Alpha protein kinase 1 inhibitor and method of use

Abstract

The present disclosure provides compounds of Formula I for use as inhibitors of alpha-kinase 1 (ALPK1), as well as related compositions and methods.

Description

[Technical Field]

[0001] The present 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 have been identified. These include α-protein kinase 1 (ALPK1), ALPK2, ALPK3, elongation factor-2 kinase (eEF2K), and transient receptor potential cation channels M6 and M7 (TRPM6 and TRPM7). See Ryazanov et al., Curr Biol 9:R43-45 (1999) and Ryazanov et al., Proc Natl Acad Sci USA 94:4884-4889 (1997).

[0003] ALPK1 is an intracellular serine-threonine protein kinase that plays a crucial role in activating the innate immune response to bacteria via TRAF-interacting proteins through forkhead-associated domain (TIFA)-dependent pro-inflammatory nuclear factor-kappa-B (NFκB) signaling. See Zimmermann et al., Cell Rep. 20:2384-2395 (2017); Milivojevic et al., PLoS Pathog. 13:E1006224-E1006224 (2017); and Zhou et al., Nature 561:122-126 (2018).

[0004] Inappropriate activation of ALPK1 signaling is associated with diseases and disorders related to excessive or inappropriate inflammation. For example, ALPK1 is involved in uric acid monosodium monohydrate (MSU)-induced inflammation and gout. Lee et al., Sci.Rep.6:25740-25740 (2016). Elevated ALPK1 expression is also associated with lymph node metastasis and tumor growth in oral squamous cell carcinoma. Chen et al., Am J Pathol 189:190-199 (2019). Furthermore, gene mutations in ALPK1 are associated with sweat adenoma, spiral carcinoma, "retinal dystrophy, optic edema, splenomegaly, anhidrosis and migraine" ("ROSAH") syndrome, and "periodic fever, aphthous stomatitis, pharyngitis and adenitis" ("PFAPA") syndrome. For example, see 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). [Overview of the project]

[0005] This disclosure provides compounds of formula I described herein, as well as lower embodiments of formula I, and related compositions and methods, which are inhibitors of ALPK1 kinase activity.

[0006] In some embodiments, compounds of formula I are provided herein. [ka] Equation I (In the formula, A, p, R 1 , R 2 , R 3 , R 4 and R 5 (as defined herein).

[0007] In some embodiments, the compound of formula I is represented by formula IA. [ka] Formula IA (where p, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、and R 9 are as defined herein).

[0008] In some embodiments, the compound of formula I is represented by formula IA-1.

Chemical formula

[0009] In some embodiments, the compound of formula I is represented by formula IB.

Chemical formula

[0010] In some embodiments, the compound of formula I is represented by formula IB-1.

Chemical formula

[0011] In some embodiments, the compound of formula I is represented by formula IC. [ka] formula IC (In the formula, p, m, R 2 , R 3 , R 4 , R 5 , R 18 (as defined herein).

[0012] In some embodiments, compounds of formula XI are provided herein. [ka] Formula XI (In the formula, X, A, p, R 1 , R 2 , R 3 , R 4 and R 5 (as defined herein).

[0013] In some embodiments, the compound of formula I is represented by formula XI-A. [ka] Formula XI-A (In the formula, X, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 (as defined herein).

[0014] In some embodiments, the compound of formula I is represented by formula XI-A-1. [ka] Formula XI-A-1 (In the formula, X, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 (as defined herein).

[0015] In some embodiments, the compound of formula I is represented by formula XI-A-1-a. [ka] Formula XI-A-1-a (In the formula, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 (as defined herein).

[0016] In some embodiments, the compound of formula I is represented by formula XI-B. [ka] Formula XI-B (In the formula, X, p, R 2 , R 3 , R 4 , R 5 , R 13 (D, E, F, and G are as defined herein).

[0017] In some embodiments, the compound of formula I is represented by formula XI-B-1. [ka] Formula XI-B-1 (In the formula, X, p, R 2 , R 3 , R 4 , R 5 , R 15 , R 16 , and R 17 (as defined herein).

[0018] In some embodiments, the compound of formula I is represented by formula XI-B-1-a.

Chemical formula

[0019] In some embodiments, the compound of formula I is represented by formula XI-C. *

Chemical formula

[0020] In some embodiments, the compound of formula XI is represented by formula XI-C-1.

Chemical formula

[0021] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C described herein, or a sub-embodiment thereof.

[0022] In embodiments, the present disclosure provides a method for inhibiting ALPK1 kinase activity in target cells or tissues requiring a therapeutic approach that inhibits ALPK1 kinase activity in those cells or tissues, the method comprising administering a compound of formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C as described herein, or a lower embodiment thereof, to the target.

[0023] In embodiments, the present disclosure provides a method for inhibiting or reducing inflammation in a target tissue of a subject requiring treatment to inhibit or reduce inflammation in the target tissue, the method comprising administering a compound of formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C described herein or a lower embodiment thereof to the subject.

