Alpha protein kinase 1 inhibitors and methods of use

Abstract

Provided are compounds of Formula 1, compositions, and methods of use thereof as inhibitors of alpha-kinase 1 (ALPK1).

Description

Technical Field

[0001] This invention relates to compounds that are inhibitors of α-protein kinase 1 (ALPK1), as well as related compositions and methods. Background Technology

[0002] α-kinases show little sequence similarity to conventional protein kinases. A total of six α-kinase members were 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 the innate immune response to bacteria via TRAF-interacting protein-fork-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 has been involved in diseases and conditions associated with excessive or inappropriate inflammation. For example, ALPK1 has been involved in monosodium urate monohydrate (MSU)-induced inflammation and gout. Lee et al., Sci. Rep. 6:25740-25740 (2016). In oral squamous cell carcinoma, elevated ALPK1 expression 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 genes have been associated with spiral adenoma, spiral adenocarcinoma, 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 formula I as inhibitors of ALPK1 kinase activity, sub-examples of formula I described herein, and related compositions and methods.

[0006] In some respects, this article provides compounds of formula I.

[0007]

[0008] Where A, p, R 1 R 2 R 3 R 4 and R 5 As defined in this article

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

[0010]

[0011] Where p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined in this article.

[0012] In some embodiments, compounds of formula I are represented by formula IA-1.

[0013]

[0014] Where p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined in this article.

[0015] In some embodiments, the compound of formula I is represented by formula IB.

[0016]

[0017] Where p, R 2 R 3 R 4 R 5 R 13 D, E, F, and G are as defined herein. In some embodiments, compounds of formula I are represented by formula IB-1.

[0018]

[0019] Where p, R 2 R 3 R 4 R 5 R 15 R 16 and R 17 As defined herein. In some embodiments, compounds of formula I are represented by formula IC.

[0020]

[0021] Where p, m, R 2 R 3 R 4 R 5 R 18 As defined in this article.

[0022] In some respects, this article provides compounds of formula XI.

[0023]

[0024] Where X, A, p, R 1 R 2 R 3 R 4 and R 5 As defined herein. In some embodiments, compounds of formula I are represented by formula XI-A.

[0025]

[0026] Where X, p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined herein. In some embodiments, compounds of formula I are represented by formula XI-A-1.

[0027]

[0028] Where X, p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined herein. In some embodiments, compounds of formula I are represented by formula XI-A-1-a.

[0029]

[0030] Where p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined in this article.

[0031] In some embodiments, compounds of formula I are represented by formula XI-B.

[0032]

[0033] Where X, p, R 2 R 3 R 4 R 5 R 13 D, E, F, and G are as defined herein. In some embodiments, compounds of formula I are represented by formula XI-B-1.

[0034]

[0035] Where X, p, R 2 R 3 R 4 R 5 R 15 R 16 and R 17As defined in this article.

[0036] In some embodiments, the compound of formula I is represented by formula XI-B-1-a.

[0037]

[0038] Where p, R 2 R 3 R 4 R 5 R 15 R 16 and R 17 As defined in this article.

[0039] In some embodiments, compounds of formula I are represented by formula XI-C.

[0040]

[0041] Where X, p, m, R 2 R 3 R 4 R 5 R 18 As defined in this article.

[0042] In some embodiments, compounds of formula XI are represented by formula XI-C-1.

[0043]

[0044] Where p, m, R 2 R 3 R 4 R 5 R 18 As defined in this article.

[0045] In the embodiments, this disclosure provides pharmaceutical compositions comprising compounds of formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or as described herein in the sub-examples thereof.

[0046] In embodiments, this disclosure provides a method for inhibiting ALPK1 kinase activity in the cells or tissues of a subject in need of such therapy, the method comprising administering to the subject a compound of formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a sub-example thereof as described herein.

[0047] 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, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a sub-example thereof as described herein.

[0048] 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, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a sub-example thereof as described herein.

[0049] In the embodiments, the disease, condition, or symptom is selected from sepsis, cancer, spiroadenoma, spiroadenocarcinoma, "Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine" ("ROSAH") syndrome and "Periodic fever, aphthous stomatitis, pharyngitis and adenitis" ("PFAPA") syndrome.

[0050] In the embodiments, the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma.

[0051] In the embodiments, the disease or condition is selected from ROSAH and PFAPA.

[0052] In this embodiment, the disease or condition is sepsis.

[0053] In the embodiments, the disease or condition is a spiral adenoma or spiral adenocarcinoma.

[0054] 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 activating mutation. Attached Figure Description

[0055] 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, V1092A), or an activating mutation combined with a kinase death mutation in ALPK1 (hALPK1-T237M-D1194S).

[0056] Figure 2 Two hours prior to the agonist D-glycero-D-manno-6-fluoro-heptaose-1β-S-ADP, the treatment group was administered the ALPK1 inhibitor A0176 at doses of 4, 10, or 25 mg / kg. Three hours after agonist administration, renal tissue was examined for inhibition of gene expression in innate immune genes, including MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6 mRNA. A0176 showed dose-dependent inhibition of gene expression levels. Two-way ANOVA showed **p<0.01, ***p<0.001 relative to the medium – oral + A0176 – intraperitoneal – 3 hours.

[0057] Figure 3 In an animal model of sepsis-induced acute kidney injury, compounds C008 and A0176 (20 mg / kg) were administered to the treatment group of animals 2 hours before surgery. Survival rates were recorded over the following 24 hours. Both compounds improved animal survival rates.

[0058] Figure 4 In an animal model of sepsis-induced acute kidney injury, compounds C008 and A0176 (20 mg / kg) were administered to the treatment group of animals 2 hours before surgery. Kidneys were collected 24 hours post-surgery for gene expression analysis by Q-PCR. Data showed that the ALPK1 inhibitor reduced the expression of pro-inflammatory genes in the kidneys, including IL6, TNFα, IL-1β, CCl2, and keratinocyte chemoattractant (KC) chemokines. *p<0.05, **p<0.01, p<0.001, relative to CLP-mediated...

[0059] Figure 5 In an animal model of sepsis-induced acute kidney injury, compounds C008 and A0176 (20 mg / kg) were administered to the treatment group 2 hours before surgery. Plasma MCP-1 concentrations were measured by ELISA 24 hours post-surgery. ALPK1 inhibitors increased plasma MCP-1 levels. ***One-way ANOVA*** p < 0.001 relative to CLP mediators Detailed Implementation

[0060] This disclosure provides compounds as ALPK1 inhibitors, compositions comprising the compounds, and methods of using them in therapy.

[0061] 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 the alternative splice variant isotype 2 (Q96QP1-2).

[0062] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic radical having the indicated number of carbon atoms. Alkyl groups can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6, and C5-6. For example, C1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl groups can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0063] 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, etc. 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 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 1 double bond. The alkenyl group can be substituted or unsubstituted.

[0064] 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, etc. 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 5-6And 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.

[0065] As used herein, the term "alkylene" refers to a straight-chain or branched saturated aliphatic radical having the indicated number of carbon atoms and being attached to at least two other groups, i.e., a divalent hydrocarbon radical. 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 radical 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. The alkylene group can be substituted or unsubstituted. In some embodiments, the alkylene group is substituted by one or two substituents. As non-limiting examples, suitable substituents include halogens and hydroxyl groups.

[0066] As used herein, the term "alkoxy" or "alkoxyl" refers to an alkyl group having an alkyl group attached to an oxygen atom at the attachment point: alkyl-O-. As for the alkyl group, the alkoxy group 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.

[0067] As used herein, the term "alkenyloxy" or "alkenyloxyl" refers to an alkenyl group as defined above, having an oxygen atom connecting the alkenyl group to the attachment point: alkenyl-O-. The alkenyloxy group may have any suitable number of carbon atoms, such as C1 to C6. The alkenyloxy group may be further substituted by the various substituents described herein. The alkenyloxy group may be substituted or unsubstituted.

[0068] "Aminoalkyl" means a straight-chain monovalent hydrocarbon radical with 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical with 3 to 6 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.

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

[0070] As used herein, the term "haloalkyl" refers to an alkyl group as defined above, in which some or all of its hydrogen atoms are replaced by halogen atoms. As for the alkyl group, the haloalkyl group can have any suitable number of carbon atoms, such as C2. 1-6 For example, alkyl halides include trifluoromethyl, fluoromethyl, 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 The alkoxy group can be replaced by one, two, three or more halogens.

[0072] As used herein, the term “deuterated alkyl” refers to an alkyl radical as defined above, wherein 1 to 6 hydrogen atoms in the alkyl radical are replaced by deuterium, such as -CH2D, -CHD2, -CD3, -CH2CD3, etc.

[0073] As used herein, the term "hydroxyalkyl" refers to an alkyl radical in which at least one of the hydrogen atoms of the alkyl radical is replaced by an OH group. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 4-hydroxy-butyl.

[0074] As used in this article, the term "oxo" refers to an oxygen atom attached to the attachment site via a double bond (=O).

[0075] 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 may 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 may be monocyclic, may fused to form bicyclic or tricyclic groups, or may be linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linker. 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 may be substituted or unsubstituted.

[0076] As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic aromatic ring combination containing 5 to 12 ring atoms, wherein 1 to 5 ring atoms are heteroatoms, such as N, O, or S. Additional heteroatoms can also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can 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 can 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 may 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 may 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 may 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.

[0077] As used herein, “cycloalkyl” refers to a saturated ring combination containing 3 to 10 ring atoms or the number of atoms shown. Cycloalkyl groups can include any number of carbons, such as C64. 3-6 C 4-6 C 5-6 C 3-8 C 4-8 C 5-8 C 6-8 When an unsaturated cycloalkyl ring can have one or two double bonds, the cycloalkyl ring can be saturated or unsaturated. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. The cycloalkyl group can be substituted or unsubstituted.

[0078] As used herein, the term "heterocyclic group" or "heterocyclic" refers to a saturated or partially saturated heterocyclic group that is monocyclic or polycyclic; it has 3 to 16, most preferably 5 to 10, and most preferably 1 or 4 ring atoms; wherein one or more, preferably 1 to 4, and especially 1 or 2 ring atoms are heteroatoms selected from oxygen, nitrogen, and sulfur (and thus the remaining ring atoms are carbon). The term heterocyclic group excludes heteroaryl groups. Heterocyclic groups can be attached to the rest 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, oxothiocyclopentane, dithiopentane, oxothiocyclohexane, thiomorpholino, ethylene oxide, acridineyl, oxocyclobutane, oxocycloheptane, aziridine, tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidine, tetrahydropyranyl, piperidinyl, morpholino, piperazine, aziridine, oxazatriol, oxazatriol, oxothiocyclohexane, thiocycloheptane, aziridine, dioxaneheptane, and diaziridineheptane.

[0079] 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” may 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.

[0080] As used in this article, "bridged heterocyclic base" 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.

[0081] 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" ring 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, benzimidazolyl, benziisoazolyl, benzofuranyl, benzopyranyl, benzothiaranyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzozolyl, chromanyl, cenylyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiaphenyl, dihydrobenzothiaranyl, dihydrobenzothiaranyl sulfone, dihydroindolyl, indolyl, isochromyl, isodihydroindolyl, isoquinolinyl, isothiazolyl, naphthidyl, pyrazolopyridyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl.

[0082] As used herein, "saturated or unsaturated" refers to a cyclic system in which two atoms in a group are bonded to each other by a single, double, or triple bond. A saturated portion is one that has only single bonds, while a portion having multiple bonds (e.g., at least one double bond or at least one triple bond) is called unsaturated.

[0083] 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, a complex group cycloalkoxy means that a cycloalkyl group is attached to the parent molecule via an oxygen group.

[0084] 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 the present invention 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, glucamine, histidine, hepatoside, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in 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, as well as salts of relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. 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). Some specific compounds of the present invention contain basic and acidic functional groups, which allow the compounds to be converted into basic addition salts or acid addition salts.

[0085] 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, the salt is otherwise equivalent to the parent form of the compound.

[0086] Some compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be covered within the scope of the present invention. In some embodiments, the compounds of the present invention are specific enantiomers, terminal isomers, or diastereomers that are substantially free of other isomers for mass spectrometry.

[0087] As used herein, the term “substantially free” means 10% or less of another isomer, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less of another form. In some embodiments, the isomer is a stereoisomer.

[0088] Detailed description of the embodiments

[0089] This disclosure provides compounds represented by formula (I) and pharmaceutically acceptable salts thereof:

[0090] This invention discloses a novel heterocyclic compound as an ALPK1 inhibitor. The compound is represented by Formula I.

[0091]

[0092] Where A, p, R 1 R 2 R 3 R 4 and R 5 As defined in this article:

[0093] A is selected from bonds, azacyclic butyl groups, -O-, -N(R) 6 )-、–CH2–N(R 6 )-、-CHR 9 -N(R 6 )-,in

[0094] R 6 Selected from H, D, and -OH, optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 haloalkyl, optionally substituted C1 to C6 alkenyl, optionally substituted C1 to C6 hydroxyalkyl, optionally substituted C1 to C6 aminoalkyl, optionally substituted C1 to C6 alkoxy, optionally substituted saturated or unsaturated C3 to C6 cycloalkyl, and optionally substituted saturated or unsaturated C3 to C6 cycloalkoxy, wherein

[0095] Optional replacement of R 6The portion contains 0 to 3 substituents, which are independently selected from -D, halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 hydroxy-deuterylalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy;

[0096] R 9 Selected from optionally substituted C1 to C6 alkyl groups, C1 to C6 haloalkyl groups, optionally substituted saturated or unsaturated C3 to C6 cycloalkyl groups, and optionally substituted saturated or unsaturated C3 to C6 cycloalkoxy groups, wherein

[0097] Optional replacement of R 9 The portion contains 0 to 2 substituents, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7f R 8f -OR 7f -OC(O)(R 7f ), -C(O)(R 7f -C(O)N(R) 7f R 8f -C(O)O(R) 7f -S(O)2(R) 7f -S(O)ON(R) 7f R 8f ) and -N(R 7f R 8f ),in

[0098] Each R 7f and R 8f It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0099] R 1Selected from H, optionally substituted C1 to C6 alkyl, optionally substituted C1 to C6 alkenyl, optionally substituted C1 to C6 hydroxyalkyl, optionally substituted C1 to C6 hydroxydeuteryl, optionally substituted C1 to C6 haloalkyl, optionally substituted C1 to C6 haloalkoxy, optionally substituted C1 to C6 aminoalkyl, optionally substituted C1 to C6 alkoxy, optionally substituted saturated or unsaturated C3 to C6 cycloalkyl, optionally substituted saturated or unsaturated C3 to C6 cycloalkoxy, optionally substituted monocyclic or bicyclic aryl, containing 1 to 4 atoms selected from N, O 5- to 10-membered heteroaryl groups with optional substitution of heteroatom ring vertices of S; saturated or unsaturated 3- to 7-membered heterocyclic groups with optional substitution of 1 to 2 heteroatom ring vertices selected from N, O, and S; saturated or unsaturated 7- to 8-membered bridged heterocyclic groups with optional substitution of 1 to 2 heteroatom ring vertices selected from N, O, and S; saturated or unsaturated 7- to 11-membered spirocyclic groups with optional substitution of 1 to 2 heteroatom ring vertices selected from N, O, and S; and saturated or unsaturated 6- to 11-membered bicyclic heterocyclic groups with optional substitution of 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0100] R, which can be arbitrarily replaced 1 The portion contains 0 to 4 substituents, which are independently selected from -D, halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 hydroxydeuterylalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -R 7a -X 1 -R 7a CHR 7a R 8a -OR 7a -OX 1 -R 7a -X 1 -OX 1 -R 7a -OC(O)(R 7a ), -OX 1 -C(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -NR 7a (CO)R 8a -C(O)O(R) 7a ), S(O)2R 7a -S(O)2N(R) 7a R 8a ), -N(R 7a R8a ), saturated or unsaturated C3 to C6 cycloalkyl groups, saturated or unsaturated C3 to C6 cycloalkoxy groups, saturated or unsaturated 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, monocyclic or bicyclic aryl groups, 5 to 10-membered heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 11-membered spirocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and 6 to 11-membered bicyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; wherein

[0101] Each X 1 C is independent 1-6 Alkylene;

[0102] Each R 7a and R 8a Independently selected from H, C1 to C6 alkyl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, aryl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, containing 1 to 2 A saturated or unsaturated 3- to 7-membered heterocyclic group selected from the apex of a heteroatomic ring of N, O, and S, wherein the aryl and 3- to 7-membered heterocyclic groups are substituted by 0 to 3 substituents selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; and

[0103] C3 to C6 cycloalkyl, C3 to C6 cycloalkoxy, 3 to 7-membered heterocyclic, monocyclic or bicyclic aryl, 5 to 10-membered heteroaryl, saturated or unsaturated 7 to 8-membered bridged heterocyclic, saturated or unsaturated 7 to 11-membered spirocyclic, and 6 to 11-membered bicyclic heterocyclic are each independently substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, saturated or unsaturated 3 to 7-membered heterocyclic containing 1 to 2 heteroatom ring vertices selected from N, O, and S, -CHR7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -NR 7b (CO)R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0104] Each R 7b and R 8b Independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; or

[0105] R 1 and R 6 Combined to form a 3- to 6-membered heterocyclic alkyl group substituted with 0 to 3 moieties, each moiety being independently selected from the group consisting of: halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy;

[0106] R 5 Selected from H, deuterium, halogens, C1 to C6 alkyl, C1 to C6 deuterated alkyl and C1 to C6 haloalkyl;

[0107] R 2 and R 3 Each of the following is independently selected from H, OH, C1 to C6 alkyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, and monocyclic or bicyclic aryl, wherein each of the C1 to C6 alkyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl, and monocyclic or bicyclic aryl is substituted by 0 to 3 moieties, which are independently selected from halogen, -OH, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -OC(O)(R 7c ), -C(O)(R 7c ), C(O)O(R) 7c ), S(O)2N(R 7c R8c ) and N(R 7c R 8c ),in

[0108] Each R 7c and R 8c It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0109] The condition is R 2 and R 3 Not all are H; or

[0110] R 2 and R 3 Combined to form a C3 to C6 cycloalkyl ring or a 3 to 7-membered heterocyclic group containing one to two heteroatom ring vertices independently selected from N, O, and S, wherein the formed ring may optionally be substituted by one to two substituents independently selected from C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, halogen, -OH, =O, -CN, OC(O)(R 7d ), -C(O)(R 7d ), C(O)O(R) 7d ), S(O)2N(R 7d R 8d ) and N(R 7d R 8d ),in

[0111] Each R 7d and R 8d It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0112] Each R 4 Independently selected from halogens, -OH, -NH2, CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, CHR 7e R 8e OR 7e OC(O)(R) 7e ), C(O)(R 7e), C(O)N(R 7e R 8e ), C(O)O(R) 7e ), S(O)2N(R 7e R 8e ) and N(R 7e R 8e ),in

[0113] Each R 7e and R 8e Independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, and

[0114] The subscript p is 0, 1, 2 or 3.

