The compound according to claim 1, wherein the compound is: , , or .

31. A compound having the following structure: (II), in: W is CR 18 Or N; R 11 is - OR 11A ; Each R 12 R 13 and R 14 Independent of hydrogen, halogen, -OR 12A Or unsubstituted C1-C6 alkyl groups; R 15 For -NR 15B R 15C Or -(CH2) n15 NR 15B R 15C ;R 16 and R 17 For H; or, R 16 For -NR 16B R 16C Or -(CH2) n16 NR 16B R 16C ;R 15 and R 17 For H; or, R 17 For -NR 17B R 17C Or -(CH2) n17 NR 17B R 17C ;R 15 and R 16 For H; R 18 It is hydrogen or an unsubstituted C1-C6 alkyl group; Each n15, n16, and n17 is an independent integer from 1 to 4; Each R 11A and R 12A Independently, it is an unsubstituted C1-C4 alkyl group; R 15B and R 15C Together with the atoms attached thereto, they are optionally linked to form substituted or unsubstituted 5- or 6-membered heterocyclic alkyl groups; R 16B and R 16C The atoms attached thereto are optionally linked to form an unsubstituted 5- to 6-membered heterocyclic alkyl group; or R 17B and R 17C The atoms attached thereto are optionally linked to form an unsubstituted 5- or 6-membered heterocyclic alkyl group; the substitution refers to substitution with -OH or C1-C6 alkyl groups; Or its salt.

32. The compound according to claim 31, wherein: R 16 and R 17 It is hydrogen; and, R 15B and R 15C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

33. The compound according to claim 32, having the following structure: (II-A) or (II-B), in: L 11 For bond or -(CH2) n15 ; R 19 It is hydrogen or an unsubstituted C1-C6 alkyl group; Each R 20.1 R 20.2 R 20.3 and R 20.4 It is hydrogen independently.

34. The compound according to claim 31, wherein: R 15 and R 17 It is hydrogen; and, R 16B and R 16C Together with the atoms attached thereto, they form substituted or unsubstituted piperazine groups.

35. The compound according to claim 32, having the following structure: (II-C), or (II-D) in: L 11 For bond, -(CH2) n16 ; R 19 It is hydrogen or an unsubstituted C1-C6 alkyl group; Each R 20.1 R 20.2 R 20.3 and R 20.4 It is hydrogen independently.

36. The compound according to any one of claims 33 and 35, wherein: L 11 For bond or methylene; and, R 19 It is hydrogen or an unsubstituted C1-C4 alkyl group.

37. The compound according to claim 31, having the following structure: (II-E), or (II-F), in: k' is 2; Each R 20.1 R 20.2 and R 20.3 Independently hydrogen or -OR 20A ; R 20A It is hydrogen.

38. The compound according to claim 37, wherein R 20.1 Independently -OH, and R 20.2 and R 20.3 It is hydrogen.

39. The compound according to claim 31, wherein R 11 It is -OCH3.

40. The compound according to claim 39, wherein R 12 For hydrogen, halogen or -OR 12A And R 12A It is an unsubstituted C1-C4 alkyl group.

41. The compound according to claim 40, wherein R 12 It can be hydrogen, -OCH3, or halogen.

42. The compound of claim 40, wherein each R 13 and R 14 It is independently hydrogen, halogen, or an unsubstituted C1-C4 alkyl group.

43. The compound according to claim 42, wherein R 13 and R 14 It is -F.

44. The compound according to claim 43, wherein R 18 It can be hydrogen or methyl.

45. The compound of claim 31, wherein the compound is selected from any of the following compounds: , , , , , , , and .

46. ​​The compound according to claim 31, wherein the compound is: 。 47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 and a pharmaceutically acceptable carrier or excipient.

48. Use of a compound according to any one of claims 1 to 46 in the preparation of a medicament for inhibiting ALPK1 kinase activity in the cells or tissues of a subject requiring such therapy.

49. Use of a compound according to any one of claims 1 to 46 in the preparation of a medicament for inhibiting or reducing inflammation in target tissues of a subject requiring such treatment.

50. Use of a compound according to any one of claims 1 to 46 in the preparation of a medicament for treating, in a subject requiring such therapy, a disease, condition or symptom characterized by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling.

51. The application according to claim 50, wherein the disease, condition or symptom is selected from systemic lupus erythematosus (SLE), sepsis, cancer, spiroadenoma, "retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine" ("ROSAH") syndrome and "periodic fever, aphthous stomatitis, pharyngitis and adenitis" ("PFAPA") syndrome.

52. The application according to claim 51, wherein the cancer is selected from lung cancer, adenocarcinoma, colon cancer, and oral squamous cell carcinoma.

53. The application according to claim 51, wherein the disease or condition is ROSAH.

54. The application according to claim 51, wherein the disease or condition is PFAPA.

55. The application according to claim 50, wherein the disease or condition is a sweat gland adenoma or spirochete carcinoma.

56. The application according to claim 51, wherein the disease or condition is systemic lupus erythematosus (SLE).

57. The application according to claim 51, wherein the disease or symptom is sepsis.

58. The application of claim 50, wherein the subject requiring such therapy is a subject carrying one or more gene mutations in ALPK1.

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