[0024] In embodiments, the Disclosure provides a method for treating a subject in need of treatment for a disease, disorder, or condition characterized by excessive or inadequate ALPK1-dependent pro-inflammatory signaling, comprising administering a compound of formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C described herein or a lower embodiment thereof to the subject.

[0025] In the embodiments, the disease, disorder, or condition is selected from sepsis, cancer, sweat adenoma, spiral gland carcinoma, "retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine" ("ROSAH") syndrome, and "periodic fever, aphthous stomatitis, pharyngitis, and adenitis" ("PFAPA") syndrome.

[0026] In this embodiment, the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma.

[0027] In this embodiment, the disease or disorder is selected from ROSAH and PFAPA.

[0028] In this embodiment, the disease or disorder is sepsis.

[0029] In this embodiment, the disease or disorder is sweat adenoma or spiral gland carcinoma.

[0030] In this embodiment, the treatment or the subject requiring such treatment is a subject that has one or more gene mutations in ALPK1. In this embodiment, at least one mutation is an activating mutation. [Brief explanation of the drawing]

[0031] [Figure 1] This bar graph shows IL-8 secretion (pg / ml) in HEK293 cells transiently transfected with an empty vector, or an expression vector encoding human ALPK1 (hALPK1), activating mutations in hALPK1 (T237M, V1092A), or an activating mutation combined with a kinase death mutation in ALPK1 (hALPK1-T237M-D1194S).

[0032] [Figure 2] The treatment group received 4, 10, or 25 mg / kg of the ALPK1 inhibitor A0176 two hours before the agonist D-glycero-D-manno-6-fluoroheptose-1β-S-ADP. Three hours after agonist administration, renal tissue was examined for suppression of gene expression of innate immunogenes, 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. **P<0.01 for vehicle PO + A0176-IP-3 hours by two-way ANOVA, ***P<0.001

[0033] [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 two hours before surgery. Survival was recorded over the following 24 hours. Both compounds improved the survival rate of the animals.

[0034] [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 prior to surgery. Kidneys were collected 24 hours after surgery for gene expression analysis by Q-PCR. The data showed that ALPK1 inhibitors reduced the expression of renal pro-inflammatory genes, including IL6, TNFα, IL-1β, CCl2, and keratinocyte chemokines (KC). *p<0.05, **p<0.01, p<0.001, vs. CLP vehicle

[0035] [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 of animals 2 hours before surgery. Plasma MCP-1 concentrations were measured by ELISA 24 hours postoperatively. ALPK1 inhibitors improved plasma MCP-1 levels. ***p<0.001 compared to the CLP vehicle by single-component ANOVA. [Modes for carrying out the invention]

[0036] This disclosure provides compounds that are inhibitors of ALPK1, compositions containing the same, and methods of using them in therapeutic applications.

[0037] The term "ALPK1" is used herein to refer interchangeably to isoform 1 (Q96QP1-1) or alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1(ALPK1_HUMAN).

[0038] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic radical having the indicated number of carbon atoms. Alkyl can contain 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 includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to an alkyl group having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. The alkyl group can be substituted or unsubstituted.

[0039] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon having at least 2 carbon atoms and at least 1 double bond. Alkenyl can contain any number of carbons such as C2, C 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.

[0040] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon having at least 2 carbon atoms and at least 1 triple bond. Alkenyl can contain any number of carbons such as C2, C 2~3 、C 2~4 、C 2~5 、C2~6 , 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 It can contain any number of carbon atoms, including 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.

[0041] As used herein, the term “alkylene” refers to a linear or branched saturated aliphatic radical having the indicated number of carbon atoms and linking at least two other groups, i.e., divalent hydrocarbon radicals. The two parts linked to the alkylene can be linked to the same or different atoms of the alkylene group. For example, a linear alkylene may 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 may be substituted or unsubstituted. In some embodiments, the alkylene group is substituted with one or two substituents. Suitable substituents, in non-limiting examples, include halogens and hydroxyls.

[0042] As used herein, the terms "alkoxy" or "alkoxyl" refer to an alkyl group having an oxygen atom connected to the alkyl group at its bonding site: alkyl-O-. With respect to alkyl groups, an alkoxyl group can have any suitable number of carbon atoms, such as C1 to C6. Examples of alkoxyl groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy. The alkoxy group may be substituted or unsubstituted.

[0043] As used herein, the terms “alkenyloxy” or “alkenyloxyl” refer to the alkenyl group as defined above, which has an oxygen atom connected to the bonding site of the alkenyl group: alkenyl-O-. The alkenyloxyl group may have any suitable number of carbon atoms, such as C1 to C6. The alkenyloxyl group may be further substituted with various substituents as described herein. The alkenyloxyl group may be substituted or unsubstituted.