[0115] In some embodiments, A in Formula I is a bond.

[0116] In some embodiments, A in Formula I is a nitrogen-containing heterocyclic butyl group.

[0117] In some embodiments, A in Formula I is -O-.

[0118] In some embodiments, A in equation I is -N(R) 6 )-.

[0119] In some embodiments, A in Formula I is –CH2–N(R) 6 )-.

[0120] In some embodiments, A in Formula I is -CHR 9 -N(R 6 )-.

[0121] In some embodiments, the compound of formula I is represented by a compound of formula IA, IA-1, IA-2 and / or its stereoisomers, stable isotopes or pharmaceutically acceptable salts.

[0122]

[0123]

[0124] Where p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined above.

[0125] In some embodiments, R in formula I, IA, IA-1 or IA-2 6 It is H, C1 to C6 alkyl or C1 to C6 hydroxyalkyl.

[0126] In some embodiments, R in Formulas I and 1A 9 It is CH3 or CH2OH.

[0127] In some embodiments, R in formulas I and IA 9 It is a saturated C3 to C6 cycloalkyl group.

[0128] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 Selected from H and optionally substituted C1 to C6 alkyl groups, wherein

[0129] The optionally substituted C1 to C6 alkyl groups comprise 0 to 4 substituents, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7a R 8a -OR 7a -OC(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -C(O)O(R) 7a -S(O)2R 7a -S(O)2N(R) 7a R 8a ) and -N(R 7a R 8a ),in

[0130] Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0131] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 Optionally substituted saturated or unsaturated C3 to C6 cycloalkyl groups, wherein

[0132] The optionally substituted C3 to C6 cycloalkyl groups comprise 0 to 4 substituents, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 alkoxy, and C1 to C6 haloalkoxy.

[0133] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 With R 6 Combined to form a 3- to 6-membered heterocyclic alkyl group substituted with 0 to 3 moieties, each moiety being independently selected from the group consisting of: halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy.

[0134] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 It is a C1 to C6 alkyl group substituted with 0 to 4 substituents, which are independently selected from -OH, C1 to C6 hydroxyalkyl, C1 to C6 alkoxy, -OC(O)(R 7a -S(O)2N(R) 7a R 8a ) and -N(R 7a R 8a ),in

[0135] Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0136] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 It is a C1 to C6 alkyl group substituted with 0 to 2 substituents, which are independently selected from -OH, C1 to C6 hydroxyalkyl and -S(O)2N(R) 7a R 8a ),in

[0137] Each R 7a and R 8a Independently selected from H and C1 to C6 alkyl groups.

[0138] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 The C1 to C6 hydroxyalkyl group may be optionally substituted.

[0139] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 It consists of 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S.

[0140] The 5- to 10-membered bicyclic heteroaryl group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, 3- to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0141] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0142] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 The pyridyl group is substituted with 0 to 3 moieties, wherein the 0 to 3 moieties are selected from halogens, -OH, -COOH, -NH2, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, or 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0143] The 3 to 7-membered heterocyclic group is substituted by 0 to 3 substituents selected from halogens, -OH, -COOH, -NH2, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, and C1 to C6 haloalkyl.

[0144] In some embodiments, R in formula I, IA, IA-1 or IA-2 1It is a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein

[0145] The 7- to 8-membered bridged heterocyclic group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0146] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0147] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 It is a saturated or unsaturated 7- to 11-membered spiroheterocyclic group containing one to two heteroatom ring vertices selected from N, O, and S, wherein

[0148] The 7- to 11-membered spiroheterocyclic group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R)7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0149] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0150] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 The aryl group is substituted with 0 to 3 substituents, wherein the 0 to 3 substituents are selected from halogens, 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and saturated or unsaturated 7 to 11-membered spirocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein

[0151] The 3- to 7-membered heterocyclic group, the 7- to 8-membered bridged heterocyclic group, and the 7- to 11-membered spiroheterocyclic group are substituted by 0 to 3 moieties, which are selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2R 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0152] Each R 7b and R 8bIndependently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy.

[0153] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 The aryl group is substituted with 0 to 3 moieties, which are selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, and 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0154] The 3- to 7-membered heterocyclic group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0155] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0156] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 The aryl group is substituted with 0 to 3 moieties selected from halogens and 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0157] The 3 to 7-membered heterocyclic group is further substituted by 0 to 3 moieties selected from -OH, -COOH, -NH2, =O, -CN and -C1 to C6 alkyl groups.

[0158] In some embodiments, a compound of formula I is represented by a compound of formula IB and / or its stereoisomers, stable isotopes, or pharmaceutically acceptable salts.

[0159]

[0160] Where p, R 2 R 3 R 4 and R 5 As defined above; and

[0161] D is CR 10 Or N;

[0162] E is CR 14 Or N;

[0163] F is CR 12 Or N;

[0164] G is CR 11 Or N;

[0165] The condition is that no more than three of D, E, F, and G are N;

[0166] R 10 R 11 R 12 R 13 and R 14 When present, each is independently selected from H, halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -R 7a -X 1 -R 7a X 1 -OX 1 -R 7a -CHR 7a R 8a -OR 7a -OX 1 -R 7a -OC(O)(R 7a ), -OX 1 -C(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a-C(O)O(R) 7a ), S(O)2R 7a -S(O)2N(R) 7a R 8a ), -N(R 7a R 8a ), saturated or unsaturated C3 to C6 cycloalkyl groups, saturated or unsaturated C3 to C6 cycloalkoxy groups, saturated or unsaturated 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, monocyclic or bicyclic aryl groups, 9 to 10-membered bicyclic heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and saturated or unsaturated 7 to 11-membered spirocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and 6 to 11-membered bicyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; wherein

[0167] Each X 1 C is independent 1-6 Alkylene;

[0168] Each R 7a and R 8a Independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; and

[0169] The 3- to 7-membered heterocyclic group, the monocyclic or bicyclic aryl group, the 9- to 10-membered bicyclic heteroaryl group, the 7- to 8-membered bridged heterocyclic group, the 7- to 11-membered spirocyclic group, and the 6- to 11-membered bicyclic heterocyclic group are each independently substituted by 0 to 2 moieties, wherein the 0 to 2 moieties are selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7g R 8g -OR 7g -OC(O)(R 7g ), -C(O)(R 7g -C(O)N(R) 7g R 8g -NR 7g (CO)R 8g -C(O)O(R) 7g -S(O)2N(R) 7g R 8g) and -N(R 7g R 8g ),in

[0170] Each R 7g and R 8g Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0171] In some embodiments, D, E, F, and G in formula IB represent CR... 10 CR 14 CR 12 and CR 11 .

[0172] In some embodiments, F and G in formula IB are respectively CR 14 and CR 11 E is N or CR 14 And D is N or CR 10 .

[0173] In some embodiments, R in formula IB 10 and R 11 Each is H, R 12 and R 14 Each is independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; R13 It is a 3- to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; or a saturated or unsaturated 7- to 11-membered spirocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein the 3- to 7-membered heterocyclic group, the 7- to 8-membered bridged heterocyclic group, and the 7- to 11-membered spirocyclic group are optionally substituted by 0 to 2 moieties, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, or saturated or unsaturated C3 to C6 cycloalkoxy.

[0174] In some embodiments, R in formula IB 12 and R 14 For H, R 10 and R 11 Each is independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; R 13It is a 3- to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; or a saturated or unsaturated 7- to 11-membered spirocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein the 3- to 7-membered heterocyclic group, the 7- to 8-membered bridged heterocyclic group, and the 7- to 11-membered spirocyclic group are optionally substituted by 0 to 2 moieties, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, or saturated or unsaturated C3 to C6 cycloalkoxy.

[0175] In some embodiments, R in formula IB 10 R 11 R 12 and R 14 Both are H; R 13 It is a saturated or unsaturated C3 to C6 cycloalkyl group, a 3 to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, a saturated or unsaturated 7 to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, or a saturated or unsaturated 7 to 11-membered spirocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, wherein the 3 to 7-membered heterocyclic group, the 7 to 8-membered bridged heterocyclic group and the 7 to 11-membered spirocyclic group are optionally substituted by 0 to 2 moieties, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, or saturated or unsaturated C3 to C6 cycloalkoxy.

[0176] In some embodiments, R in formula IB 10 R 11 R 12 and R 14 Each is H; R 13 It is a 3- to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, which is substituted by 0 to 2 moieties independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy.

[0177] In some embodiments, R in formula IB 10R 11 R 12 and R 14 Each is H; R 13 It is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, which is substituted by 0 to 2 substituents selected from -OH, -COOH, -NH2, =O, -CN and -C1 to C6 alkyl groups.

[0178] In some embodiments, a compound of formula IB is represented by a compound of formula IB-1 or IB-2 and / or its stereoisomers, stable isotopes, or pharmaceutically acceptable salts.

[0179]

[0180] Where p, R 2 R 3 R 4 and R 5 As defined above; and

[0181] R 16 and R 17 Each is independently selected from halogens and C1 to C6 alkyl groups;

[0182] R 15 Selected from -OH, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -C(O)(R) 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2R 7b and -S(O)2N(R 7b R 8b ),in

[0183] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0184] In some embodiments, R in formula IB-1 or IB-2 15Selected from C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy; saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b ,in

[0185] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0186] In some embodiments, R in formula IB-1 or IB-2 15 It is a C1 to C6 alkyl group.

[0187] In some embodiments, R in formula IB-1 or IB-2 2 and R 3 All of them are methyl groups.

[0188] In some embodiments, R in formula IB-1 or IB-2 2 and R 3 Each is independently a methyl or ethynyl group. In some embodiments, IB-1 is represented by formula IB-1-a or formula IB-2-a.

[0189]

[0190] Or its pharmaceutically acceptable salt.

[0191] In some embodiments, IB-1 is represented by formula IB-1-b or formula IB-2-b.

[0192]

[0193] Or a pharmaceutically acceptable salt thereof, wherein R 4 It is halogen.

[0194] In some embodiments, IB-1 is represented by formula (IB-1-c) or formula IB-2-c.

[0195]

[0196] Or its pharmaceutically acceptable salt.

[0197] In some embodiments, R in formula IB-1 or IB-2 5 It is H or methyl.

[0198] This invention discloses a novel heterocyclic compound as an ALPK1 inhibitor. The compound is represented by formula C1.

[0199]

[0200] Where R 2 R 3 R 4 and R 5 As defined in Equation I above; and

[0201] m is an integer from 0 to 6;

[0202] R 18 Selected from H, halogen, -OH, -COOH, -NH2, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -R 7a -X 1 -R 7a CHR 7a R 8a -OR 7a -OX 1 -R 7a X 1 -OX 1 -R 7a -OC(O)(R 7a ), -OX 1 -C(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -NR 7a (CO)R 8a -C(O)O(R) 7a ), S(O)2R 7a -S(O)2N(R) 7a R 8a ), -N(R 7a R 8a), saturated or unsaturated C3 to C6 cycloalkyl groups, saturated or unsaturated C3 to C6 cycloalkoxy groups, saturated or unsaturated 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; monocyclic or bicyclic aryl groups, 9 to 10-membered bicyclic heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 11-membered spirocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and 6 to 11-membered bicyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; wherein

[0203] Each X 1 C is independent 1-6 Alkylene;

[0204] Each R 7a and R 8a Independently selected from H, C1 to C6 alkyl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, aryl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, containing 1 to 2 A saturated or unsaturated 3- to 7-membered heterocyclic group selected from the apex of a heteroatomic ring of N, O, and S, wherein the aryl and 3- to 7-membered heterocyclic groups are substituted by 0 to 3 substituents selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; and

[0205] The C3 to C6 cycloalkyl, C3 to C6 cycloalkoxy, 3 to 7-membered heterocyclic group, monocyclic or bicyclic aryl, 9 to 10-membered bicyclic heteroaryl, saturated or unsaturated 7 to 8-membered bridged heterocyclic group, saturated or unsaturated 7 to 11-membered spirocyclic group, and 6 to 11-membered bicyclic heterocyclic group are each independently substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, saturated or unsaturated 3 to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, -CHR7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -NR 7b (CO)R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0206] In some embodiments, m in formula IC is 1;

[0207] In some embodiments, R in formula IC 18 For H.

[0208] This invention also discloses a novel heterocyclic compound as an ALPK1 inhibitor. This compound is represented by formula XI.

[0209]

[0210] Where A, p, R 1 R 2 R 3 R 4 and R 5 As defined in this article; and

[0211] X is selected from –S-, -O-, -NR a -, –CH=N- and -CH=CH-, where

[0212] R a It is H or C1 to C6 alkyl.

[0213] In some embodiments, X in equation XI is S.

[0214] In some embodiments, X in equation XI is O.

[0215] In some embodiments, X in formula XI is NH.

[0216] In some embodiments, A in formula XI is a bond.

[0217] In some embodiments, A in Formula XI is a nitrogen-containing heterocyclic butyl group.

[0218] In some embodiments, A in formula XI is -O-.

[0219] In some embodiments, A in equation XI is -N(R) 6 )-.

[0220] In some embodiments, A in formula XI is –CH2–N(R) 6 )-.

[0221] In some embodiments, A in formula XI is -CHR 9 -N(R 6 )-.

[0222] In some embodiments, the Formula I compound is represented by a compound of Formula XI-A, Formula XI-A-1, Formula XI-A-2 and / or its stereoisomers, stable isotopes or pharmaceutically acceptable salts.

[0223]

[0224] In some embodiments, the compound of formula XI is represented by a compound of formula XI-A-1-a and / or its stereoisomers, stable isotopes, or pharmaceutically acceptable salts.

[0225]

[0226] X, p, R 1 R 2 R 3 R 4 R 5 R 6 and R 9 As defined above.

[0227] In some embodiments, X in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a is S, O, or NH.

[0228] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 6 It is H, C1 to C6 alkyl or C1 to C6 hydroxyalkyl.

[0229] In some embodiments, R in formulas XI and XI-A 9 It is CH3 or CH2OH.

[0230] In some embodiments, R in formulas XI and XI-A 9 It is a saturated C3 to C6 cycloalkyl group.

[0231] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 Selected from H and optionally substituted C1 to C6 alkyl groups, wherein

[0232] The optionally substituted C1 to C6 alkyl groups comprise 0 to 4 substituents, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7a R 8a -OR 7a -OC(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -C(O)O(R) 7a -S(O)2R 7a -S(O)2N(R) 7a R 8a ) and -N(R 7a R 8a ),in

[0233] Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0234] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 The substituted saturated or unsaturated C3 to C6 cycloalkyl group, wherein

[0235] The optionally substituted C3 to C6 cycloalkyl groups comprise 0 to 4 substituents, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 alkoxy, and C1 to C6 haloalkoxy.

[0236] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 and R 6Combined to form a 3- to 6-membered heterocyclic alkyl group substituted with 0 to 3 moieties, each moiety being independently selected from the group consisting of: halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy.

[0237] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 It is a C1 to C6 alkyl group substituted with 0 to 4 substituents, which are independently selected from -OH, C1 to C6 hydroxyalkyl, C1 to C6 alkoxy, -OC(O)(R 7a -S(O)2N(R) 7a R 8a ) and -N(R 7a R 8a ),in

[0238] Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0239] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 It is a C1 to C6 alkyl group substituted with 0 to 2 substituents, which are independently selected from -OH, C1 to C6 hydroxyalkyl and -S(O)2N(R) 7a R 8a ),in

[0240] Each R 7a and R 8a Independently selected from H and C1 to C6 alkyl groups.

[0241] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 The C1 to C6 hydroxyalkyl group may be optionally substituted.

[0242] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 It consists of 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S.

[0243] The 5- to 10-membered bicyclic heteroaryl group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, 3- to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0244] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0245] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 The pyridyl group is substituted with 0 to 3 moieties, wherein the 0 to 3 moieties are selected from halogens, -OH, -COOH, -NH2, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, or 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0246] The 3 to 7-membered heterocyclic group is substituted by 0 to 3 substituents selected from halogens, -OH, -COOH, -NH2, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, and C1 to C6 haloalkyl.

[0247] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 It is a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein

[0248] The 7- to 8-membered bridged heterocyclic group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0249] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0250] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 It is a saturated or unsaturated 7- to 11-membered spiroheterocyclic group containing one to two heteroatom ring vertices selected from N, O, and S, wherein

[0251] The 7- to 11-membered spiroheterocyclic group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R7b R 8b ),in

[0252] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0253] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 The aryl group is substituted with 0 to 3 substituents, wherein the 0 to 3 substituents are selected from halogens, 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and saturated or unsaturated 7 to 11-membered spirocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein

[0254] The 3- to 7-membered heterocyclic group, the 7- to 8-membered bridged heterocyclic group, and the 7- to 11-membered spiroheterocyclic group are substituted by 0 to 3 moieties, which are selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2R 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0255] Each R 7b and R 8b Independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy.

[0256] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 The aryl group is substituted with 0 to 3 moieties, which are selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, and 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0257] The 3- to 7-membered heterocyclic group is substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ),in

[0258] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0259] In some embodiments, R in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 The aryl group is substituted with 0 to 3 moieties selected from halogens and 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S.

[0260] The 3 to 7-membered heterocyclic group is further substituted by 0 to 3 moieties selected from -OH, -COOH, -NH2, =O, -CN and -C1 to C6 alkyl groups.

[0261] In some embodiments, compounds of formula XI are represented by compounds of formula XI-B and / or their stereoisomers, stable isotopes, or pharmaceutically acceptable salts.