[0044] "Aminoalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with -NR'R'' (wherein R' and R'' are independently hydrogen, alkyl, haloalkyl, or hydroxyalkyl as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, etc.).

[0045] As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, bromine, and iodine.

[0046] As used herein, the term "haloalkyl" refers to the alkyl group defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to alkyl groups, haloalkyl groups are C 1~6 It can have any appropriate number of carbon atoms, such as trifluoromethyl and fluoromethyl. For example, haloalkyls include trifluoromethyl and fluoromethyl.

[0047] As used herein, the terms "haloalkoxyl" or "haloalkoxy" refer to an alkoxyl group in which some or all of the hydrogen atoms are substituted with halogen atoms. With respect to alkyl groups, a haloalkoxy group is C 1~6 It can have any appropriate number of carbon atoms, such as the following. The alkoxy group can be substituted with one, two, three or more halogens.

[0048] As used herein, the term “deuterated alkyl” means an alkyl radical as defined above, in which 1 to 6 hydrogen atoms in the alkyl radical are replaced by deuterium, such as -CH2D, -CHD2, -CD3, -CH2CD3, etc.

[0049] As used herein, the term "hydroxyalkyl" refers to an alkyl radical in which at least one hydrogen atom of the alkyl radical is replaced by an OH group. Examples of hydroxyalkyls include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and 4-hydroxybutyl.

[0050] As used herein, the term "oxo" refers to an oxygen atom bonded to a bond site by a double bond (=O).

[0051] 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 contain any suitable number of ring atoms, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6-10, 6-12, or 6-14 ring members. An aryl group may be monocyclic, condense to form a bicyclic or tricyclic group, or bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linkage. Some aryl groups have 6-12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6-10 ring members, e.g., phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. An aryl group may be substituted or unsubstituted.

[0052] As used herein, the term “heteroaryl” refers to a monocyclic or fused bicyclic aromatic ring assembly containing 5 to 12 ring atoms, where 1 to 5 ring atoms are heteroatoms such as N, O, or S. Further heteroatoms, including but not limited to B, Al, Si, and P, may also be useful. Heteroatoms can also be oxidized, including but not limited to -S(O)- and -S(O)2-. A heteroaryl group can contain any number of ring atoms, e.g., 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. Any suitable number of heteroatoms can be included in a heteroaryl group, 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. A heteroaryl group 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 can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (isomers of 1,2,3-, 1,2,4-, and 1,3,5-), and purine. Heteroaryl groups can also condense with aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrrole, e.g., indole and isoindole, benzopyridine, e.g., quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine, e.g., phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0053] As used herein, "cycloalkyl" refers to a saturated ring assembly containing 3 to 10 ring atoms, or the number of atoms indicated. A cycloalkyl can contain any number of carbon atoms, for example, C 3~6 , C 4~6 , C 5~6 , C 3~8 , C4~8 , C 5~8 , C 6~8 This may include the following: The cycloalkyl ring may be saturated or unsaturated if the unsaturated cycloalkyl ring may have one or two double bonds. Examples of cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. The cycloalkyl group may be substituted or unsubstituted.

[0054] As used herein, the terms “heterocyclyl” or “heterocyclic” refer to a heterocyclic group that is saturated or partially saturated and is a monocyclic or polycyclic ring, having 3 to 16, most preferably 5 to 10, most preferably 1 or 4 ring atoms, where 1 or more, preferably 1 to 4, in particular 1 or 2 ring atoms are heteroatoms selected from oxygen, nitrogen, and sulfur (the remaining ring atoms are carbon). The term heterocyclyl excludes heteroaryls. The heterocyclic group can be bonded to the rest of the molecule via heteroatoms or carbon atoms selected from oxygen, nitrogen, and sulfur. Heterocyclyls may include condensed or bridging rings as well as spirorings. Examples of heterocyclils include dihydrofuranil, dioxolanil, dioxanil, dithianil, piperazinil, pyrrolidine, dihydropyranil, oxathiolanil, dithiolane, oxathianil, thiomorpholino, oxyranil, azilidinil, oxetanil, oxepanil, azetidinil, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidine, tetrahydropyranil, piperidinil, morpholino, piperazinil, azepinil, oxapinil, oxazepanil, oxathianil, thiepanil, azepanil, dioxepanil, and diazepanil.

[0055] As used herein, “spiroheterocyclyl” refers to a specific bicyclic heterocyclic group in which two ring systems are bonded via a single carbon atom. For example, the term “spiroheterocyclyl” can refer to 6–10 spiroheterocyclyls. 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.

[0056] As used herein, "crosslinked heterocyclyl" refers to the C defined above. 3~6 This refers to a cycloalkyl ring or a 3- to 6-membered heterocyclyl ring, where two non-adjacent ring vertices ("bridgehead atoms") of the cycloalkyl ring or heterocyclyl ring are linked to form an additional cyclic portion ("bridge"). A bridge contains 1 to 4 ring vertices that do not contain 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]hepta-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.