[0262]

[0263] Where X, p, R 2 R 3 R 4 and R 5 As defined above; and

[0264] D is CR 10 Or N;

[0265] E is CR 14 Or N;

[0266] F is CR 12 Or N;

[0267] G is CR 11 Or N;

[0268] The condition is that no more than three of D, E, F, and G are N;

[0269] R 10 R 11 R 12 R 13 and R 14 When present, each is independently selected from H, halogen, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -R 7a -X 1 -R 7a X 1 -OX 1 -R 7a -CHR 7a R 8a -OR 7a -OX 1 -R 7a -OC(O)(R 7a ), -OX 1 -C(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -C(O)O(R) 7a ), S(O)2R 7a -S(O)2N(R) 7a R 8a), -N(R 7a R 8a ), saturated or unsaturated C3 to C6 cycloalkyl groups, saturated or unsaturated C3 to C6 cycloalkoxy groups, saturated or unsaturated 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, monocyclic or bicyclic aryl groups, 9 to 10-membered bicyclic heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and saturated or unsaturated 7 to 11-membered spirocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and 6 to 11-membered bicyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; wherein

[0270] Each X 1 C is independent 1-6 Alkylene;

[0271] Each R 7a and R 8a Independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; and

[0272] The 3- to 7-membered heterocyclic group, the monocyclic or bicyclic aryl group, the 9- to 10-membered bicyclic heteroaryl group, the 7- to 8-membered bridged heterocyclic group, the 7- to 11-membered spirocyclic group, and the 6- to 11-membered bicyclic heterocyclic group are each independently substituted by 0 to 2 moieties, wherein the 0 to 2 moieties are selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR7gR 8g -OR 7g -OC(O)(R 7g ), -C(O)(R 7g -C(O)N(R) 7g R 8g -NR 7g (CO)R 8g -C(O)O(R) 7g -S(O)2N(R) 7g R 8g ) and -N(R 7g R 8g ),in

[0273] Each R 7g and R 8gEach is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0274] In some embodiments, D, E, F, and G in formula XI-B are respectively CR 10 CR 14 CR 12 and CR 11 .

[0275] In some embodiments, F and G in formula XI-B are respectively CR 14 and CR 11 E is N or CR 14 And D is N or CR 10 .

[0276] In some embodiments, R in formula XI-B 10 and R 11 Each is H, R 12 and R 14 Each is independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; R 13It is a 3- to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; or a saturated or unsaturated 7- to 11-membered spirocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein the 3- to 7-membered heterocyclic group, the 7- to 8-membered bridged heterocyclic group, and the 7- to 11-membered spirocyclic group are optionally substituted by 0 to 2 moieties, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, or saturated or unsaturated C3 to C6 cycloalkoxy.

[0277] In some embodiments, R in formula XI-B 12 and R 14 For H, R 10 and R 11 Each is independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; R 13It is a 3- to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S; or a saturated or unsaturated 7- to 11-membered spirocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, wherein the 3- to 7-membered heterocyclic group, the 7- to 8-membered bridged heterocyclic group, and the 7- to 11-membered spirocyclic group are optionally substituted by 0 to 2 moieties, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, or saturated or unsaturated C3 to C6 cycloalkoxy.

[0278] In some embodiments, R in formula XI-B 10 R 11 R 12 and R 14 Both are H; R 13 It is a saturated or unsaturated C3 to C6 cycloalkyl group, a 3 to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, a saturated or unsaturated 7 to 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, or a saturated or unsaturated 7 to 11-membered spirocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, wherein the 3 to 7-membered heterocyclic group, the 7 to 8-membered bridged heterocyclic group and the 7 to 11-membered spirocyclic group are optionally substituted by 0 to 2 moieties, which are independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, or saturated or unsaturated C3 to C6 cycloalkoxy.

[0279] In some embodiments, R in formula XI-B 10 R 11 R 12 and R 14 Each is H; R 13 It is a 3- to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, which is substituted by 0 to 2 moieties independently selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy.

[0280] In some embodiments, R in formula XI-B10 R 11 R 12 and R 14 Each is H; R 13 It is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O and S, which is substituted by 0 to 2 substituents selected from -OH, -COOH, -NH2, =O, -CN and -C1 to C6 alkyl groups.

[0281] In some embodiments, the XI-B compound is represented by a XI-B-1 or XI-B-2 compound and / or its stereoisomers, stable isotopes, or pharmaceutically acceptable salts.

[0282]

[0283]

[0284] In some embodiments, compounds of formula XI-B-1 or XI-B-2 are represented by compounds of formula XI-B-1-a, XI-B-2-a and / or their stereoisomers, stable isotopes or pharmaceutically acceptable salts.

[0285]

[0286] Where p, R 2 R 3 R 4 and R 5 As defined above; and

[0287] R 16 and R 17 Each is independently selected from halogens and C1 to C6 alkyl groups;

[0288] R 15 Selected from -OH, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b -C(O)(R) 7b -C(O)N(R) 7b R 8b -C(O)O(R) 7b -S(O)2R 7b and -S(O)2N(R 7b R 8b ),in

[0289] Each R7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0290] In some embodiments, R in formula XI-B-1 or XI-B-2 15 Selected from C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy; saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, -CHR 7b R 8b ,in

[0291] Each R 7b and R 8b It is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0292] In some embodiments, R in formula XI-B-1 or XI-B-2 15 It is a C1 to C6 alkyl group.

[0293] In some embodiments, R in formula XI-B-1 or XI-B-2 2 and R 3 All of them are methyl groups.

[0294] In some embodiments, R in formula XI-B-1 or XI-B-2 2 and R 3 Each is independently a methyl or ethynyl group.

[0295] In some embodiments, XI-B-1-a is represented by equation XI-B-1-aI, and XI-B-2-a is represented by equation XI-B-2-aI.

[0296]

[0297] Or a pharmaceutically acceptable salt thereof, wherein R 4 It is halogen.

[0298] In some embodiments, XI-B-1-a is represented by equation XI-B-1-a-II, and XI-B-2-a is represented by equation XI-B-2-a-II.

[0299]

[0300] Or its pharmaceutically acceptable salt.

[0301] In some embodiments, XI-B-1-a is represented by formula XI-B-1-a-III, and XI-B-2-a is represented by formula XI-B-2-a-III.

[0302]

[0303] Or its pharmaceutically acceptable salt.

[0304] In some embodiments, XI-B-1-a is represented by equation XI-B-1-a-IV, and XI-B-2-a is represented by equation XI-B-2-a-IV.

[0305]

[0306] Or its pharmaceutically acceptable salt.

[0307] In some embodiments, R in formula XI-B-1 or XI-B-2 5 It is H or methyl.

[0308] This invention discloses a novel heterocyclic compound as an ALPK1 inhibitor. The compound is represented by formula XI-C.

[0309]

[0310] Among them, X and R 2 R 3 R 4 and R 5 As defined by equation XI above; and

[0311] m is an integer from 0 to 6;

[0312] R 18 Selected from H, halogen, -OH, -COOH, -NH2, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -R 7a -X 1 -R 7a CHR 7a R 8a -OR 7a -OX 1 -R 7a X 1 -OX 1 -R 7a -OC(O)(R 7a ), -OX1 -C(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -NR 7a (CO)R 8a -C(O)O(R) 7a ), S(O)2R 7a -S(O)2N(R) 7a R 8a ), -N(R 7a R 8a ), saturated or unsaturated C3 to C6 cycloalkyl groups, saturated or unsaturated C3 to C6 cycloalkoxy groups, saturated or unsaturated 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, monocyclic or bicyclic aryl groups, 9 to 10-membered bicyclic heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 11-membered spirocyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and 6 to 11-membered bicyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; wherein

[0313] Each X 1 C is independent 1-6 Alkylene;

[0314] Each R 7a and R 8a Independently selected from H, C1 to C6 alkyl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, aryl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, containing 1 to 2 A saturated or unsaturated 3- to 7-membered heterocyclic group selected from the apex of a heteroatomic ring of N, O, and S, wherein the aryl and 3- to 7-membered heterocyclic groups are substituted by 0 to 3 substituents selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; and

[0315] The C3 to C6 cycloalkyl, C3 to C6 cycloalkoxy, 3 to 7-membered heterocyclic group, monocyclic or bicyclic aryl, 9 to 10-membered bicyclic heteroaryl, saturated or unsaturated 7 to 8-membered bridged heterocyclic group, saturated or unsaturated 7 to 11-membered spirocyclic group, and 6 to 11-membered bicyclic heterocyclic group are each independently substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, saturated or unsaturated 3 to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -NR 7b (CO)R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy.

[0316] In some embodiments, compounds of formula XI-C are represented by compounds of formula XI-C-1 and / or their stereoisomers, stable isotopes, or pharmaceutically acceptable salts.

[0317]

[0318] Where R 2 R 3 R 4 and R 5 As defined in Equation I above; and

[0319] m is an integer from 0 to 6;

[0320] R 18Selected from H, halogen, -OH, -COOH, -NH2, -CN, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -R 7a -X 1 -R 7a CHR 7a R 8a -OR 7a -OX 1 -R 7a X 1 -OX 1 -R 7a -OC(O)(R 7a ), -OX 1 -C(O)(R 7a ), -C(O)(R 7a -C(O)N(R) 7a R 8a -NR 7a (CO)R 8a -C(O)O(R) 7a ), S(O)2R 7a -S(O)2N(R) 7a R 8a ), -N(R 7a R 8a ), saturated or unsaturated C3 to C6 cycloalkyl groups, saturated or unsaturated C3 to C6 cycloalkoxy groups, saturated or unsaturated 3 to 7-membered heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, monocyclic or bicyclic aryl groups, 9 to 10-membered bicyclic heteroaryl groups containing 1 to 4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 8-membered bridged heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7 to 11-membered spirocyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and 6 to 11-membered bicyclic heterocyclic groups containing 1 to 2 heteroatom ring vertices selected from N, O, and S; wherein

[0321] Each X 1 C is independent 1-6 Alkylene;

[0322] Each R 7a and R 8aIndependently selected from H, C1 to C6 alkyl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, aryl, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, containing 1 to 2 A saturated or unsaturated 3- to 7-membered heterocyclic group selected from the apex of a heteroatomic ring of N, O, and S, wherein the aryl and 3- to 7-membered heterocyclic groups are substituted by 0 to 3 substituents selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, and saturated or unsaturated C3 to C6 cycloalkoxy; and

[0323] The C3 to C6 cycloalkyl, C3 to C6 cycloalkoxy, 3 to 7-membered heterocyclic group, monocyclic or bicyclic aryl, 9 to 10-membered bicyclic heteroaryl, saturated or unsaturated 7 to 8-membered bridged heterocyclic group, saturated or unsaturated 7 to 11-membered spirocyclic group, and 6 to 11-membered bicyclic heterocyclic group are each independently substituted by 0 to 3 moieties selected from halogens, -OH, -COOH, -NH2, =O, -CN, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl, saturated or unsaturated C3 to C6 cycloalkoxy, saturated or unsaturated 3 to 7-membered heterocyclic group containing 1 to 2 heteroatom ring vertices selected from N, O, and S, -CHR 7b R 8b -OR 7b -OC(O)(R 7b ), -C(O)(R 7b -C(O)N(R) 7b R 8b -NR 7b (CO)R 8b -C(O)O(R) 7b -S(O)2N(R) 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8bEach is independently selected from H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, saturated or unsaturated C3 to C6 cycloalkyl and saturated or unsaturated C3 to C6 cycloalkoxy;

[0324] In some embodiments, m in formula XI-C or XI-C-1 is 1.

[0325] In some embodiments, R in formula XI-C or XI-C-1 18 For H.

[0326] In some embodiments, R in each of the formulas described herein 2 and R 3 All are C1 to C6 alkyl groups;

[0327] In some embodiments, in each of the formulas described herein, R 2 It is methyl and R 3 It is CH2OMe.

[0328] In some embodiments, in each of the formulas described herein, R 2 and R 3 Each is a methyl group.

[0329] In some embodiments, in each of the formulas described herein, R 2 It is methyl and R 3 It is an acetylene group.

[0330] In some embodiments, R 2 It is methyl and R 3 It is a C3 to C6 cycloalkyl group.

[0331] In some embodiments, R 2 It is methyl, and R 3 It is a phenyl group.

[0332] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 Attached to the benzene ring as shown below:

[0333]

[0334] The wavy lines represent the attachment points of the rest of the equation.

[0335] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 It is a halogen that attaches to a benzene ring as shown below:

[0336]

[0337] The wavy lines represent the attachment points of the rest of the equation.

[0338] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 It is chlorine attached to the benzene ring as shown below:

[0339]

[0340] The wavy lines represent the attachment points of the rest of the equation.

[0341] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 It is a methoxy group attached to a benzene ring as shown below:

[0342]

[0343] The wavy lines represent the attachment points of the rest of the equation.

[0344] In some embodiments, R in each of the formulas described herein 5 For H.

[0345] In some embodiments, R in each of the formulas described herein 5 It is deuterium.

[0346] In some embodiments, R in each of the formulas described herein 5 It is a C1 to C6 deuterated alkyl group. In some embodiments, R in each of the formulas described herein 5 Choose from the following groups: -CH2D, -CHD2, and -CD3.

[0347] In some embodiments, R attached to each of the formulas described herein 2 and R 3 The carbon atoms are chiral. In such embodiments, it should be understood that R 2 and R 3 Not the same. In some embodiments, R attached to each of the formulas described herein 2 and R 3 The carbon atom is an S isomer, meaning that the absolute stereochemistry at that carbon atom is present. In some embodiments, R attached to each of the formulas described herein is... 2 and R 3 The carbon atom is an R isomer, meaning that the absolute stereochemistry at that carbon atom is... In some embodiments, R... 2 It is methyl and R 3 It is acetylene group. In some embodiments, R 2It is methyl and R 3 It is a C3 to C6 cycloalkyl group. In some embodiments, R 2 It is methyl, and R 3 It is phenyl. In some embodiments, R 3 It is methyl and R 2 It is acetylene group. In some embodiments, R 3 It is methyl and R 2 It is a C3 to C6 cycloalkyl group. In some embodiments, R 3 It is methyl, and R 2 It is a phenyl group.

[0348] In some embodiments, the compound of formula I is selected from

[0349]

[0350]

[0351] In some embodiments, the compound of formula I is selected from

[0352]

[0353]

[0354] In some embodiments, the compound is selected from the examples provided herein.

[0355] Preparation of Formula I compounds and exemplary compounds

[0356] Analysis details

[0357] 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 in ppm low magnetic field from the TMS, 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 for dimethyl sulfoxide (δ 2.50 ppm), chloroform (δ 7.26 ppm), methanol (δ 3.31 ppm), or other solvents as shown in the NMR spectral data.

[0358] LC-MS: Shimadzu 20A-2010MS

[0359] Tested: SPD-M20A

[0360] Column: Merck, RP-18e 25-2mm;

[0361] Wavelength: UV 220nm, 254nm;

[0362] Column temperature: 50℃; MS ionization: ESI

[0363] Mobile phase: water containing 1.5 mL / 4 L TFA (solvent A) and acetonitrile containing 0.75 mL / 4 L TFA (solvent B), using an elution gradient of 5% to 95% (solvent B) for 0.7 min and holding at 95% for 0.4 min, at a flow rate of 1.5 mL / min;

[0364] Rapid column chromatography system

[0365] System: CombiFlash Rf+

[0366] Pillar: Santai Technologies, Inc.

[0367] Samples are usually adsorbed onto the isolute

[0368] HPLC separation conditions

[0369] System: Trilusion LC 4.0

[0370] Tested by: Gilson 159UV-VIS

[0371] Condition 1: Column: Phenomenex Gemini-NX 80*40mm*3um

[0372] Eluent A: Water (0.05% NH3H2O ​​+ 10mM NH4HCO3)

[0373] Elution Buffer B: CH3CN

[0374] Start B: 20% to 45%, End B: 80% to 20%, Gradient Time (minutes): 8

[0375] Condition 2: Column: Ultimate C18 10μm 250mm*50mm;

[0376] Eluent A: Water (0.04% NH3H2O ​​+ 10mM NH4HCO3).

[0377] Eluent B: CH3CN 50% to 80%; Gradient time (minutes): 8

[0378] SFC chiral separation conditions

[0379] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 30% to 30%, 35% to 35%, or 45% to 45%

[0380] Pillar: Daicel (DAICEL) CHIRALCEL OJ-H (250mm*30mm, 5um);

[0381] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 30% to 30%, 40% to 40%;

[0382] Pillar: Ceramic CHIRALPAK AD (250mm*30mm, 10um);

[0383] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 35% to 35%;

[0384] Pillar: Ceramic CHIRALPAK AS (250mm*30mm, 10um);

[0385] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 35% to 35%

[0386] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of this invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art.

[0387] The following is a list of abbreviations used in chemistry:

[0388]

[0389]

[0390] Reaction scheme 1:

[0391]

[0392] The appropriately substituted compound M1, wherein R is a suitable 1 to 3 groups, such as halogens or C1 to C6 alkyl groups, and R1 and R2 are suitable groups, such as independently selected from H, C1 to C6 alkyl, and C2 to C6 alkynyl groups, is converted to an acyl chloride by heating or at room temperature with SOCl2 or (COCl)2. The acyl chloride is reacted with N,O-dimethylhydroxylamine hydrochloride at 0°C to form a Weinreb amide. The Weinreb amide is then given a ketone by adding a Grignard reagent-containing THF at 0°C, which is then converted to M5 by bromination. Cyclization with thiourea under basic conditions yields intermediate M6.

[0393] Example 1: Preparation of 4-(2-(4-bromophenyl)prop-2-yl)thiazol-2-amine (intermediate 1)

[0394]

[0395] Step 1. Preparation of compound 2-(4-bromophenyl)-2-methylpropionyl chloride

[0396]

[0397] The compound 2-(4-bromophenyl)-2-methylpropionic acid (100 g, 411 mmol, 1.0 equivalent) in SOCl2 (175 mL, 6 equivalents) was heated to reflux for 2 hours. The solution was then cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a dry acyl chloride (yellow oil), which was used in the next step without further purification.

[0398] Step 2. Preparation of compound 2-(4-bromophenyl)-N-methoxy-N,2-dimethylpropionamide

[0399]

[0400] The solution of N,O-dimethylhydroxylamine HCl salt (48.2 g, 49 mmol, 1.2 equivalents) in DCM (300 mL) was cooled to 0 °C. Then, crude acyl chloride (1.0 equivalent) obtained from step 1 was added to a mixture of DCM (200 mL) and TEA (114 mL, 2 equivalents), and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with H₂O (200 mL). The mixture was extracted with DCM (200 mL × 3), and the combined organic layers were washed with water (200 mL × 3) and brine (200 mL × 3), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The desired compound (108 g, pure) was obtained as a pale yellow oil and used in the next step without further purification.

[0401] 1 H NMR (400MHz, CDCl3) δ7.42 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 3.08 (s, 3H), 2.71 (s, 3H), 1.49 (s, 6H).