[0057] The term "bicyclic heterocyclyl" refers to the heterocyclic group defined above, in which two ring systems are connected via two adjacent ring vertices (e.g., fused ring systems). A typical "bicyclic heterocyclyl" ring contains 6 to 11 ring members with 1 to 4 heteroatom ring vertices selected from N, O, and S (the remaining ring atoms are carbon). Examples include, but are not limited to, benzodioxolyl, benzimidazolyl, benzisoxazolyl, benzoflazanil, benzopyranil, benzothiopyranil, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, chromanil, sinnolinil, dihydrobenzofuryl, dihydroisobenzofuranil, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranylsulfone, indolinil, indolyl, isochromanil, isoindolinil, isoquinolinil, isothiazolidinil, naphthilidinil, pyrazolopyridinil, quinazolinil, quinolinil, quinoxalinil, tetrahydroisoquinolinil, and tetrahydroquinolinil.

[0058] As used herein, “saturated or unsaturated” refers to a cyclic system in which two atoms in the group may be bonded to each other by single, double, or triple bonds. The saturated portion is one which has only single bonds, while the portion with multiple bonds (e.g., at least one double bond or at least one triple bond) is called unsaturated.

[0059] Where necessary, any definitions herein may be used in combination with any other definitions used to describe complex structural groups. By convention, any element following any such definition is that which is bonded to the parent moiety. For example, the complex group cycloalkoxyl means that a cycloalkyl group is bonded to the parent molecule via an oxyl group.

[0060] The term "pharmaceutically acceptable salt" means that, depending on the specific substituents found in the compounds described herein, salts of the active compound prepared using relatively non-toxic acids or bases may be included. If the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, and zinc. Examples of pharmaceutically acceptable salts derived from 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, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in either neat or 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, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.This also includes salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups that enable the conversion of the compound into either a base-addition salt or an acid-addition salt.

[0061] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. The parent form of a compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents; otherwise, the salt is equivalent to the parent form of the compound for the purposes of this disclosure.

[0062] Certain compounds of the present invention have an asymmetric carbon atom (optical center) or a double bond, and racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., distinct enantiomers) are all intended to be included within the scope of the present invention. In some embodiments, the compounds of the present invention are specific enantiomers, anomers, or diastereomers that are substantially free of others for ms.

[0063] As used herein, the term “substantially absent” means an amount of 10% or less of the other isomer, preferably 8%, 5%, 4%, 3%, 2%, 1%, or 0.5% or less of the other form. In some embodiments, the isomers are stereoisomers.

[0064] Detailed description of the embodiment This disclosure provides compounds represented by formula (I) and pharmaceutically acceptable salts thereof.

[0065] This invention discloses a novel heterocyclic compound as an inhibitor of ALPK1. The compound is represented by formula I, [ka] Equation I In the formula, A, p, R 1 , R 2 , R 3 , R 4 and R 5 This is defined as herein, A is a bond, azetidinyl, -O-, -N(R 6 )-,-CH2-N(R 6 )-,-CHR 9 -N(R 6 )- Selected from, here, R 6 is selected from H, D, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 alkoxyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, and optionally substituted saturated or unsaturated C3-C6 cycloalkoxyl, where, R may be substituted. 6 The part comprises 0 to 3 substituents independently selected from -D, halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 hydroxydeuterated alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl. R 9 This is selected from optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, and optionally substituted saturated or unsaturated C3-C6 cycloalkoxyl, where, R may be substituted. 9 The parts are halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7f 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 It includes 0 to 2 substituents independently selected from ) Each R 7f and R 8f These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy. R 1This includes H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 hydroxydeuterated alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 alkoxyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkoxyl, optionally substituted monocyclic or bicyclic aryl, optionally substituted N, O, and Selected from: 5-10 member heteroaryls containing 1-4 heteroatomic ring vertices selected from S; substituted or unsubstituted saturated or unsaturated 3-7 member heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; substituted or unsubstituted saturated or unsaturated 7-8 member bridging heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; substituted or unsaturated 7-11 member spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; and substituted or unsaturated 6-11 member bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, R may be substituted. 1 The parts are -D, halo, -OH, -COOH, -NH2, =O, -CN, C1~C6 alkyl, C1~C6 alkenyl, C1~C6 hydroxyalkyl, C1~C6 hydroxydeuterated alkyl, C1~C6 haloalkyl, C1~C6 aminoalkyl, C1~C6 alkoxyl, C1~C6 haloalkoxyl, -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)(R7a ), -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 ), comprising 0 to 4 substituents independently selected from saturated or unsaturated C3-C6 cycloalkyls, saturated or unsaturated C3-C6 cycloalkoxyls, saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, monocyclic or bicyclic aryls, 5-10 membered heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-11 membered spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, and 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, each X 1 C is independent 1~6 It is alkylene, Each R 7a and R 8aThe following are selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, N, O, and S. A saturated or unsaturated 3-7 membered heterocycline is independently selected from a saturated or unsaturated heterocycline containing one or two selected heteroatom ring vertices, and the aryl and the 3-7 membered heterocycline group are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclil, monocyclic or bicyclic aryl, 5-10 membered heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclil, saturated or unsaturated 7-11 membered spiroheterocyclil, and 6-11 membered bicyclic heterocyclil are each independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclil containing 1-2 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(R7b R 8b ) and -N(R 7b R 8b ) is replaced with 0 to 3 parts selected from, Each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl and saturated or unsaturated C3-C6 cycloalkoxyl, or R 1 and R 6 These bonds to form a 3-6 membered heterocycloalkyl group substituted with 0-3 moieties independently selected from the group consisting of halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl. R 5 This is selected from H, deuterium, halo, C1-C6 alkyl, C1-C6 deuterated alkyl, and C1-C6 haloalkyl. R 2 and R 3 Each is independently selected from H, OH, C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl and monocyclic or bicyclic aryl, where C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl and monocyclic or bicyclic aryl are, respectively, halo, -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -OC(O)(R 7c ), -C(O)(R 7c ), C(O)O(R 7c ), S(O)2N(R 7c R 8c ) and N(R 7c R 8c ) is replaced by 0 to 3 parts selected independently of it, Each R 7c and R 8c These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. However, R 2 and R 3 Both are not H, or R 2 and R 3 These atoms bond to form a C3-C6 cycloalkyl ring or a 3-7 membered heterocyclyl ring containing 1-2 heteroatom ring vertices independently selected from N, O, and S, wherein the formed ring is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, halo, -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 ) may be substituted with one or two substituents independently selected from ) Each R 7d and R 8d These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. Each R 4 This includes halo, -OH, -NH2, CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and CHR. 7e R 8e , OR 7e , OC(O)(R7e ), 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 ) were independently selected, and here, Each R 7e and R 8e These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, The subscript 'p' is 0, 1, 2, or 3.