[0402] Step 3. Preparation of compound 3-(4-bromophenyl)-3-methylbut-2-one

[0403]

[0404] The solution of the compound obtained in step 2 above (54 g, 189 mmol, 1 equivalent) in anhydrous THF (500 mL) was cooled to 0 °C. CH3MgBr (3 M, 253 mL, 757.8 mmol, 4 equivalents in THF solution) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with EA (300 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered, and concentrated to give the residue. The desired compound (90.4 g, pure) was obtained as a pale yellow oil and was used in the next step without further purification.

[0405] 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 1.90 (s, 3H), 1.44 (s, 6H).

[0406] Step 4. Preparation of compound 1-bromo-3-(4-bromophenyl)-3-methylbut-2-one

[0407]

[0408] Br2 (14.7 mL, 286 mmol, 1.5 equivalents) was added dropwise to a solution of the compound obtained in step 3 above (46 g, 191 mmol, 1 equivalent) in DCM / EtOH (250 mL / 250 mL). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was quenched with saturated Na2SO3 (150 mL). The mixture was extracted with DCM (300 mL × 2), and the combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered, and concentrated to give the residue. The desired compound (118.8 g, crude) was obtained as a white solid and used in the next step without further purification.

[0409] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 3.82 (s, 2H), 1.52 (s, 6H).

[0410] Step 5. Preparation of 4-(2-(4-bromophenyl)prop-2-yl)thiazol-2-amine

[0411]

[0412] Thiourea (14.3 g, 188 mmol, 1.2 equivalents) was added to a solution of the compound obtained in step 4 (50 g, 156 mmol, 1 equivalent) in MeOH (500 mL). The mixture was stirred at 50 °C for 1.5 h. The mixture was concentrated under reduced pressure. The mixture was extracted with EA (300 mL × 2), the combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered and concentrated to obtain the residue. The residue was purified by silica gel chromatography (PE / EA = 10:1) to obtain pure desired compound (34 g, white solid).

[0413] 1 H NMR (400MHz, DMSO-d6) δ7.39 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.78 (s, 2H), 6.22 (s, 1H), 1.50 (s, 6H). MS(ESI)m / z(M+H) + =297.0.

[0414] Example 2:

[0415] 4-(1-(4-bromophenyl)cyclopentyl)thiazol-2-amine (intermediate 2)

[0416]

[0417] Step 1. Preparation of compound 1-(4-bromophenyl)cyclopentane-1-carboxylic acid ethyl ester

[0418]

[0419] NaH (8.3 g, 207 mmol) was slowly added to a solution of ethyl 2-(4-bromophenyl)acetate (10 g, 41.3 mmol) in DMF (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. 1,4-Dibromobutane (8.8 g, 41.3 mmol) was then slowly added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give a residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 5:1). The title compound was given (7.8 g, yield: 63.8%).

[0420] MS(ESI)m / z(M+H) + =297.0

[0421] Step 2. Preparation of compound 1-(4-bromophenyl)cyclopentane-1-carboxylic acid

[0422]

[0423] To a solution of ethyl 1-(4-bromophenyl)cyclopentane-1-carboxylic acid (7.8 g, 26.3 mmol) in THF (25 mL), NaOH (3.2 g, 79 mmol) and H₂O (5 mL) were added, and the reaction mixture was stirred overnight at 40 °C. After cooling, the pH of the reaction solution was adjusted to 6. The reaction mixture was concentrated to obtain a residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 1:2). The desired compound was obtained (5.6 g, yield: 79.4%).

[0424] MS(ESI)m / z(M+H) + =269.0

[0425] The synthesis of the following steps is similar to that described in intermediate 1.

[0426] Example 3:

[0427] 4-(2-(5-bromopyridin-2-yl)propyl-2-yl)thiazolyl-2-amine (Intermediate 3)

[0428]

[0429] Step 1. Preparation of compound methyl 2-(5-bromopyridin-2-yl)-2-methylpropionate

[0430]

[0431] NaH (1.3 g, 32.4 mmol, 3.5 equivalents) was added to a solution of 3-(5-bromopyridin-2-yl)-2-oxopropionic acid (2 g, 9.26 mmol, 1.0 equivalent) in DMF (20 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. CH3I (2 mL, 3.5 equivalents) was added to the mixture at 0 °C and stirred for 6 h. The reaction mixture was quenched with water (50 mL), extracted with EA (25 mL × 2) and washed with brine (10 mL × 2), then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give the desired compound (1.95 g, yield: 93%).

[0432] Step 2. Preparation of compound 2-(5-bromopyridin-2-yl)-2-methylpropionic acid

[0433]

[0434] A mixture of 2-(5-bromopyridin-2-yl)-2-methylpropionate (1.95 g, 7.56 mmol, 1.0 equivalent) and KOH (1.9 mL, 2 M in H₂O, 3.0 equivalent) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and quenched with 0.1 M HCl, extracted with EA, washed with brine, dried over Na₂SO₄, filtered, and evaporated to dryness to give the desired compound (1.82 g, yield: 98%).

[0435] The following steps are similar to those described in Intermediate 1.

[0436] The following example is similar to the procedure for intermediate 1, using appropriate starting materials and thiourea for synthesis:

[0437] Table 1

[0438]

[0439]

[0440]

[0441] Reaction scheme 2:

[0442]

[0443] The suitably substituted compound M7 (where R is a suitable 1 to 3 groups, such as halogen or C1 to C6 alkyl) is acetylated with a lithium base at temperatures below -60°C. M9 is obtained by alkyl substitution of M8 (such as C1 to C6 alkyl groups) under alkaline conditions at 50 to 70°C. After bromination, M10 is obtained. M10 is cyclized with thiourea under alkaline conditions to give the thiazole intermediate M11. A suitable protecting group is introduced to protect the amine. The ester is reduced to an alcohol by LiBH4 at 0°C to produce M13, which is oxidized to the corresponding aldehyde using a Desmond-Martin periodoyl (DMP) reagent. M14 is treated with 1-diazo-1-dimethoxyphosphoryl-prop-2-one at room temperature under alkaline conditions by a Sefert-Gilbert homologation reaction to obtain the alkynylthiazolamine intermediate M15. Finally, deprotection is given to intermediate M16.

[0444] Example 4:

[0445] Preparation of 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazolyl-2-amine (intermediate 27)

[0446]

[0447] Step 1. Preparation of compound methyl 2-(4-chlorophenyl)-3-oxobutyrate

[0448]

[0449] LiHMDS (1M, 65.0 mL) was added dropwise to a solution of methyl 2-(4-chlorophenyl)acetate (10 g, 54.2 mmol, 8.77 mL) in THF (80 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min. Then, acetoacetate (5.53 g, 54.17 mmol, 5.07 mL) was added at -78 °C. The mixture was warmed to 0 °C and stirred at 0 °C for 2 h. The mixture was quenched with saturated NH4Cl (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 5:1). The desired compound (7.47 g, yield: 60.9%) was obtained as a pale yellow oil.

[0450] MS(ESI)m / z(M+H) + =227.1.

[0451] Step 2. Preparation of compound methyl 2-(4-chlorophenyl)-2-methyl-3-oxobutyrate

[0452]

[0453] Iodimethane (13.10 g, 92.28 mmol, 5.74 mL) was added to a solution of the compound obtained from step 1 (7.47 g, 33.0 mmol) and K₂CO₃ (22.8 g, 165 mmol) in acetone (60 mL). The mixture was stirred at 70 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated to give the residue. The desired compound (7.79 g, yield: 98.2%) was obtained as a pale yellow oil and was used in the next step without further purification.

[0454] MS(ESI)m / z(M+H) + =241.1.

[0455] Step 3. Preparation of compound methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutyrate

[0456]

[0457] Br2 (4.66 g, 29.1 mmol, 1.50 mL) was added to a solution of the compound obtained in step 2 (7.79 g, 32.4 mmol) in CHCl3 (80 mL). The mixture was stirred at 75 °C for 16 hours. The reaction mixture was adjusted to pH 6 to 7 with NaOH (1N), washed with H2O (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The desired compound (9.91 g, yield: 95.8%) was obtained as a light brown oil, which was used in the next step without further purification.

[0458] MS(ESI)m / z(M+H) + =319.0.

[0459] Step 4. Preparation of methyl 2-(2-aminothiazol-4-yl)-2-(4-chlorophenyl)propionate

[0460]

[0461] To a solution of the compound obtained in step 3 above (9.91 g, 31.0 mmol) and thiourea (2.83 g, 37.2 mmol) in MeOH (60 mL), NaHCO3 (3.13 g, 37.2 mmol, 1.45 mL) was added. The mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated to obtain a residue. The precipitate was ground in H2O (100 mL) and collected by filtration. The desired compound (8.49 g, yield: 92.3%) was obtained as a brown solid.

[0462] MS(ESI)m / z(M+H) + =297.0.

[0463] Step 5. Preparation of methyl 2-(2-acetaminothiazol-4-yl)-2-(4-chlorophenyl)propionate

[0464]

[0465] Acetyl chloride (794 mg, 10.1 mmol, 721 μL) was added to a solution of the compound obtained in step 4 above (3 g, 10.1 mmol, 2.11 mL) in DCM (60 mL) at 0 °C. The mixture was stirred at 25 °C for 1.5 h. A second batch of acetyl chloride (794 mg, 10.1 mmol, 721 μL) and TEA (1.53 g, 15.2 mmol, 2.11 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 1 h. A third batch of acetyl chloride (793.5 mg, 10.11 mmol, 721.38 μL) and TEA (1.53 g, 15.16 mmol, 2.11 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with H2O (3 mL), then anhydrous Na2SO4 was added, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 2:1). The desired compound was obtained as a pale yellow solid (1.4 g, yield: 32.6%).

[0466] MS(ESI)m / z(M+H) + =339.1.

[0467] Step 6. Preparation of compound N-(4-(2-(4-chlorophenyl)-1-hydroxypropyl-2-yl)thiazolyl-2-yl)acetamide

[0468]

[0469] To a solution of the compound obtained in step 5 above (1.4 g, 4.13 mmol) in THF (50 mL), LiBH4 (450 mg, 20.66 mmol) was partially added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated NH4Cl (40 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 2:3). The desired compound (970 mg, yield: 73.4%) was given as a pale yellow solid.

[0470] MS(ESI)m / z(M+H) + =311.1.

[0471] Step 7. Preparation of compound N-(4-(2-(4-chlorophenyl)-1-oxopropyl-2-yl)thiazolyl)acetamide

[0472]

[0473] To a solution of the compound obtained in step 6 above (970 mg, 3.12 mmol) in DCM (30 mL), partially add 20 mL of DCM containing DMP (1.72 g, 4.06 mmol). Stir the mixture at 25 °C for 2 hours. Add 20 mL of DCM containing DMP (1.72 g, 4.06 mmol) and stir the mixture at 25 °C for 1 hour. Add 20 mL of DCM containing DMP (1.06 g, 2.50 mmol) and stir the mixture at 25 °C for 2 hours. The reaction mixture was diluted with DCM (40 mL), quenched with saturated Na₂S₂O₃ / saturated NaHCO₃ (1 / 1, 200 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (60 mL). The combined organic layers were washed with saturated Na₂S₂O₃ / saturated NaHCO₃ (1 / 1, 100 mL), water (200 mL × 2), and brine (200 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the residue. The desired compound (1.03 g, crude) was obtained as a yellow solid and used in the next step without further purification.

[0474] Step 8. Preparation of compound N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazolyl)acetamide

[0475]

[0476] To a solution of the compound obtained in step 7 above (1.03 g, 3.34 mmol) and 1-diazo-1-dimethoxyphosphoryl-prop-2-one (961 mg, 5.00 mmol) in MeOH (40 mL), K₂CO₃ (922 mg, 6.67 mmol) was added. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 1:1). The residue was then purified by preparative HPLC (column: Venusil ASB Phenyl 150 × 30 mm × 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55% to 85%, 9 min). The desired compound was given as a white solid (219 mg, yield: 21.54%).

[0477] 1 H NMR (400MHz, CDCl3) δ9.98 (br s, 1H), 7.45 (d, J = 8.5Hz, 2H), 7.30 (d, J = 8.5Hz, 2H), 6.88 (s, 1H), 2.63 (s, 1H), 2.25 (s, 3H), 1.99 (s, 3H). MS(ESI)m / z(M+H) + =305.1.

[0478] Step 9. Preparation of compound 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazolyl-2-amine

[0479]

[0480] To a solution of the compound obtained in step 8 above (180 mg, 591 μmol) in MeOH (10 mL), methanesulfonic acid (284 mg, 2.95 mmol, 210 μL) was added. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was adjusted to pH 9 to 10 with solid NaHCO3 and concentrated to give a residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 2:1). The desired compound (137 mg, yield: 88.3%) was obtained as a pale yellow solid.

[0481] 1 H NMR (400MHz, CDCl3) δ7.39-7.32(m,2H),7.20-7.16(m,2H),6.35(s,1H),4.90(br s,2H),2.46(s,1H),1.82(s,3H). MS(ESI)m / z(M+H) + =263.0.

[0482] The following examples are similar to the procedure in Example 4 (Intermediate 27) for the synthesis of thiourea using appropriate starting materials:

[0483] Table 2

[0484]

[0485]

[0486] Example 5:

[0487] 4-(2-(4-bromophenyl)-1-methoxypropyl-2-yl)thiazolyl-2-amine (Intermediate 33)

[0488]

[0489] Step 1. Preparation of compound N-(4-(2-(4-bromophenyl)-1-methoxypropyl-2-yl)thiazolyl-2-yl)acetamide

[0490]

[0491] Trimethyloxonium tetrafluoroborate (416 mg, 2.8 mmol) was added to a solution of N-(4-(2-(4-bromophenyl)-1-hydroxypropyl-2-yl)thiazolyl-2-yl)acetamide (200 mg, 563 μmol, synthesized by a similar method as described in intermediate 46) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (603 mg, 2.81 mmol) in DCM (10 mL) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with DCM (10 mL), quenched with NH3·H2O (10 mL), washed with H2O (30 mL), HCl (1N, 20 mL), saturated NaHCO3 (20 mL), and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 1:1). The desired compound was obtained as a white solid (41 mg, yield: 19.72%).

[0492] 1 H NMR (400MHz, CDCl3) δ8.69 (br s,1H),7.39(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),6.69(s,1H),3.80(s,2H),3.34(s,3H),2.20(s,3H),1.68(s,3H). MS(ESI)m / z(M+H) + =371.0.

[0493] Step 2. Preparation of compound 4-(2-(4-bromophenyl)-1-methoxypropyl-2-yl)thiazol-2-amine

[0494]

[0495] The synthesis was similar to that described in intermediate 44. The desired compound was obtained as a white solid (20 mg, yield: 90.3%).

[0496] 1 H NMR (400MHz, CDCl3) δ7.42-7.36(m,2H),7.18-7.13(m,2H),6.22(s,1H),4.83(br s,2H),3.84-3.73(m,2H),3.34(s,3H),1.65(s,3H). MS(ESI)m / z(M+H) + =327.0.

[0497] The following intermediates are synthesized using appropriate starting materials and thiourea, following a procedure similar to that of Example 5 (Intermediate 33):

[0498] Table 3

[0499]

[0500] Example 6:

[0501] 1-(2-Aminothiazol-4-yl)-1-(4-bromophenyl)ethyl-1-ol (Intermediate 38)

[0502]

[0503] Step 1. Preparation of compound 1-(4-bromophenyl)propane-1,2-dione

[0504]

[0505] SeO2 (3.12 g, 28.1 mmol, 3.0 equivalent) was added to a solution of compound 1-(4-bromophenyl)propane-2-one (2.0 g, 9.4 mmol, 1.0 equivalent) in dioxane (20 mL). The mixture was stirred at 110 °C for 4 hours. After cooling, the reaction mixture was concentrated to give a residue. The residue was purified by rapid silica gel chromatography (PE:EA = 96%:4%). The desired compound (960 mg, yield: 45%) was given as a yellow oil.

[0506] Step 2. Preparation of compound 3-bromo-1-(4-bromophenyl)propane-1,2-dione

[0507]

[0508] To a solution of the compound obtained in step 1 above (960 mg, 4.23 mmol, 1.0 equivalent) in CH3Cl (20 mL), Br2 (1.05 g, 6.34 mmol, 1.5 equivalent) and AcOH (3 drops) were added. The mixture was stirred at 60 °C for 16 hours. The reaction mixture was quenched with saturated Na2SO3 (aqueous solution) (20 mL), extracted with DCM (20 mL × 2) and washed with brine (15 mL), then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by rapid silica gel chromatography (PE:EA = 94%:6%). The desired compound (800 mg, yield: 74%) was obtained as a yellow oil.

[0509] Step 3. Preparation of compound (2-aminothiazol-4-yl)(4-bromophenyl) methyl ketone

[0510]

[0511] Thiourea (200 mg, 2.62 mmol, 1.0 equivalent) and NaHCO3 were added to a solution of the compound obtained in step 2 above (800 mg, 2.62 mmol, 1.0 equivalent) in MeOH (8 mL). The mixture was stirred at 50 °C for 1.5 hours. The mixture was concentrated under reduced pressure, extracted with EA (15 mL × 2), the combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered and concentrated to obtain the residue, which was purified by rapid silica gel chromatography (PE:EA = 3:1) to obtain the desired group (680 mg, yield: 90%).

[0512] Preparation of compound 1-(2-aminothiazol-4-yl)-1-(4-bromophenyl)ethyl-1-ol in step 4

[0513]

[0514] A solution of (2-aminothiazol-4-yl)(4-bromophenyl) methyl ketone (200 mg, 0.71 mmol, 1.0 equivalent) in anhydrous THF (4 mL) was cooled to 0 °C, and CH3MgBr (3 M, 1.6 mL, 4.9 mmol, 7.0 equivalent in THF) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl, extracted with EA (20 mL × 2), and the combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to give the residue. The residue was purified by preparative TLC to give the desired compound (40 mg, yield: 20%).

[0515] 1 H NMR (400MHz, DMSO) δ7.45–7.38(m,2H),7.22(t,J=7.5Hz,2H),7.12(t,J=7.3Hz,1H),6.77(s,2H),6.30(s,1H),5.37(s,1H),1.67(s,3H).

[0516] MS(ESI)m / z(M+H) + =221.0

[0517] Example 7: 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazolyl-5-d-2-amine

[0518]

[0519] Step 1. Preparation of compound N-(5-bromo-4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazolyl)acetamide

[0520]

[0521] A mixture of DMF (10 mL) containing N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazolyl-2-yl]acetamide (1 g, 3.28 mmol) and NBS (700.74 mg, 3.94 mmol) was stirred at 50 °C for 2 hours. The reaction was cooled to room temperature, diluted with H₂O (50 mL), extracted with EtOAc (30 mL × 3), the organic phases were combined and washed with brine (50 mL × 3), and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (PE:EA = 1:0 to 3:1). The desired compound was given as a yellow solid (800 mg, yield: 52.6%).