[0066] In some embodiments, A in formula I is a bond.

[0067] In some embodiments, A in formula I is azetidinyl.

[0068] In some embodiments, A in formula I is -O-.

[0069] In some embodiments, A in formula I is -N(R 6 )-is.

[0070] In some embodiments, A in formula I is -CH2-N(R 6 )-is.

[0071] In some embodiments, A in formula I is -CHR 9 -N(R 6 )-is.

[0072] In some embodiments, the compound of formula I is represented by compounds of formula IA, formula IA-1, formula IA-2 and / or their stereoisomers, stable isotopes, or pharmaceutically acceptable salts. [ka] Formula IA [ka] Formula IA-1 [ka] Formula IA-2 (In the formula, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 (As defined above).

[0073] In some embodiments, R in formula I, IA, IA-1, or IA-2 6 These are H, C1-C6 alkyl, or C1-C6 hydroxyalkyl.

[0074] In some embodiments, R in formulas I and 1A 9 It is either CH3 or CH2OH.

[0075] In some embodiments, R in formulas I and 1A 9 These are saturated C3-C6 cycloalkyl groups.

[0076] In some embodiments, R in formula I 1 IA, IA-1, or IA-2 are selected from H and optionally substituted C1-C6 alkyl groups, where, The C1-C6 alkyls which may be substituted include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR 7a R 8a , -OR 7a -OC(O)(R 7a ), -C(O)(R 7a ), -C(O)N(R7a R 8a ), -C(O)O(R 7a ), -S(O)2R 7a -S(O)2N(R 7a R 8a ) and -N(R 7a R 8a ) comprises 0 to 4 substituents independently selected from, Each R 7a and R 8a These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0077] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 is a saturated or unsaturated C3-C6 cycloalkyl which may be substituted, in the formula, The optionally substituted C3-C6 cycloalkyl groups contain 0-4 substituents independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, and C1-C6 haloalkoxyl.

[0078] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 R 6 It combines with to form a 3-6 membered heterocycloalkyl group substituted with 0-3 moieties independently selected from the group consisting of halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl.

[0079] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, -OC(O)(R 7a), -S(O)2N(R 7a R 8a ) and -N(R 7a R 8a A C1-C6 alkyl group substituted with 0-4 substituents independently selected from ), where, Each R 7a and R 8a These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0080] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 -OH, C1-C6 hydroxyalkyl and -S(O)2N(R 7a R 8a A C1-C6 alkyl group substituted with 0-2 substituents independently selected from ), where, Each R 7a and R 8a The element is independently selected from H and C1-C6 alkyl groups.

[0081] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 This is a C1-C6 hydroxyalkyl group which may be substituted.