[0522] 1 H NMR (400MHz, CDCl3) δ8.89(br.s,1H),7.33-7.41(m,2H),7.24-7.32(m,2H),2.61(s,1H),2.29(s,3H),2.00(s,3H). MS(ESI)m / z(M+H) + =384.8.

[0523] Step 2. Preparation of compound 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]-5-deuterium-thiazolyl-2-amine

[0524]

[0525] A mixture of CD3OD (8 mL) containing the compound obtained from step 1 above (600 mg, 1.56 mmol) and MsOH (751.43 mg, 7.82 mmol) was stirred at 80 °C for 16 hours. The reaction mixture was adjusted to pH 8 to 9 with saturated aqueous NaHCO3 and extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with brine (30 mL), and concentrated to give the residue. The residue was purified by silica gel chromatography (PE:EA = 1:0 to 3:1) to give the product, which was further purified by preparative TLC (PE:EA = 1:0 to 3:1). The desired compound (100 mg, yield: 20.8%) was obtained as a yellow oil.

[0526] 1 H NMR (400MHz, CDCl3) δ8.89(br.s,1H),7.33-7.41(m,2H),7.24-7.32(m,2H),2.61(s,1H),2.29(s,3H),2.00(s,3H). MS(ESI)m / z(M+H) + =263.8.

[0527] Simultaneously, a yellow solid byproduct, 5-bromo-4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-amine (300 mg, yield: 52.2%), was obtained.

[0528] MS(ESI)m / z(M+H) + =343.1.

[0529] General Method I

[0530] At 0 to 10 °C, add NaH (1.2 to 1.5 equivalents) to a solution of thiazolamide (1 equivalent) in a suitable organic solvent (such as DMF), and stir the resulting mixture for 5 to 30 minutes. Add the amine activated by CDI to the mixture and stir for 4 to 16 hours. Once the reaction is complete, dilute the resulting suspension with an organic solvent and wash with brine, then dry. After filtration and evaporation, purify the residue by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0531] Example 8: 4-(4-((3-(4-(2-(4-chloro-3-fluorophenyl)prop-2-yl)thiazolyl)ureo)methyl)phenyl) Preparation of piperazine-1-carboxylic acid tert-butyl ester

[0532]

[0533] To a solution of 4-(2-(4-chloro-3-fluorophenyl)prop-2-yl)thiazol-2-amine (40 mg, 0.15 mmol, 1 equivalent) in DMF (5 mL), NaH (7 mg, 0.3 mmol, 2 equivalents) was added. The resulting mixture was stirred for 5 minutes. Tert-butyl 4-(4-((1H-imidazol-1-carboxymethyl)phenyl)piperazine-1-carboxylate (58 mg, 0.15 mmol, 1 equivalent) was added to the mixture, and the mixture was stirred overnight. The reaction mixture was quenched with water, extracted with EA, and the combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and evaporated to dryness. The resulting residue was purified by preparative TLC (PE:EA = 3:1) to give 35 mg (0.06 mmol) of the title compound in 40% yield. MS (ESI) m / z (M+H) + =588.2

[0534] General Method II

[0535] Slowly add phenyl chloroformate (2 equivalents) to a solution of amine fragment (1 equivalent) and pyridine in a suitable solvent (e.g., anhydrous DCM) at below 20°C. Stir the mixture at room temperature for 4 to 6 hours. Once the reaction is complete, dilute the resulting reactant with an organic solvent and wash with brine, then dry. After filtration and evaporation, purify the residue by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0536] Example 9: 4-(5-((3-(4-(2-(4-bromophenyl)prop-2-yl)thiazolyl)ureo)methyl)pyrimidin-2-yl) Preparation of piperazine-1-carboxylic acid tert-butyl ester

[0537]

[0538] At -20°C, phenyl chloroformate (336 mg, 2.2 mmol, 269.0 μL) was added to a mixture of CH3CN (15 mL) containing 4-(5-(aminomethyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (600 mg, 2.1 mmol) and pyridine (194 mg, 2.5 mmol, 198 μL). After addition, the mixture was heated to 25°C and stirred at 25°C for 0.25 h. The solvent was removed under vacuum. The residue was ground with ice water (15 mL). A white solid precipitated from the mixture. The mixture was filtered and the solid was collected and dried under vacuum. 420 mg (yield: 38.2%) of 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was given as a white solid. MS (ESI) m / z (M+H) + =414.2.

[0539] DMAP (41.0 mg, 337.0 μmol, 2 equivalents) was added to a mixture of DCE (10 mL) containing tert-butyl 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (139 mg, 336 μmol) and 4-(2-(4-bromophenyl)prop-2-yl)thiazol-2-amine (50 mg, 168 μmol). The mixture was stirred at 85 °C for 16 h. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 13:1) and further purified by preparative TLC (SiO2, DCM:MeOH = 12:1). The desired compound was obtained as a white solid (60 mg, yield: 57.7%).

[0540] MS(ESI)m / z(M+H) + =616.2.

[0541] General Method III

[0542] Phenyl chloroformate (2 equivalents) was slowly added to a solution of substituted thiazole-2-amine and hunig base (N,N-diisopropylethylamine) or pyridine in a suitable solvent (such as DCM or CH3CN or DCM / water) at 0°C to room temperature. The mixture was stirred at room temperature for 2 to 4 hours, and the resulting reaction mixture was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the residue was purified by chromatography to give the substituted thiazole-2-amine carbamate.

[0543] A mixture containing a substituted thiazole-2-amine carbamate, an amine, and DMAP in a suitable solvent (such as THF) is heated to reflux for 1 to 2 hours. After cooling, the resulting reaction mixture is evaporated and diluted with a suitable organic solvent (such as EA), washed with brine, and then dried. After filtration and evaporation, the residue is purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0544] Example 10: 1-(4-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzyl)-3-(4-(2- Preparation of (4-methoxyphenyl)prop-2-yl)thiazolyl)urea

[0545]

[0546] To a solution of 4-(2-(4-bromophenyl)prop-2-yl)thiazol-2-amine (100 mg, 0.34 mmol, 1 equivalent) and triethylamine in anhydrous DCM (5 mL), phenyl chloroformate (106 mg, 0.68 mmol, 2 equivalents) was slowly added and the mixture was stirred at room temperature for 4 hours. The mixture was quenched with brine, extracted with EA, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography to give phenyl (4-(2-(4-bromophenyl)prop-2-yl)thiazol-2-yl)carbamate (112 mg).

[0547] A mixture containing phenyl 4-(2-(4-bromophenyl)prop-2-yl)thiazolyl)carbamate (112 mg, 0.27 mmol, 1 equivalent), tert-butyl (1-(4-(aminomethyl)phenyl)piperidin-4-yl)methyl)carbamate (24 mg, 0.27 mmol, 1 equivalent), and DMAP (52 mg, 0.4 mmol, 1.5 equivalent) in THF (5 mL) was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was added between H₂O (15 mL) and EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain tert-butyl carbamate (42 mg) as a white powder.

[0548] General Method IV

[0549] A mixture of amine and isocyanate-alkane-containing THF was stirred overnight at room temperature. Once the reaction was complete, the resulting suspension was diluted with an organic solvent and washed with brine, then dried. After filtration and evaporation, the residue was purified by grinding / preparative TLC / preparative HPLC to obtain the product.

[0550] Example 11: Preparation of 1-ethyl-3-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)urea

[0551]

[0552] To a solution of 4-(2-(4-methoxyphenyl)propyl-2-yl)thiophene-2-amine (200 mg, 0.67 mmol) in THF (5 mL), ethane isocyanate (48 mg, 0.67 mmol) and TEA (136 mg, 1.34 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure at 45 °C to remove THF. 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 preparative TLC to give the desired compound as a pale yellow solid (164 mg, yield: 65.4%). MS (ESI) m / z (M+H) + =367.1.

[0553] General methods for removing BOC

[0554] 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.

[0555] Example 12: Preparation of compound 1-(4-(2-(4-bromophenyl)prop-2-yl)thiazolyl)-3-((6-(piperazin-1-yl)pyridin-3-yl)methyl)urea hydrochloride

[0556]

[0557] To a solution of tert-butyl piperazine-1-carboxylate (70.0 mg, 113.71 μmol) in MeOH (2 mL), HCl / MeOH (4 M, 2 mL) was added. The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under vacuum. The desired compound was obtained as a white solid (47.0 mg, yield: 74.1%, HCl).

[0558] 1 H NMR(400MHz,DMSO-d6)δ10.90(br s,1H),9.66(br s,2H),8.05-7.92(m,2H),7.48-7.28(m,4H),7.21-7.10(m,2H),6.75(s,1H),4.30-4.20(m,2H),4.04-3.92(m,4H),3.24(br s,4H),1.57(s,6H). MS(ESI)m / z(M+H) + =517.2.

[0559] The following examples are similar to the programs in Examples 8, 9, 10, 11, and 12, using appropriate intermediates and corresponding fragments for synthesis:

[0560] Table 4

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622] Example 13: 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazolyl-2-yl)ureoyl)methyl)phenyl)piperazine-1- Preparation of tert-butyl formate

[0623]

[0624] Pd / C (12 mg) was added to a solution of 120 mg of 4-(4-((3-(4-(1-(4-bromophenyl)ethenyl)thiazo-2-yl)ureo)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester in MeOH (5 mL), and the mixture was stirred overnight at room temperature under hydrogen pressure. After filtration and evaporation, the residue was purified by silica gel column chromatography to give 73 mg of 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazo-2-yl)ureo)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester.

[0625] Example 14: 4-(5-((3-(4-(2-(4-bromophenyl)prop-2-yl)thiazolyl)ureoyl)methyl)-3-fluoropyridine Preparation of tert-butyl 2-pyridylpiperazine-1-carboxylate

[0626]

[0627] A suspension of 1-(4-(2-(4-bromophenyl)prop-2-yl)thiazolyl)-3-((6-chloro-5-fluoropyridin-3-yl)methyl)urea (174 mg, 0.4 mmol), piperazine-1-carboxylic acid tert-butyl ester (82 mg, 0.44 mmol), X-phos (39 mg, 0.08 mmol), Pd2(dba)3 (36.6 mg, 0.04 mmol), and t-BuONa (46.1 mg, 0.48 mmol) in toluene (5 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solid was filtered off. The residue was dissolved in ethyl acetate (100 mL) and washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography to give the desired product (67 mg, 25% yield).

[0628] Example 15: 5-((3-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)ureoyl)methyl)-2-(3-methyl) Preparation of 1-pyropiperazine-1-yl)benzamide

[0629]

[0630] Step 1: Preparation of 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-5-((3-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)ureo)methyl)benzoic acid

[0631]

[0632] A mixture of tert-butyl 4-(2-(methoxycarbonyl)-4-((3-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)ureido)methyl)phenyl)-2-methylpiperazin-1-carboxylate (270 mg, 0.42 mmol, 1 equivalent) and KOH (23.5 mg, 0.42 mmol, 1 equivalent) was heated to reflux for 0.5 hours. After cooling, the reaction was quenched with saturated NH4Cl (aqueous solution), extracted with EA, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative TLC to give the desired compound (215 mg).

[0633] Step 2: Preparation of tert-butyl 4-(2-carbamoyl-4-((3-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)ureo)methyl)phenyl)-2-methylpiperazine-1-carboxylate

[0634]

[0635] A mixture of 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-5-((3-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)ureo)methyl)benzoic acid (215 mg, 0.34 mmol, 1 equivalent), EDCI (132 mg, 0.69 mmol, 2 equivalent), HOBt (93 mg, 0.69 mmol, 2 equivalent), and DIEA (133 mg, 1.03 mmol, 3 equivalent) was dissolved in THF (0.1 M) and stirred at room temperature for 15 min. Then, NH4Cl (36.9 mg, 0.69 mmol, 2 equivalent) was added in a single batch and the reaction was stirred at room temperature. Once the reaction was complete as determined by TLC analysis, 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 or preparative TLC to obtain the desired product (201 mg).

[0636] Example 16: 1-((6-((2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)) Preparation of propionyl-2-yl)thiazolyl)urea

[0637]

[0638] A mixture of EtOH containing 1-((6-fluoropyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propyl-2-yl)thiazolyl-2-yl)urea (50 g, 0.13 mmol, 1.0 equivalent) and 2-aminoethanol (11.9 mg, 0.19 mmol, 1.5 equivalent) was heated to 90 °C for 14 hours. After cooling the reaction to room temperature, the mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography to give 1-((6-((2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propyl-2-yl)thiazolyl-2-yl)urea (21 mg).

[0639] Example 17: 1-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazolyl-2-yl)-3-(1-(4-(piperazine-1- Preparation of phenyl ethyl urea

[0640]

[0641] Step 1. Preparation of methyl (4-methoxyphenyl)acetate

[0642]

[0643] H₂SO₄ (1.2 g, 12.0 mmol, 642 μL) was added to a mixture of MeOH (100 mL) containing 2-(4-methoxyphenyl)acetic acid (20.0 g, 120.4 mmol) at 15 °C. The mixture was stirred at 85 °C for 12 hours. The mixture was diluted with EA (400 mL) and washed with saturated NaHCO₃. It was washed with saturated NaHCO₃ aqueous solution (100 mL) and brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 15%). The desired product (21.6 g, yield: 99.7%) was given as a yellow oil.

[0644] 1 H NMR(400MHz, CDCl3)δ7.21(d,J=8.8Hz,2H)6.87(d,J=8.8Hz,2H),3.80(s,3H),3.69(s,3H),3.58(s,2H)

[0645] Step 2. Preparation of compound methyl 2-(4-methoxyphenyl)-3-oxobutyrate

[0646]

[0647] LiHMDS (1M, 159mL) was added to a solution of the compound obtained in step 1 above (23.8g, 132.2mmol) in THF (200mL) at -78°C. The mixture was stirred at -78°C for 20 minutes. Acetyl acetate (13.5g, 132.2mmol) was added to the solution. The mixture was then warmed to 0°C and stirred at 0°C for 2 hours. The mixture was quenched with saturated NH4Cl aqueous solution (50mL) and extracted with EA (3×50mL). The combined organic layers were washed with brine (10mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0 to 15%) to give the desired compound (14.23g, yield: 48.4%) as a yellow oil.

[0648] 1 H NMR (400MHz, CDCl3) δ12.97(s,1H),7.25-7.23(m,1.5H),7.07-7.03(m,2H),6.87 -6.85(m,2H),4.63(s,0.5H),3.80(s,3H),3.78(s,1.5H),3.73(s,1.5H),3.67(s,3H),2.15(s,1.5H),1.83(s,3H). MS(ESI)m / z(M+H)+ =223.1

[0649] Step 3. Preparation of compound methyl 2-(4-methoxyphenyl)-2-methyl-3-oxobutyrate

[0650]

[0651] CH3I (26.0 g, 183.3 mmol) was added to a mixture of acetone (100 mL) containing the compound obtained from step 2 above (14.5 g, 65.4 mmol) and K2CO3 (45.2 g, 326.9 mmol) at 15 °C. The mixture was stirred at 70 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 15%). The desired compound (9.76 g, yield: 63.2%) was obtained as a colorless oil.

[0652] 1 H NMR (400MHz, CDCl3) δ7.25-7.19(m,2H),6.95-6.86(m,2H),3.82(s,3H),3.79(s,3H),2.10(s,3H),1.77(s,3H)

[0653] Step 4. Preparation of methyl 4-bromo-2-(4-methoxyphenyl)-2-methyl-3-oxobutyrate

[0654]

[0655] Br2 (676 mg, 4.2 mmol) was added to a solution of the compound obtained in step 3 (1 g, 4.2 mmol) in CHCl3 (20 mL) at 15 °C. The mixture was stirred at 73 °C for 12 hours. The mixture was washed with H2O (20 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The desired product (1.03 g, crude product) was obtained as a colorless oil. The crude product was used directly in the next step without further purification.

[0656] MS(ESI)m / z(M+H) + =315.1

[0657] Step 5. Preparation of methyl 2-(2-aminothiazol-4-yl)-2-(4-methoxyphenyl)propionate

[0658]

[0659] A mixture containing the compound obtained from step 4 above (1.03 g, 3.3 mmol), thiourea (299 mg, 3.9 mmol), and NaHCO3 (329 mg, 3.9 mmol) in MeOH (15 mL) was stirred at 50 °C for 1 hour. The mixture was concentrated directly under vacuum. The residue was ground with H2O (20 mL) at 15 °C for 10 minutes, filtered, and the filter cake was concentrated under vacuum to obtain the residue. The desired product (0.79 g, yield: 82.68%) was obtained as a yellow solid.

[0660] 1 H NMR (400MHz, CDCl3) δ7.20-7.18(m,2H),6.97-6.92(m,2H),6.88–6.86(m,2H),5.95(s,1H),3.73(s,3H),3.61(s,3H),1.77(s,3H).

[0661] Step 6. Preparation of methyl 2-(4-methoxyphenyl)-2-(2-((phenoxycarbonyl)amino)thiazol-4-yl)propionate

[0662]

[0663] To a mixture of CH3CN (3 mL) containing the compound obtained from step 5 above (300 mg, 1.03 mmol) and pyridine (97.4 mg, 1.23 mmol), phenyl chloroformate (169 mg, 1.08 mmol) was added at 0 °C. The mixture was stirred at 15 °C for 3 hours. The mixture was concentrated directly under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 30%) to give the desired compound (330 mg, yield: 77.97%) as a yellow oil.

[0664] MS(ESI)m / z(M+H) + =413.0

[0665] Step 7. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(1-methoxy-2-(4-methoxyphenyl)-1-oxopropyl-2-yl)thiazolyl-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylic acid

[0666]

[0667] A mixture containing 2 mL of THF (330 mg, 800 μmol) of the compound obtained from step 6 above and tert-butyl piperazine-1-carboxylate (269 mg, 880 μmol) was stirred in a microwave oven at 100 °C for 1 hour. The mixture was concentrated directly under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 80%). The desired compound (441 mg, yield: 88.37%) was obtained as a yellow oil.

[0668] MS(ESI)m / z(M+H) + =646.2

[0669] Step 8. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(1-hydroxy-2-(4-methoxyphenyl)propyl-2-yl)thiazolyl-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylic acid

[0670]

[0671] LiBH4 (26 mg, 1.2 mmol) was added to a solution of the compound obtained in step 7 above (370 mg, 593 μmol) in THF (10 mL) at 15 °C. The mixture was stirred at 15 °C for 12 hours. The mixture was diluted with saturated NH4Cl (15 mL) and extracted with EA (3 × 15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 100%) to give the desired compound (307 mg, yield: 87.0%) as a yellow solid.

[0672] 1 H NMR (400MHz, CDCl3) δ7.17 (d, J = 8.4Hz, 2H), 7.09-7.06 (m, 2H), 6.86-6.80 (m, 4H), 6.45 (s, 1H), 4.94-4.91 (m, 1H), 4.05-4.0 0(m,1H),3.81-3.77(m,4H),3.56-3.54(m,4H)3.09-3.07(m,4H),1.56(d,J=1.6Hz,3H),1.49(s,9H),1.46(d,J=6.8Hz,3H).

[0673] Step 9. Preparation of compound 1-(4-(1-hydroxy-2-(4-methoxyphenyl)propyl-2-yl)thiazolyl-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea hydrochloride

[0674]

[0675] HCl / EtOAc (4M, 2mL) was added to a solution of the compound obtained in step 8 above (50mg, 83.93μmol) in DCM (2mL) at 15°C. The mixture was stirred at 15°C for 12 hours. The mixture was concentrated under vacuum to give the desired compound (34mg, yield: 76.1%) as a yellow solid.

[0676] 1 H NMR(400MHz,DMSO)δ10.47(br s,1H),9.11(br s,2H),7.36-7.23(m,1H),7.19(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),6.75(d,J=8.0Hz,2H),6.69(s,1H),4.7 7-4.73(m,1H),3.80-3.76(m,1H),3.70(s,3H)3.34-3.31(m,4H),3.24-3.16(m,4H),2.07(s,1H),1.55(s,3H),1.33(d,J=6.8Hz,3H). MS(ESI)m / z(M+H) + =496.2

[0677] Step 10. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(2-(4-methoxyphenyl)-1-oxopropyl-2-yl)thiazolyl-2-yl)ureoyl)ethyl)phenyl)piperazine-1-carboxylic acid

[0678]

[0679] DMSO (66 mg, 839 μmol) was added to a solution of oxalyl chloride (68.2 g, 537.14 μmol) in DCM (2 mL) at -78 °C. After 10 minutes, DCM (2 mL) containing the compound obtained from step 9 above (100 mg, 168 μmol) was added and the mixture was stirred at -78 °C for 1 hour. Et3N (170 mg, 1.68 mmol) was added and the mixture was stirred for another 10 minutes, then heated to 15 °C and stirred for another hour. The mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The desired product (120 mg, crude product) was obtained as a yellow oil. The crude product was used directly in the next step without further purification.

[0680] Step 11. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazolyl-2-yl)ureoyl)ethyl)phenyl)piperazine-1-carboxylate

[0681]

[0682] A mixture of MeOH (5 mL) containing the compound obtained from step 10 above (100 mg, 168 μmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (49 mg, 252.6 μmol), and K2CO3 (47 mg, 337 μmol) was stirred at 15 °C for 1 hour. The reaction mixture was concentrated directly under vacuum. The residue was purified by preparative HPLC (column: Venusil ASB Phenyl 150*30 mm*5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 65% to 95%, 10 min) to obtain the desired compound (50 mg, yield: 50.34%) as a yellow oil.

[0683] MS(ESI)m / z(M+H) + =590.3

[0684] Step 12. Preparation of compound 1-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazolyl-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea

[0685]

[0686] The desired compound (39 mg, yield: 87.4%) was obtained as a yellow solid by the de-BOC method.

[0687] 1 H NMR(400MHz,DMSO-d6)δ10.50(br s,1H),9.22(br s,2H),7.31(d,J=8.8Hz,2H),7.19(d,J=8.4Hz,3H),6.95(d,J=8.4Hz,2H),6.85(dd,J=8.4,1.2Hz,2H),6.81-6.79(m,1H),4. 76-4.73(m,1H),3.71(s,3H),3.39(s,1H),3.35-3.32(m,4H)3.24-3.16(m,4H),1.82(d,J=2.4Hz,3H),1.33(d,J=6.8Hz,3H).

[0688] MS(ESI)m / z(M+Na) + =512.3

[0689] Example 18: 1-(4-(2-(4-cyclopropylphenyl)propyl-2-yl)thiazolyl-2-yl)-3-(4-(piperazin-1-yl)benzyl) Preparation of urea

[0690]

[0691] Step 1: Preparation of tert-butyl piperazine-1-carboxylate

[0692]

[0693] To a solution of the compound obtained in step 1 above (81 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL), cyclopropylboronic acid (14 mg, 0.16 mmol), Pd(dppf)Cl2 (10 mg, 0.013 mmol), and KOAc (25 mg, 0.26 mmol) were added. The reaction mixture was stirred overnight at 115 °C under a N2 atmosphere. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was filtered through a diatomaceous earth filter and washed with EA. The filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 2:1) to give the desired compound (45 mg, yield: 60.2%) as a white solid.

[0694] Step 2. Preparation of compound 1-(4-(2-(4-cyclopropylphenyl)prop-2-yl)thiazolyl)-3-(4-(piperazin-1-yl)benzyl)urea

[0695]

[0696] The desired compound (40 mg, HCl salt, yield: 100%) was obtained as a white solid using the procedure described in Example 9. MS (ESI) m / z (M+H) + =476.2.

[0697] Example 19: 1-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazolyl)-3-(2-hydroxyethyl-2,2-d2)urea

[0698]

[0699] Step 1. Preparation of compound N-(2,2-dideuterium-2-hydroxyethyl)carbamate tert-butyl ester

[0700]

[0701] LiAlD4 (364.8 mg, 7.93 mmol) was added to a solution of methyl 2-((tert-butoxycarbonyl)amino)acetate (1 g, 5.29 mmol) in THF (20 mL) at 0 °C, and the mixture was stirred at 80 °C for 3 hours. EA (20 mL) and H2O (5 mL) were added dropwise, followed by extraction with EA (100 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The desired compound (610 mg, yield: 70.7%) was obtained as a yellow oil and used in the next step without further purification.

[0702] 1 H NMR (400MHz, CDCl3) δ5.17 (br s, 1H), 3.24 (d, J = 5.6Hz, 2H), 3.08 (br s, 1H), 1.42 (s, 9H).

[0703] Step 2. Preparation of compound 2-amino-1,1-dideuterium-ethanol

[0704]

[0705] The mixture of HCl / MeOH (4M, 5mL) containing the compound obtained from step 1 above (610 mg, 3.74 mmol) was stirred at 25°C for 3 hours. The reaction mixture was concentrated. The desired compound (520 mg, crude, HCl) was obtained as a yellow oil, which was used in the next step without further purification.

[0706] 1 H NMR (400MHz, DMSO-d6) δ2.80 (q, J=5.7Hz, 2H).

[0707] Step 3. Preparation of compound N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazolyl-2-yl]carbamate

[0708]

[0709] To a solution of 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-amine (500 mg, 1.90 mmol) and pyridine (752.60 mg, 9.51 mmol) in MeCN (20 mL), phenyl chloroformate (327.7 mg, 2.09 mmol) was added, and the mixture was stirred at 0 °C for 1 hour. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The desired compound (830 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification.

[0710] MS(ESI)m / z(M+H) + =383.0

[0711] Step 4. Preparation of compound 1-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazolyl-2-yl]-3-(2,2-dideuter-2-hydroxyethyl)urea

[0712]

[0713] A mixture of DCE (20 mL) containing the compound obtained from step 3 above (400 mg, 1.04 mmol), the compound obtained from step 2 above (98.9 mg, 1.57 mmol), and DMAP (12.8 mg, 104.48 μmol) was stirred at 80 °C for 5 hours. The reaction mixture was concentrated. The residue was passed through a preparative HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (HCl)-ACN]; B%: 28% to 58%, 10 min). The desired compound was obtained as a white solid (90 mg, yield: 24.5%).

[0714] MS(ESI)m / z(M+H) + =352.1.

[0715] SFC: Column: ChiralPak IG-3 100×4.6mm ID, 3µm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Gradient: 5% to 40% B over 5.5 min and hold at 40% for 3 min, then 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C (P1:Rf = 4.159 min, P2:Rf = 4.831 min).

[0716] Step 5. Preparation of compound 1-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazolyl-2-yl]-3-(2,2-dideuter-2-hydroxyethyl)urea

[0717]

[0718] The compound from step 4 above (90 mg, 255.79 μmol) was obtained by SFC (column: CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2OETOH]; B%: 40% to 40%, min). Chiral isomer 1 (26.85 mg, yield: 29.8%) was obtained as a white solid.

[0719] 1 H NMR (400MHz, CDCl3) δ7.34-7.28(m,2H),7.22-7.19(m,2H),6.69(s,1H),3.23(d,J=5.5Hz,2H),2.48(s,1H),1.84(s,3H). MS(ESI)m / z(M+H) + =351.9. SFC Rf=4.151 minutes.

[0720] Chiral isomer 2 was obtained as a white solid (27.90 mg, yield: 31.0%).

[0721] 1 H NMR (400MHz, CDCl3) δ7.43-7.35(m,2H),7.31-7.27(m,2H),6.76(s,1H),3.31(d,J=5.5Hz,2H),2.55(s,1H),1.92(s,3H). MS(ESI)m / z(M+H) + =351.9. SFC:Rf=4.815 minutes.

[0722] General Method A

[0723] Carboxylic acid (1 equivalent), EDCI (2 to 2.5 equivalents), with or without HOBt (2 equivalents), and DIEA (3 equivalents) / pyridine / DMAP were dissolved in THF / DMF and stirred at room temperature 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 residue was purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0724] Example 20: Compound 4-((2-hydroxyethyl)amino)-N-(4-(2-(4-methoxyphenyl)propyl-2-yl)thiazolyl-2- Preparation of (B-)benzamide

[0725]

[0726] EDCI (440.84 mg, 2.30 mmol) was added to a solution of 4-((2-hydroxyethyl)amino)benzoic acid (200 mg, 1.10 mmol) and 4-[1-(4-methoxyphenyl)-1-methyl-ethyl]thiazol-2-amine (261.98 mg, 919.85 μmol, HCl) in Py (8 mL). The mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was subjected to preparative HPLC (column: Agela ASB 150 × 25 mm × 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 48% to 78%, 10 min). The desired compound was given as a yellow solid (52 mg, yield: 13.57%).

[0727] 1 H NMR(400MHz,DMSO-d6)δ12.06(br s,1H),7.87(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),6.86(s,1H),6.82(d,J=8.8Hz,2H),6. 62(d,J=8.8Hz,2H),3.70(s,3H),3.54(t,J=5.9Hz,2H),3.16(t,J=5.9Hz,2H),1.62(s,6H). MS(ESI)m / z(M+H) + =412.5.

[0728] General Method B

[0729] Acyl chlorides were obtained by using SOCl2 in a suitable solvent (e.g., DCM). TEA or pyridine (3 equivalents) and an amine (1 equivalent) were slowly added to a solution of acyl chloride in DCM at 0°C under N2, and the mixture was further stirred at room temperature for 0.5 to 2 hours. Once the reaction was complete, it was quenched with H2O, extracted with EA and washed with brine, then dried (Na2SO4), filtered, and evaporated to dryness. The resulting residue was purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0730] Example 21

[0731]

[0732] SOCl2 (31.8 μL, 438.16 μL) was added to a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (150 mg, 438.16 μL) in DCM (6 mL). The mixture was stirred at 25 °C for 1 hour. Py (176.74 μL, 2.19 mmol) was added and the reaction mixture was stirred at 25 °C for 5 minutes, followed by the addition of 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-amine (115.07 mg, 437.94 μL) and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to give a residue. The residue was subjected to rapid silica gel chromatography (PE:EA = 1:0 to 1:1). The desired compound was given as a colorless oil (152 mg, yield: 54.4%).

[0733] MS(ESI)m / z(M+H) + =587.1.

[0734] Example 22: Compound N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)-1H-imidazol-2-yl)-2,6-difluoro- Preparation of 4-(piperazin-1-yl)benzamide

[0735]

[0736] Step 1. Preparation of methyl 2-(4-chlorophenyl)-2-(imidazo[1,2-a]pyrimidin-2-yl)propionate

[0737]

[0738] A mixture of EtOH (20 mL) containing pyrimidine-2-amine (1.0 g, 10.5 mmol) and methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxo-butyrate (3.36 g, 10.5 mmol) was stirred at 80 °C for 16 hours. The reaction was concentrated under reduced pressure and diluted with CH2Cl2 (40 mL) and saturated NaHCO3 aqueous solution (20 mL), and the aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give methyl 2-(4-chlorophenyl)-2-imidazo[1,2-a]pyrimidine-2-yl propionate (1.48 g, yield: 40.1%) as a white solid.

[0739] MS(ESI)m / z(M+H) + =316.0.

[0740] Step 2. Preparation of methyl 2-(2-amino-1H-imidazol-4-yl)-2-(4-chlorophenyl)propionate

[0741]

[0742] To a solution of methyl 2-(4-chlorophenyl)-2-imidazo[1,2-a]pyrimidin-2-yl propionate (600 mg, 1.90 mmol) in dioxane (5 mL), NH₂NH₂·H₂O (650 mg, 11.04 mmol, 85% purity) was added. After addition, the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO₂, DCM:MeOH = 100 / 1 to 10 / 1) to give methyl 2-(2-amino-1H-imidazo-4-yl)-2-(4-chlorophenyl) propionate (60 mg, yield: 33.9%) as a white solid.

[0743] MS(ESI)m / z(M+H) + =280.1.

[0744] 1 H NMR (400MHz, CD3OD) δ7.29 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 3.72 (s, 3H), 1.79 (s, 3H).

[0745] Step 3. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)-1-methoxy-1-oxopropyl-2-yl)-1H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0746]

[0747] SOCl2 (92 mg, 772 μmol) was added to a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (220 mg, 644 μmol) in DCM (10 mL), followed by the addition of DMF (13 mg, 172 μmol). The reaction mixture was stirred at 25 °C for 1 hour. Then, Py (204 mg, 2.57 mmol) was added to the reaction mixture and stirred at 25 °C for 10 minutes. Finally, methyl 2-(2-amino-1H-imidazol-4-yl)-2-(4-chlorophenyl)propionate (120 mg, 429 μmol) was added to the reaction mixture and stirred at 25 °C for 16 hours. The reaction mixture was washed with saturated NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (120 mg, yield: 38.9%, purity 84%).

[0748] MS(ESI)m / z(M+H) + =604.1.

[0749] Step 4. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)-1-hydroxypropyl-2-yl)-1H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0750]

[0751] LiBH4 (4M, 248 μL) was added to a solution of 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (120 mg, 199 μmol) in THF (8 mL) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into 5 mL of saturated NH4Cl and extracted with EtOAc (8 mL × 2). The extract was washed with water (8 mL × 3) and brine (8 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-hydroxy-1-methyl-ethyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (110 mg, crude product), which was used in the next step without any purification.

[0752] MS(ESI)m / z(M+H) + =576.1.

[0753] Step 5. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)-1-oxopropyl-2-yl)-1H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0754]

[0755] DMP (500 mg, 1.18 mmol) was added to a solution of 4-[4-[[4-[1-(4-chlorophenyl)-2-hydroxy-1-methyl-ethyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (170 mg, 295 μmol) in DCM (10 mL). After addition, the reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with DCM (10 mL), washed three times with saturated NaHCO3 / saturated Na2S2O3 (10 mL / 10 mL), then washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-2-oxo-ethyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (150 mg, crude), which was used in the next step without any purification.

[0756] Step 6. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)but-3-yn-2-yl)-1H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0757]

[0758] To a solution of tert-butyl piperazine-1-carboxylate (150 mg, 261 μmol) and 1-diazo-1-dimethoxyphosphoryl-prop-2-one (75.3 mg, 392 μmol) in MeOH (8 mL), K₂CO₃ (72.2 mg, 522.63 μmol) was added. After addition, the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was diluted with 10 mL of water and extracted with EtOAc (10 mL × 2). The combined extracts were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (FA conditions) to give tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (12 mg, yield: 8.1%) as a milky white solid.

[0759] Step 7. Preparation of compound N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)-1H-imidazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide

[0760]

[0761] To a solution of 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazin-1-carboxylic acid tert-butyl ester (12 mg, 21.05 μmol) in MeOH (0.3 mL), HCl / dioxane (4 M, 900 μL) was added. After addition, the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (TFA conditions) to give N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]-1H-imidazol-2-yl]-2,6-difluoro-4-piperazin-1-yl-benzamide (5 mg, yield: 40.2%, 2HCl salt) as a light brown solid.

[0762] MS(ESI)m / z(M+Na) + =492.3.

[0763] 1H NMR (400MHz, CD3OD) δ7.52(br d,J=8.4Hz,2H),7.40(br d,J=8.4Hz,2H),7.22(s,1H),6.76(br d,J=12.4Hz,2H),3.65-3.59(m,4H),3.39-3.32(m,4H),3.20(s,1H),1.97(s,3H).

[0764] Example 23: N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)oxazol-2-yl)-2,6-difluoro-4-(piperazine-1-) Preparation of (B-)benzamide

[0765] Step 1. Preparation of methyl 2-(2-aminooxazol-4-yl)-2-(4-chlorophenyl)propionate

[0766] Urea (282 mg, 4.69 mmol) was added to a solution of methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutyrate (1.00 g, 3.13 mmol) in EtOH (30 mL), and the mixture was stirred at 80 °C for 20 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give methyl 2-(2-aminooxazol-4-yl)-2-(4-chlorophenyl)propionate (50.0 mg, yield: 4.2%) as a yellow solid.

[0767] MS(ESI)m / z(M+H) + =281.1.

[0768] 1 H NMR (400MHz, CD3OD) δ7.31 (s, 4H), 6.98 (s, 1H), 3.71 (s, 3H), 1.85-1.79 (m, 3H).

[0769] Step 2. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)-1-methoxy-1-oxopropyl-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0770]

[0771] SOCl2 (38.0 mg, 321 μmol) was added to a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (91.0 mg, 267 μmol) in DCM (5 mL). DMF (5.0 mg, 71.3 μmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. Then, Py (85.0 mg, 1.07 mmol) was added to the above reaction mixture, and the mixture was stirred at 25 °C for 10 minutes. Then, methyl 2-(2-aminooxazol-4-yl)-2-(4-chlorophenyl)propionate (50.0 mg, 178 μmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was washed with saturated NaHCO3 (3 mL) and brine (3 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (42.0 mg, yield: 30%) as a colorless gel.