[0082] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 It is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S. 5-10 membered bicyclic heteroaryls include 3-7 membered heterocyclines containing 1-2 heteroatom ring vertices selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, N, O, and S, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, Each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0083] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 is a pyridiyl substituted with 0 to 3 moieties selected from a 3 to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, N, O, and S, where, 3- to 7-membered heterocyclyls are substituted with 0 to 3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, and C1-C6 haloalkyl.

[0084] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 is a saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, where, 7-8 membered cross-linked heterocyclyls include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0085] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 is a saturated or unsaturated 7-11 member spiroheterocycline containing 1-2 heteroatom ring vertices selected from N, O, and S, where, 7-11 member spiroheterocyclyls include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -CHR. 7b R 8b , -OR 7b -OC(O)(R 7b ), -C(O)(R 7b ), -C(O)N(R7b R 8b ), -C(O)O(R 7b ), -S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0086] In some embodiments, R in formulas I, IA, IA-1, or IA-2 1 These are aryls substituted with 0 to 3 substituents selected from 3 to 7-membered heterocyclines containing 1 to 2 heteroatomic ring vertices selected from halo, N, O, and S; 7 to 8-membered bridged heterocyclines containing 1 to 2 heteroatomic ring vertices selected from N, O, and S; and saturated or unsaturated 7 to 11-membered spiroheterocyclines containing 1 to 2 heteroatomic ring vertices selected from N, O, and S. 3-7 membered heterocyclyls, 7-8 membered cross-linked heterocyclyls, and 7-11 membered spiroheterocyclyls are defined as halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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(R7b R 8b ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0087] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 This is an aryl substituted with 0 to 3 moieties selected from halo-OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, and 3-7 membered heterocyclyls containing 1-2 heteroatom ring vertices selected from N, O, and S. 3-7 member heterocyclyls include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8bThese are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0088] In some embodiments, R in formula I, IA, IA-1, or IA-2 1 This is an aryl substituted with 0 to 3 moieties selected from a 3 to 7-membered heterocycline containing a halo and 1 to 2 heteroatom ring vertices selected from N, O, and S. 3- to 7-membered heterocyclyls are further substituted with 0 to 3 moieties selected from -OH, -COOH, -NH2, =O, -CN, and -C1-C6 alkyl groups.

[0089] In some embodiments, the compound of formula I is represented by the compound of formula IB and / or its stereoisomers, stable isotopes, or pharmaceutically acceptable salts. [ka] Formula IB (In the formula, p, R 2 , R 3 , R 4 and R 5 As defined above, D is CR 10 or N, E is CR 14 or N, F is CR 12 or N, G is CR 11 or N, However, if three or fewer of D, E, F, and G are N, R 10 , R 11 , R 12 , R 13 and R 14If present, each is independently H, halo, -OH, -COOH, -NH2, =O, -CN, C1~C6 alkyl, C1~C6 alkenyl, C1~C6 hydroxyalkyl, C1~C6 haloalkyl, C1~C6 aminoalkyl, C1~C6 alkoxyl, C1~C6 haloalkoxyl, -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 ), selected from saturated or unsaturated C3-C6 cycloalkyls, saturated or unsaturated C3-C6 cycloalkoxyls, saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S; saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; and saturated or unsaturated 7-11 membered spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; and 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, where, each X 1 C is independent 1~6 It is alkylene, Each R 7a and R 8aThese are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. 3-7 membered heterocyclils, monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls, 7-8 membered cross-linked heterocyclils, 7-11 membered spiroheterocyclils, and 6-11 membered bicyclic heterocyclils are each independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is replaced with 0 to 2 parts selected from, where, Each R 7g and R 8g Each of these is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0090] In some embodiments, D, E, F, and G in formula IB are, respectively, CR 10 CR 14 CR 12 and CR 11 That is the case.

[0091] In some embodiments, F and G in formula IB are, respectively, CR 14 and CR 11 And E is N or CR 14 And D is N or CR 10 That is the case.

[0092] In some embodiments, R in formula IB 10 and R 11 H and R 12 and R 14 These are independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is selected, where each R 7b and R 8b R is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl, 13The three- to seven-membered heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated seven to eight-membered bridged heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated seven to eleven-membered spiroheterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, wherein the three- to seven-membered heterocyclils, seven to eight-membered bridged heterocyclils, and seven to eleven-membered spiroheterocyclils may be substituted with 0 to 2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0093] In some embodiments, R in formula IB 12 and R 14 H is R 10 and R 11 These are independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is selected, where each R 7b and R 8bR is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl, 13 The three- to seven-membered heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated seven to eight-membered bridged heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated seven to eleven-membered spiroheterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, wherein the three- to seven-membered heterocyclils, seven to eight-membered bridged heterocyclils, and seven to eleven-membered spiroheterocyclils may be substituted with 0 to 2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0094] In some embodiments, R in formula IB 10 , R 11 , R 12 and R 14 All are H, and R 13The 3-7 member heterocyclils, 7-8 member bridged heterocyclils, and 7-11 member spiroheterocyclils are substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0095] In some embodiments, R in formula IB 10 , R 11 , R 12 and R 14 These are H and R respectively. 13 These are 3- to 7-membered heterocyclines containing 1-2 heteroatom ring vertices selected from N, O, and S, substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0096] In some embodiments, R in formula IB 10 , R 11 , R 12 and R 14 These are H and R respectively. 13 This is a substituted or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, substituted with 0-2 substituents selected from -OH, -COOH, -NH2, =O, -CN, and -C1-C6 alkyl groups.