[0772] MS(ESI)m / z(M+H) + =605.1.

[0773] Step 3. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)-1-hydroxypropyl-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0774]

[0775] Under a nitrogen atmosphere at 0°C, a solution of 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (40.0 mg) in THF (2 mL) was added to a solution of LiBH4 (4 M, 83 μL) in THF (3 mL). After addition, the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into 5 mL of saturated NH4Cl and extracted with EtOAc (8 mL × 2). The extract was washed with water (8 mL × 3) and brine (8 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-hydroxy-1-methyl-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (28.0 mg, crude) as a white solid, which was used in the next step without any purification.

[0776] Step 4. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)-1-oxopropyl-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0777]

[0778] DMP (41.0 mg, 97.05 μmol) was added to a solution of 4-[4-[[4-[1-(4-chlorophenyl)-2-hydroxy-1-methyl-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (28.0 mg, crude) in DCM (5 mL). After addition, the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was diluted with DCM (10 mL), washed three times with saturated NaHCO3 / Na2S2O3 (10 mL / 10 mL), then washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-2-oxo-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (30.0 mg, crude) as a light brown solid, which was used in the next step without any purification.

[0779] MS(ESI)m / z(M+H) + =575.1.

[0780] Step 5. Preparation of compound 4-(4-((4-(2-(4-chlorophenyl)but-3-yn-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0781]

[0782] K₂CO₃ (14.0 mg, 10⁴ μmol) was added to a solution of 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-2-oxo-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (30.0 mg, crude) and 1-diazo-1-dimethoxyphosphoryl-prop-2-one (15.0 mg, 78.3 μmol) in MeOH (4 mL). After addition, the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under vacuum, the residue was diluted with H2O (5 mL), extracted with EtOAc (5 mL × 3), the combined extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (28.0 mg, crude product), which was a light brown gel.

[0783] MS(ESI)m / z(M+H) + =571.1.

[0784] Step 6. Preparation of compound N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)oxazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide

[0785]

[0786] TFA (2 mL) was added to a solution of 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylic acid tert-butyl ester (25.0 mg, crude) in DCM (2 mL). After addition, the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (FA conditions) to give N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]oxazol-2-yl]-2,6-difluoro-4-piperazine-1-yl-benzamide (7.5 mg, yield: 28.7%, TFA salt) as a light brown solid.

[0787] MS(ESI)m / z(M+H) + =471.3.

[0788] 1H NMR (400MHz, CD3OD) δ7.64 (s, 1H), 7.58 (br d, J = 8.0Hz, 2H), 7.39-7.29 (m, 2H), 6.72 (br d,J=11.8Hz,2H),3.65-3.54(m,4H),3.42-3.35(m,4H),2.98(s,1H),1.90(s,3H).

[0789] General Method C

[0790] Carboxylic acid (1 equivalent), HATU (1.2 equivalents) or HBTU or PyBOP, and TEA or DIEA (3 equivalents) are dissolved in a suitable organic solvent (such as THF or DMF) and stirred at room temperature for 15 to 30 minutes. Then, an amine (1 to 1.5 equivalents) is added in a single addition, and the reaction mixture is stirred at room temperature to 100°C for 4 to 16 hours. Once the reaction is complete, the resulting suspension is diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the residue is purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0791] Example 24: Preparation of compound N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazolyl)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-methylformamide

[0792]

[0793] PyBOP (2.00 g, 3.84 mmol) was added to a solution of 3-[tert-butyl(diphenyl)silyl]oxocyclobutanecarboxylic acid (1.36 g, 3.84 mmol) in DCM (10 mL) at 25 °C. After stirring for 10 min, methyl 2-(2-aminothiazol-4-yl)-2-(4-bromophenyl)propionate (523.61 mg, 1.53 mmol) and DIPEA (594.97 mg, 4.60 mmol) were added at 25 °C, and the mixture was stirred at 25 °C for 12 h. The mixture was diluted with DCM (30 mL), washed with H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 25%). The desired compound (1.4 g, crude) was obtained as a yellow oil. MS(ESI)m / z(M+H) + =643.1

[0794] Table 5. The following examples are similar to the programs in Examples 20, 21, and 24, synthesized using appropriate intermediates and corresponding fragments.

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817] Table 6: The following examples are similar to the programs in Examples 20, 21, 22, 23, and 24, synthesized using appropriate intermediates and corresponding fragments.

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829] Table 7. The following examples are similar to the programs in Examples 21 and 24, synthesized using appropriate intermediates and corresponding fragments.

[0830]

[0831]

[0832]

[0833] Example 25: 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propyl-2-yl)thia (Zyr-2-yl)nicotinamide

[0834]

[0835] Step 1. Preparation of compound 6-chloro-N-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)nicotinamide

[0836]

[0837] A mixture of pyridine (3 mL) containing compound 4-(2-(4-methoxyphenyl)propyl-2-yl)thiazol-2-amine (100 mg, 0.35 mmol, HCl salt), compound 6-chloronicotinic acid (83.0 mg, 0.53 mmol), and EDCI (135 mg, 0.70 mmol) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (PE:EA = 2:1). The desired compound was given as a yellow oil (63 mg, 46.26% yield).

[0838] MS(ESI)m / z(M+H) + =388.0

[0839] Step 2. Preparation of compound 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl)nicotinamide

[0840]

[0841] A mixture of DMF (5 mL) containing the compound obtained from step 1 above (63 mg, 0.16 mmol), N,N-dimethylethane-1,2-diamine (43.0 mg, 0.49 mmol), and DIEA (84.0 mg, 0.65 mmol) was stirred at 65 °C for 16 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC (water (0.05% HCl)-ACN). The desired compound was obtained as a yellow solid (25.01 mg, 35.0% yield).

[0842] 1 H NMR(400MHz,MeOD)δ8.43-8.32(m,1H),8.18-8.11(m,1H),7.35(s,1H),7.23 -7.14(m,3H),6.83(d,J=8.8Hz,2H),6.79(s,1H),3.76(m,4H),1.70(s,6H).

[0843] MS(ESI)m / z(M+H) + =440.2

[0844] Example 26: Compound 6-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-N-(4-(2-(p-tolyl)prop-2-yl) Preparation of (2-yl)thiazolyl)nicotinamide

[0845]

[0846] To a solution of compound 6-(piperazin-1-ylmethyl)-N-(4-(2-(p-tolyl)propyl-2-yl)thiazolyl-2-yl)nicotinamide (0.03 g, 69 μmol, 1 equivalent) in CH3CN (10 mL), 2-bromoethanol (9.47 mg, 76 μmol, 5 μL, 1.1 equivalent) and K2CO3 (19 mg, 137.8 μmol, 2 equivalent) were added. The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (water (0.225% FA)-ACN; B%: 15% to 45%, 7.5 min). The compound was given as a white solid (2.3 mg, yield: 6.9%).

[0847] 1H NMR (400MHz, CDCl3) δ9.09-9.05(m,1H),8.33-8.28(m,1H),7.75(br d,J=8.8Hz,3H),7.45-7.41(m,1H),7.13-7.08(m,3H),7.06-7.02(m,1H),6.61-6.57(m,1H),3.83-3 .77(m,3H),3.64-3.55(m,1H),2.45-2.38(m,8H),2.26-2.18(m,1H),1.63-1.58(m,3H),1.19(s,6H). MS(ESI)m / z(M+H) + =480.3.

[0848] Example 27: (1r,3r)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazolyl-2-yl)-3-(hydroxymethyl)cyclo Butane-1-carboxamide

[0849]

[0850] Step 1. Preparation of compound methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane carboxylate

[0851]

[0852] TBDPSCl (458 mg, 1.66 mmol, 427 μL) was added to a solution of methyl 3-(hydroxymethyl)cyclobutanecarboxylate (200 mg, 1.39 mmol) and imidazole (189 mg, 2.77 mmol) in DCM (5 mL) at 25 °C. The solution was stirred at 25 °C for 12 hours. The mixture was diluted with DCM (30 mL), washed with H2O (3 × 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 20%). The desired compound was given as a yellow oil (420 mg, yield: 79.1%).

[0853] MS(ESI)m / z(M+H) + =383.1

[0854] Step 2. Preparation of compound 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylic acid

[0855]

[0856] At 0°C, LiOH·H2O (90.6 mg, 2.16 mmol) was added to a mixture of THF (1.5 mL), MeOH (0.5 mL), and H2O (0.5 mL) containing the compound obtained from step 1 (412 mg, 1.08 mmol). The mixture was stirred at 25°C for 3 hours. The mixture was diluted with H2O (15 mL) to adjust the pH to 6 to 7, and extracted with EA (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The desired compound (413 mg, crude) was obtained as a yellow solid. The crude product was used directly in the next step without further purification.

[0857] MS(ESI)m / z(M+Na) + =391.1

[0858] Step 3. Preparation of methyl 2-(4-bromophenyl)-2-(2-((1R,3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutaneformamido)thiazolyl-4-yl)propionate

[0859]

[0860] A solution of the compound obtained in step 2 above (410 mg, 1.11 mmol) and DIPEA (173 mg, 1.34 mmol, 233 μL) in DCM (5 mL) was stirred at 20 °C for 10 min. Methyl 2-(2-aminothiazol-4-yl)-2-(4-bromophenyl)propionate (152 mg, 446 μmol) and PyBOP (580 mg, 1.11 mmol) were added at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with DCM (30 mL), washed with H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 20%). The desired compound A (194 mg, crude) was obtained as a yellow oil. Another desired compound B (186 mg, crude) was obtained as a yellow oil. The crude product is used directly in the next step without further purification. The chiral product is then identified in the final step.

[0861] Step 4. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)-1-hydroxypropyl-2-yl)thiazolyl-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutaneformamide

[0862]

[0863] LiBH4 (31 mg, 1.40 mmol) was added to a solution of the compound obtained in step 3 above in THF (5 mL) at 20 °C. The mixture was stirred at 20 °C for 12 hours. The mixture was quenched with saturated NH4Cl aqueous solution (10 mL), diluted with H2O (20 mL), and extracted with EA (20 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 30%). The desired compound was given as a yellow oil (77 mg, yield: 41.4%).

[0864] MS(ESI)m / z(M+H) + =663.1

[0865] Step 5. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)-1-oxopropyl-2-yl)thiazolyl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane formamide

[0866]

[0867] A solution of the compound obtained in step 4 above (77 mg, 132 μmol) in DCM (2 mL) was added to a mixture containing Desmond (73 mg, 171.2 μmol, 53 μL) at 20 °C. The mixture was stirred at 20 °C for 3 hours. The mixture was quenched with saturated NaHCO3 (10 mL) / saturated Na2S2O4 (10 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the residue. The desired compound (77 mg, crude) was obtained as a yellow solid. The crude product was used directly in the next step without further purification.

[0868] Step 6. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazolyl-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutaneformamide

[0869]

[0870] A solution of the compound obtained in step 5 above (77 mg, 116 μmol), 1-diazo-1-dimethoxyphosphoryl-prop-2-one (34 mg, 174.5 μmol), and K2CO3 (32 mg, 232.7 μmol) in MeOH (2 mL) was stirred at 20 °C for 12 hours. The mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 15%). The desired compound (37 mg, yield: 48.3%) was obtained as a yellow oil.

[0871] MS(ESI)m / z(M+H) + =657.1

[0872] Step 7. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazolyl)-3-(hydroxymethyl)cyclobutaneformamide

[0873]

[0874] TBAF (1M, 0.1mL) was added to a solution of the compound obtained in step 6 above (37mg, 56.3μmol) in THF (2mL) at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with EA (50mL), washed with H2O (10mL×3) and brine (10mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate in petroleum ether = 0 to 15%). The desired compound was given as a yellow solid (12.61mg, yield: 53.5%).

[0875] 1 H NMR (400MHz, CDCl3) δ13.28 (br s, 1H), 7.56-7.48 (m, 4H), 6.91 (s, 1H), 3.65 (d, J = 4.4Hz, 2H), 3.34 -3.30(m,1H),2.77(s,1H),2.63-2.61(m,1H),2.52-2.43(m,2H),2.34-2.32(m,2H),2.15(s,3H). MS(ESI)m / z(M+H) + =419.0.

[0876] Other isomers can be synthesized using a procedure similar to that described above.

[0877] Example 28: 4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-N-(4-(2-(4-methoxyphenyl)propyl-2-yl) Thiazol-2-yl)benzamide

[0878]

[0879] To a solution of compound 4-formyl-N-(4-(2-(4-methoxyphenyl)prop-2-yl)thiazolyl-2-yl)benzamide (120 mg, 0.32 mmol) and 2-(piperazin-1-yl)ethanol-1-ol (42 mg, 0.32 mmol) in DCM (5 mL), NaBH3CN (59 mg, 0.95 mmol) and HOAc (2 drops) were added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give a residue. The residue was purified by rapid silica gel chromatography (DCM:MeOH = 1:0 to 10:1). The desired compound was given as a white solid (80 mg, yield: 51.4%).

[0880] MS(ESI)m / z(M+H) + =495.2

[0881] How to use

[0882] ALPK1 is a cytoplasmic serine-threonine protein kinase that plays a crucial role in activating the innate immune response. ALPK1 binds to bacterial pathogen-associated molecular pattern metabolites (PAMPs), specifically ADP-D-glycero-β-D-mannohepose (ADP-heptaose). ALPK1-ADP-heptaose binding occurs via a direct interaction at the N-terminal domain of ALPK1. This interaction stimulates the kinase activity of ALPK1, its phosphorylation, and activation of the TRAF-interacting protein-fork-associated domain (TIFA). TIFA activation, in turn, triggers pro-inflammatory NF-κB signaling, including the expression and / or secretion of pro-inflammatory cytokines and chemokines. Therefore, the compounds disclosed herein can generally be used as inhibitors of ALPK1 kinase activity and downstream activation of NF-κB pro-inflammatory signaling.

[0883] This disclosure provides the use of a compound of Formula I or a sub-example thereof as described herein for inhibiting ALPK1 kinase activity and reducing inflammation in target tissues. The method also covers the use of a compound of Formula I or a sub-example thereof as described herein for treating diseases, conditions, or symptoms characterized by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling. In the embodiments, the disease, condition, or symptom is selected from sepsis, cancer, spirochetal adenoma, spirochetal adenocarcinoma, ROSAH syndrome ("Retinal Dystrophy, Optic Edema, Splenomegaly, Anhidrosis, and Migraine"), and PFAPA syndrome ("Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis"). In the embodiments, the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma. In the embodiments, the cancer is oral squamous cell carcinoma.

[0884] In embodiments, this disclosure provides a method for inhibiting ALPK1 kinase activity in mammalian cells or target tissues by contacting them with a compound of Formula I 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 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 a compound of Formula I or a sub-example described herein or a pharmaceutical composition comprising the compound to the subject.

[0885] In embodiments, this disclosure provides a method for treating a subject suffering from a disease or condition characterized by excessive or inappropriate activation of ALPK1 kinase activity, the method comprising administering a compound of formula I or a sub-example described herein to the subject. In embodiments, the disease or condition is selected from sepsis, cancer, spirochetal adenoma, spirochetal adenocarcinoma, ROSAH syndrome, and PFAPA syndrome.

[0886] In an embodiment, the disease or condition is a spiral adenoma or spiral adenocarcinoma, and the method comprises administering a compound of formula I or a sub-embodiment described herein to a subject requiring such treatment. In an embodiment, the subject requiring treatment is a subject diagnosed with a spiral adenoma or spiral adenocarcinoma and carrying one or more gene mutations in ALPK1. In an embodiment, at least one of the gene mutations is an activating mutation. In an embodiment, the gene variant in ALPK1 is p.V1092A, as described by Rashid et al., Nature Communications (2019).

[0887] In an embodiment, the disease or condition is ROSAH, and the method comprises administering a compound of formula I or a sub-embodiment described herein to a subject who requires 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 of the gene mutations 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., Medical Genetics 21:2103-2115 (2019).

[0888] In an embodiment, the disease or condition is PFAPA, and the method comprises administering a compound of formula I or a sub-embodiment described herein to a subject requiring such treatment. In an embodiment, the subject requiring treatment is a subject diagnosed with PFAPA or exhibiting clinical symptoms of PFAPA and carrying one or more gene mutations in ALPK1. In an embodiment, at least one of the gene mutations 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).

[0889] 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.

[0890] In embodiments, this disclosure further provides a method for identifying a disease, condition, or symptom for treatment with a compound of Formula I or a sub-example described herein, the method comprising determining 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, compared to reference cells or tissues not involved in the disease, condition, or symptom. In an embodiment, the activating mutation in ALPK1 is 2770T>C, p.(S924P).

[0891] In the context of the methods described herein, the term "treatment" may refer to the improvement or stabilization of one or more symptoms associated with the disease, condition, or symptom being treated. The term "treatment" may also encompass the management of a disease, condition, or symptom, referring to a beneficial effect obtained by a subject from a therapy that does not result in a cure for the underlying disease, condition, or symptom.

[0892] In embodiments in which a therapeutically effective amount of the compound described herein 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.

[0893] 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.

[0894] 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.

[0895] In this embodiment, human subjects are selected from adults, children, or elderly patients, terms that are understood by a practicing physician, such as those defined by the U.S. Food and Drug Administration.

[0896] Pharmaceutical Composition

[0897] In the embodiments, this disclosure provides pharmaceutical compositions comprising a compound of formula I or a sub-example thereof as described herein, and one or more carriers or excipients, preferably pharmaceutically acceptable carriers or excipients. As used herein, the phrase “pharmaceutically acceptable” means those compounds, materials, compositions, carriers, and / or dosage forms that are suitable for contact with human and animal tissues 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.

[0898] 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 the active compound calculated to produce the desired therapeutic effect, along 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.

[0899] 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 symptom, disease, or condition.

[0900] The pharmaceutical compositions described herein can 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 orally acceptable dosage forms, including but not limited to capsules, tablets, sublingual forms, lozenges, sugar tablets, 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 such as 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.

[0901] In the embodiments, the pharmaceutical composition is in tablet form. 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. Those that are sold will achieve this.

[0902] 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 lauryl 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 sugars. 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, dehydrated sorbitol ester, colloidal silica, phosphates, sodium lauryl sulfate, magnesium aluminum silicate, and triethanolamine.

[0903] In the embodiments, the pharmaceutical composition is in the form of hard or soft gelatin capsules. According to this formulation, the compounds of the present invention can be in solid, semi-solid, or liquid form.

[0904] 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, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0905] 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. The solution or suspension may be prepared in water with the aid of 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.

[0906] 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 bottles, vials, ampoules, blister packs, and syringes. The kit may further comprise 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.

[0907] Unless otherwise specified, all percentages and ratios used herein are by weight.

[0908] The invention is further described and illustrated by the following non-limiting examples.

[0909] Example

[0910] In the embodiments, the compound of Formula I or the sub-examples described herein are inhibitors of ALPK1, such as those measured in in vitro kinase assays, or assays designed to measure the activation of downstream targets of ALPK1 pathway activation (e.g., NF-κB transcriptional activation) and the secretion of pro-inflammatory cytokines and chemokines (e.g., IL-8, also known as CXCL-8). Typically, the computer program XL fitting 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 logical equation: Y = minimum + (maximum - minimum) / (1 + (X / IC50)^-1), where Y is the value at compound concentration X. Concentration response curve fitting is performed using GraphPad Prism version 6.00 software.

[0911] ALPK1 in vitro kinase assay

[0912] ALPK1 kinase activity was measured in an in vitro assay 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.

[0913] In short, cultured in antibiotics (penicillin / streptomycin, G418) supplemented with 10% fetal bovine serum (FBS, Hyclone) TMHEK293 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 of 2 nM in the reaction mixture), and kinase buffer (100 mM HEPES pH 7.4, 4 mM DTT, 40 mM MgCl2, 20 mM β-glycerophosphate disodium salt, 0.4 mM Na3VO4, 0.16 mg / mL). Titration solutions of the test compounds were prepared in dimethyl sulfoxide (DMSO). The reaction was initiated by the addition of ATP and ADP-heptanose.

[0914] For HTRF, refer to the manufacturer's instructions (PerkinElmer). TM (PerkinElmer TM CisBio TM The sample was incubated with a Tb-labeled anti-HA antibody to capture the HA-labeled protein, and the fluorescence signal (Tecan Infinite F NANO+) was quantified. 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).

[0915] In this assay, all compounds showed a dose-dependent decrease in TIFA phosphorylation. IC50 values ​​were determined using GraphPadPrism version 6.00 with 3- or 4-parameter logic equations. 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 1000 nM and are shown below. Tables 4 to 7 middle.

[0916] NFκB gene reporter alkaline phosphatase assay

[0917] The inhibition of ALPK1-dependent NF-κB reporter gene activation was measured using an alkaline phosphatase reporter gene 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. TMCells were incubated overnight in 293% expression medium (Thermo Fisher Scientific). Cells were pretreated with serially diluted compounds for 30 minutes, 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 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 1 to 10 μM and are shown in [Figure / Table / Insert Table ... surface 4 to 7 middle.

[0918] Inhibition of activated ALPK1

[0919] 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.

[0920] First, in preliminary experiments, we determined that IL-8 secretion was significantly increased in cells transiently expressing either of the 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). TMTransfection was performed using 3000 (Thermo Fisher Scientific). Transfected cells were selected, seeded into 96-well plates, and treated with serially diluted test compounds for 6.5 hours. After treatment, cell viability was measured using a luminescent cell viability assay (Cell Counting-Lite Assay or “CCL 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 of the test groups. 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.

[0921] Next, we tested a group of representative compounds to inhibit IL-8 secretion in cells expressing each of the ALPK1 mutants T237M and V1092A. Table 8 The inhibition of IL-8 secretion was observed in cells transfected with T237M, and Table 9 This demonstrates the inhibition of IL-8 secretion in cells transfected with the V1092A mutant. 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. Cell viability and IL-8 secretion were determined using the above-described CCL assay and IL-8 ELISA assay 16 hours after the second addition of the compound. Table 8 The half-maximal inhibitory concentration (IC50) of IL-8 secretion in A2 cells was shown relative to IL-8 secretion from wild-type HEK293 cells, making knockdown to IL-8 levels from wild-type cells considered as 100% inhibition.

[0922] Table 8. The half-maximal inhibitory concentration (IC50) of IL-8 secretion in cells expressing the T237M mutant:

[0923]

[0924]

[0925] for Table 9The 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. Cell viability and IL-8 secretion were determined using the above-mentioned CCL assay and IL-8 ELISA assay 6 hours after the second addition of the compound. Table 9 shows the half-maximal inhibitory concentration (IC50) of IL-8 secretion relative to wild-type HEK293 cells.

[0926] Table 9. The half-maximal inhibitory concentration (IC50) of IL-8 secretion in cells expressing the V1092A mutant.

[0927] A175 4.025 A176 1.546 A251 0.892 A252 0.723 A245 0.304 A249 11.690 A292 0.547 A261 0.573 A276 1.650 A281 0.486 A310 1.907 A311 1.156 A312 16.020 A313 10.170 A314 3.996 A315 2.769 A316 16.450 A317 1.930 A319 7.860 A289 0.439 A244 4.787 B067 0.215 B068 27.090 B099 0.427 B100 0.429 B074 0.264 B075 12.990 B076 0.128 C048 5.572 C034 0.277 C035 0.067 C039 0.959 C037 8.297 C038 0.352 C046 4.447 C041 0.954 C040 0.068 C042 0.225 C008 0.048 C002 3.369 C016 1.585 C018 1.917 C011 0.353

[0928] Inhibition of activated ALPK1 in the kidney

[0929] To test the effect of ALPK1 inhibitors on the expression of innate immune genes activated after ALPK1 activation, SD rats were orally administered an ALPK1 inhibitor, followed by intraperitoneal administration of the ALPK1 agonist D-glycero-D-manno-6-fluoro-heptaose-1β-S-ADP to activate innate immune genes. Kidney tissue was harvested and gene expression was measured. In short, 20 male Sprague-Dawley (SD) rats were randomly divided into 5 groups. The control group was orally administered the mediator (0.5% MC). Two hours later, PBS was administered via intraperitoneal injection. The control group was orally administered the mediator (0.5% MC). Two hours later, D-glycero-D-manno-6-fluoro-heptaose-1β–S-ADP (50 μpk) was administered via intraperitoneal injection. The other three groups were orally administered the ALPK1 inhibitor A0176 (4, 10, and 25 mpk). Two hours later, D-glycero-D-manno-6-fluoro-heptaose-1β–S-ADP (50 μpk) was administered intraperitoneally. Three hours after intraperitoneal injection of D-glycero-D-manno-6-fluoro-heptaose-1β–S-ADP (50 μpk), kidneys from each group were collected. Samples were isolated for RT-PCR to identify the mRNA expression levels of MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6. Total RNA was extracted from the kidneys according to the Rneasy Mini Kit (QIAGEN, Germany). Messenger RNA was reverse transcribed into cDNA using the HiScript Q RT SuperMix for qPCR Kit (Novizan, Nanjing, China). Quantitative PCR was performed using the AceQ qPCR SYBR Green Master Mix Kit (Novizan, Nanjing, China) on a QuantStudio 5 biosystem (Thermo Scientific, USA). Relative mRNA levels were calculated using the 2-ΔΔCT method, with HPRT used as a reference for gene expression normalization. Data are expressed as fold changes. Figure 2 As shown, A0176 exhibits dose-dependent inhibition of gene expression levels of many innate immune genes, including MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6.

[0930] Therapeutic effects of sepsis-induced acute kidney injury animal models

[0931] 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 a rat CLP model to evaluate the effects of the compounds described in this paper on sepsis. Briefly, the rat cecum was ligated with sterile silk sutures, then punctured twice with a needle, gently squeezed to expel a small amount of fecal material, and then the abdominal incision was closed. Compounds C008 and A0176 (20 mg / kg) were administered 2 hours before surgery, and survival was recorded over the next 24 hours. Additionally, 24 hours post-surgery, kidneys were collected for gene expression analysis by Q-PCR, and plasma was collected for measuring plasma MCP-1 concentration by ELISA. Results are shown in... Figure 3 , 4 In 5 cases, ALPK1 inhibitors improved animal survival rates. Figure 3 ); reduced the expression of pro-inflammatory genes in the kidneys ( Figure 4 ); and increased plasma MCP-1 levels ( Figure 5 ).

[0932] 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. Such equivalents are intended to be covered by the following claims.

[0933] All references cited in this paper are incorporated herein by full citation and used for all purposes, to the extent that each individual publication or patent or patent application is specifically and individually indicated to be incorporated herein by full citation and used for all purposes.

[0934] 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. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A compound of formula XI-B Formula XI-B Or its pharmaceutically acceptable salt, wherein X is –S-, D is CR 10 Or N; E is CR 14 Or N; F is CR 12 Or N; G is CR 11 Or N; The condition is that no more than three of D, E, F, and G are N; R 10 R 11 R 12 and R 14 When present, they are each independently selected from halogens, -OH, -NH2, and -R. 7a -X 1 -R 7a -CHR 7a R 8a -OR 7a -OX 1 -R 7a and -C(O)N(R) 7a R 8a ); R 13 Halogen, -OH, -NH2, -R 7a -X 1 -R 7a -CHR 7a R 8a -OR 7a -OX 1 -R 7a -C(O)N(R) 7a R 8a ), -N(R 7a R 8a Unsaturated 3- to 7-membered heterocyclic groups containing 1 to 2 N heteroatom ring vertices or saturated 7- to 8-membered bridged heterocyclic groups containing 1 to 2 N heteroatom ring vertices; in, Each X 1 C is independent 1-6 Alkylene; Each R 7a and R 8a Independently selected from H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, and saturated 3 to 7-membered heterocyclic groups containing 1 to 2 N heteroatom ring vertices, wherein the 3 to 7-membered heterocyclic group is substituted by 0 to 3 substituents selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy; and The unsaturated 3- to 7-membered heterocyclic group containing 1 to 2 N heteroatom ring vertices and the saturated 7- to 8-membered bridged heterocyclic group are each independently substituted by 0 to 3 moieties, wherein the 0 to 3 moieties are selected from halogens, -OH, -NH2, =O, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, -CHR 7b R 8b -OR 7b and -N(R) 7b R 8b ),in Each R 7b and R 8b Independently selected from H and C1 to C6 alkyl groups; R 5 Selected from H, deuterium, halogens, C1 to C6 alkyl, C1 to C6 deuterated alkyl and C1 to C6 haloalkyl; R 2 and R 3 Each is independently selected from H, C1 to C6 alkyl, C2 to C6 alkynyl, C3 to C6 cycloalkyl and monocyclic aryl, wherein the C1 to C6 alkyl and the monocyclic or bicyclic aryl are each substituted by 0 to 3 moieties, the 0 to 3 moieties being independently selected from halogen, C1 to C6 alkyl, C1 to C6 haloalkyl and C1 to C6 alkoxy; The condition is R 2 and R 3 Not all are H; or R 2 and R 3 Combined to form C3 to C6 cycloalkyl rings; Each R 4 Independently selected from halogens, C1 to C6 alkyl groups, and C1 to C6 alkoxy groups, wherein and The subscript p is 0, 1, 2, or 3; And the XI-B compound is not or .

2. The compound according to claim 1, Or its pharmaceutically acceptable salt, wherein Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl and C1 to C6 alkoxy.

3. The compound according to claim 2, wherein D, E, F and G are respectively CR 10 CR 14 CR 12 and CR 11 .

4. The compound according to claim 2, wherein F and G are respectively CR 12 and CR 11 E is N or CR 14 And D is N or CR 10 .

5. The compound according to any one of claims 2 to 4, wherein R 10 and R 11 Each is H; R 12 and R 14 Each is independently selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, -CHR 7b R 8b -OR 7a and -C(O)N(R) 7a R 8a ),in R 7a and R 8a Each is independently selected from H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy; and R 13 Selected from 3- to 7-membered heterocyclic groups containing 1 to 2 N heteroatom ring vertices and saturated 7- to 8-membered bridged heterocyclic groups containing 1 to 2 N heteroatom ring vertices, wherein The 3- to 7-membered heterocyclic groups and the 7- to 8-membered bridged heterocyclic groups are optionally substituted by 0 to 2 portions, the 0 to 2 portions being independently selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy.

6. The compound according to any one of claims 2 to 4, wherein R 12 and R 14 It is H; R 10 and R 11 Each is independently selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, -CHR 7a R 8a -OR 7a and -C(O)N(R) 7a R 8a ),in R 7a and R 8a Each is independently selected from H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy; and R 13 Selected from 3- to 7-membered heterocyclic groups containing 1 to 2 N heteroatom ring vertices and saturated 7- to 8-membered bridged heterocyclic groups containing 1 to 2 N heteroatom ring vertices, wherein The 3- to 7-membered heterocyclic groups and the 7- to 8-membered bridged heterocyclic groups are optionally substituted by 0 to 2 portions, the 0 to 2 portions being independently selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy.

7. The compound according to any one of claims 2 to 4, wherein R 10 R 11 R 12 and R 14 Each is H when it exists; and R 13 Selected from 3- to 7-membered heterocyclic groups containing 1 to 2 N heteroatom ring vertices and saturated 7- to 8-membered bridged heterocyclic groups containing 1 to 2 N heteroatom ring vertices, wherein The 3- to 7-membered heterocyclic groups and the 7- to 8-membered bridged heterocyclic groups are optionally substituted by 0 to 2 portions, the 0 to 2 portions being independently selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, and C1 to C6 alkoxy.

8. The compound according to any one of claims 2 to 4, wherein R 10 R 11 R 12 and R 14 Each is H when it exists; and R 13 It is a 3- to 7-membered heterocyclic group containing 1 to 2 N heteroatom ring vertices and 0 to 2 parts substituted, wherein the 0 to 2 parts are independently selected from halogens, -OH, -NH2, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl and C1 to C6 alkoxy.

9. The compound according to any one of claims 2 to 4, wherein R 10 R 11 R 12 and R 14 Each is H when it exists; and R 13 It is a saturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 N heteroatom ring vertices, optionally substituted with 0 to 2 substituents, wherein the 0 to 2 substituents are selected from -OH, -NH2 and -C1 to C6 alkyl groups.

10. The compound according to claim 2, having the formula XI-B-1 or XI-B-2. Formula XI-B-1 Formula XI-B-2 Or its pharmaceutically acceptable salt, wherein R 15 Selected from -OH, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, -CHR 7a R 8a and -C(O)N(R) 7a R 8a ),in Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl and C1 to C6 alkoxy.

11. The compound according to claim 10, wherein R 10 R 11 R 12 and R 14 Each is independently selected from halogens and C1 to C6 alkyl groups.

12. The compound according to claim 10 or 11, wherein R 15 Selected from C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy and -CHR 7a R 8a ,in Each R 7a and R 8a It is independently selected from H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C1 to C6 haloalkyl, C1 to C6 aminoalkyl and C1 to C6 alkoxy.

13. The compound according to claim 10 or 11, wherein R 15 It is a C1 to C6 alkyl group.

14. The compound according to claim 10 or 11, having the formula XI-B-1-a or XI-B-2-a Formula XI-B-1-a Formula XI-B-2-a.

15. The compound according to claim 10 or 11, having the formula XI-B-1-aI or XI-B-2-aI (XI-B-1-aI) (XI-B-2-aI) Or a pharmaceutically acceptable salt thereof, wherein R 4 It is halogen.

16. The compound according to claim 10 or 11, having the formula XI-B-1-a-II or the formula XI-B-2-a-II (XI-B-1-II) (XI-B-2-a-II) Or its pharmaceutically acceptable salt.

17. The compound according to claim 10 or 11, having the formula XI-B-1-a-III or the formula XI-B-2-a-III (XI-B-1-to-III) (XI-B-2-to-III) Or its pharmaceutically acceptable salt.

18. The compound according to any one of claims 10 or 11, having the formula XI-B-1-a-IV or the formula XI-B-2-a-IV (XI-B-1-a-IV) (XI-B-2-a-IV) Or its pharmaceutically acceptable salt.

19. The compound according to claim 1, wherein R 2 and R 3 All are C1 to C6 alkyl groups.

20. The compound according to claim 1, wherein R 2 and R 3 All are methyl groups.

21. The compound according to claim 1, wherein R 2 It is methyl and R 3 It is an acetylene group.

22. The compound according to claim 1, wherein R 2 It is methyl and R 3 It is CH2OMe.

23. The compound according to claim 1, wherein the subscript p is 1, and R 4 Connected to the benzene ring as shown below: ， The wavy lines represent the connection points with the rest of the expression.

24. The compound according to claim 1, wherein the subscript p is 1, and R 4 It is a halogen attached to a benzene ring as shown below: ， The wavy lines represent the connection points with the rest of the expression.

25. The compound according to claim 1, wherein the subscript p is 1, and R 4 It is chlorine attached to a benzene ring as shown below: ， The wavy lines represent the connection points with the rest of the expression.

26. The compound according to claim 1, wherein the subscript p is 1, and R 4 It is a methoxy group attached to a benzene ring as shown below: ， The wavy lines represent the connection points with the rest of the expression.

27. The compound according to claim 1, wherein R 5 It is H or methyl.

28. The compound according to claim 1, wherein R 5 It's H.

29. The compound according to claim 1, wherein R 5 It is deuterium.

30. The compound according to claim 1, wherein R 5 It is a C1 to C6 deuterated alkyl group.

31. The compound according to claim 1, wherein R 5 Choose from the following groups: -CH2D, -CHD2, and -CD3.

32. The compound of claim 1, wherein the linker to R is... 2 and R 3 The carbon atom is an S isomer.

33. The compound of claim 1, wherein the linker to R... 2 and R 3 The carbon atom is an R isomer.

34. A compound selected from... and .

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 and a pharmaceutically acceptable carrier or excipient.

36. Use of a compound according to any one of claims 1 to 34 in the preparation of a medicament for inhibiting ALPK1 kinase activity in the cells or tissues of a subject requiring treatment.

37. Use of a compound according to any one of claims 1 to 34 in the preparation of a medicament for inhibiting or reducing inflammation in target tissues of a subject requiring treatment.

38. Use of a compound according to any one of claims 1 to 34 in the preparation of a medicament for treating a disease, condition, or symptom characterized by excessive or inappropriate ALPK1-dependent pro-inflammatory signaling in a subject requiring treatment.

39. The application according to claim 38, wherein the disease, symptom or condition is selected from sepsis, cancer, spiroadenoma, spiroadenocarcinoma, ROSAH syndrome and PFAPA syndrome.

40. The application according to claim 39, wherein the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma.

41. The application according to claim 38, wherein the disease or condition is ROSAH.

42. The application according to claim 38, wherein the disease or symptom is PFAPA.

43. The application according to claim 38, wherein the disease or condition is a spiral adenoma or spiral adenocarcinoma.

44. The application according to claim 38, wherein the disease or symptom is sepsis.

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