[0097] In some embodiments, the compound of formula IB is represented by the compound of formula IB-1 or IB-2 and / or its stereoisomer, stable isotope, or pharmaceutically acceptable salt. [ka] Formula IB-1 [ka] Formula IB-2 (In the formula, p, R 2 , R 3 , R 4 and R 5 As defined above, R 16 and R 17 Each is independently selected from halo and C1-C6 alkyl groups. R 15 -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is selected, and here, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0098] In some embodiments, R in formula IB-1 or IB-2 15 C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR 7b R 8b Selected from, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0099] In some embodiments, R in formula IB-1 or IB-2 15 These are C1-C6 alkyl groups.

[0100] In some embodiments, R in formula IB-1 or IB-2 2 and R 3 Both are methyl groups.

[0101] In some embodiments, R in formula IB-1 or IB-2 2 and R 3 These are, independently, a methyl group or an ethynyl group.

[0102] In some embodiments, IB-1 is represented by formula IB-1-a or formula IB-2-a, [ka] (IB-1-a) [ka] (IB-2-a) or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, IB-1 is represented by formula IB-1-b or formula IB-2-b, [ka] (IB-1-b) [ka] (IB-2-b) or a pharmaceutically acceptable salt thereof (wherein R 4 (This is a halo.)

[0104] In some embodiments, IB-1 is represented by formula (IB-1-c) or formula IB-2-c. [ka] (IB-1-c) [ka] (IB-2-c) or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, R in formula IB-1 or IB-2 5 is either H or methyl.

[0106] This invention discloses a novel heterocyclic compound as an inhibitor of ALPK1. The compound is represented by formula IC. [ka] formula IC (In the formula, R 2 , R 3 , R 4 and R 5 As defined in equation I above, m is an integer from 0 to 6. R 18H, halo, -OH, -COOH, -NH2, -CN, C1~C6 alkenyl, C1~C6 hydroxyalkyl, C1~C6 haloalkyl, C1~C6 aminoalkyl, C1~C6 alkoxyl, C1~C6 haloalkoxyl, -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 ), selected from saturated or unsaturated C3-C6 cycloalkyls, saturated or unsaturated C3-C6 cycloalkoxyls, saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-11 membered spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, and 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, each X 1 C is independent 1~6 It is alkylene, Each R 7a and R 8aThe following are selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, N, O, and S. A saturated or unsaturated 3-7 membered heterocycline is independently selected from a saturated or unsaturated heterocycline containing one or two selected heteroatom ring vertices, and the aryl and the 3-7 membered heterocycline group are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclil, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclil, saturated or unsaturated 7-11 membered spiroheterocyclil, and 6-11 membered bicyclic heterocyclil are each independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclil containing 1-2 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 ) is replaced by 0 to 3 parts selected from, where each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. In some embodiments, m in formula IC is 1.

[0107] In some embodiments, R in formula IC 18 H is H.

[0108] The present invention also discloses a novel heterocyclic compound as an inhibitor of ALPK1. The compound is represented by formula XI. [ka] Formula XI (In the formula, A, p, R 1 , R 2 , R 3 , R 4 and R 5 This is defined herein, X is -S-, -O-, -NR a -, -CH=N-, and -CH=CH- are selected, where, R a (It is H or C1-C6 alkyl).

[0109] In some embodiments, X in equation XI is S.

[0110] In some embodiments, X in equation XI is O.

[0111] In some embodiments, X in formula XI is NH.

[0112] In some embodiments, A in formula XI is a bond.

[0113] In some embodiments, A in formula XI is azetidinyl.

[0114] In some embodiments, A in formula XI is -O-.

[0115] In some embodiments, A in formula XI is -N(R 6 )-is.

[0116] In some embodiments, A in formula XI is -CH2-N(R 6 )-is.

[0117] In some embodiments, A in formula XI is -CHR 9 -N(R 6 )-is.

[0118] In some embodiments, the compound of formula I is represented by compounds of formula XI-A, formula XI-A-1, formula XI-A-2, and / or their stereoisomers, stable isotopes, or pharmaceutically acceptable salts. [ka] Formula XI-A [ka] Formula XI-A-1 [ka] Formula XI-A-2

[0119] In some embodiments, the compound of formula XI is represented by the compound of formula XI-A-1-a and / or its stereoisomer, stable isotope, or pharmaceutically acceptable salt. [ka] Formula XI-A-1-a X, p, R 1, R 2 , R 3 , R 4 ,R 5 , R 6 , and 9 It is defined as above.

[0120] 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.

[0121] In some embodiments, R of formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 6 These are H, C1-C6 alkyl, or C1-C6 hydroxyalkyl.

[0122] In some embodiments, R in formulas XI and XI-A 9 It is either CH3 or CH2OH.

[0123] In some embodiments, R in formulas XI and XI-A 9 These are saturated C3-C6 cycloalkyl groups.

[0124] In some embodiments, the R of formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 is selected from H and optionally substituted C1-C6 alkyl groups, where, The C1-C6 alkyls which may be substituted include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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(R7a R 8a ) and -N(R 7a R 8a ) comprises 0 to 4 substituents independently selected from, Each R 7a and R 8a These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0125] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 is a saturated or unsaturated C3-C6 cycloalkyl group which may be substituted, where, The optionally substituted C3-C6 cycloalkyl groups contain 0-4 substituents independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, and C1-C6 haloalkoxyl.

[0126] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 R 6 It combines with to form a 3-6 membered heterocycloalkyl group substituted with 0-3 moieties independently selected from the group consisting of halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl.

[0127] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, -OC(O)(R 7a ), -S(O)2N(R 7a R8a ) and -N(R 7a R 8a A C1-C6 alkyl group substituted with 0-4 substituents independently selected from ), where, Each R 7a and R 8a These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0128] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 These are -OH, C1-C6 hydroxyalkyl, and -S(O)2N(R 7a R 8a A C1-C6 alkyl group substituted with 0-2 substituents independently selected from ) Each R 7a and R 8a The element is independently selected from H and C1-C6 alkyl groups.

[0129] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 is a C1-C6 hydroxyalkyl group which may be substituted.

[0130] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 It is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S. The aforementioned 5-10 membered bicyclic heteroaryls include 3-7 membered heterocyclines containing 1-2 heteroatom ring vertices selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, N, O, and S, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0131] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 is a pyridiyl substituted with 0 to 3 moieties selected from a 3 to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, N, O, and S, where, 3- to 7-membered heterocyclyls are substituted with 0 to 3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, and C1-C6 haloalkyl.

[0132] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 is a saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, where, 7-8 membered cross-linked heterocyclyls include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0133] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 is a saturated or unsaturated 7-11 member spiroheterocycline containing 1-2 heteroatom ring vertices selected from N, O, and S, where, 7-11 member spiroheterocyclyls include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0134] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 These are aryls substituted with 0 to 3 substituents selected from 3 to 7-membered heterocyclines containing 1 to 2 heteroatomic ring vertices selected from halo, N, O, and S; 7 to 8-membered bridged heterocyclines containing 1 to 2 heteroatomic ring vertices selected from N, O, and S; and saturated or unsaturated 7 to 11-membered spiroheterocyclines containing 1 to 2 heteroatomic ring vertices selected from N, O, and S. 3-7 membered heterocyclyls, 7-8 membered cross-linked heterocyclyls, and 7-11 membered spiroheterocyclyls are defined as halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0135] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 This is an aryl substituted with 0 to 3 moieties selected from halo-OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, and 3-7 membered heterocyclyls containing 1-2 heteroatom ring vertices selected from N, O, and S. 3-7 member heterocyclyls include halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and -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 ) is replaced with 0 to 3 parts selected from, where, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0136] In some embodiments, R in formulas XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a 1 This is an aryl substituted with 0 to 3 moieties selected from a 3 to 7-membered heterocycline containing a halo and 1 to 2 heteroatom ring vertices selected from N, O, and S. 3- to 7-membered heterocyclyls are further substituted with 0 to 3 moieties selected from -OH, -COOH, -NH2, =O, -CN, and -C1-C6 alkyl groups.

[0137] In some embodiments, the compound of formula XI is represented by the compound of formula XI-B and / or its stereoisomers, stable isotopes, or pharmaceutically acceptable salts. [ka] Formula XI-B (In the formula, X, p, R 2 , R 3 , R 4 and R 5 As defined above, D is CR 10 or N, E is CR 14 or N, F is CR 12 or N, G is CR 11 or N, However, if three or fewer of D, E, F, and G are N, R 10 , R 11 , R 12 , R 13 and R 14 If present, each is independently H, halo, -OH, -COOH, -NH2, =O, -CN, C1~C6 alkyl, C1~C6 alkenyl, C1~C6 hydroxyalkyl, C1~C6 haloalkyl, C1~C6 aminoalkyl, C1~C6 alkoxyl, C1~C6 haloalkoxyl, -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), selected from saturated or unsaturated C3-C6 cycloalkyls, saturated or unsaturated C3-C6 cycloalkoxyls, saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S; saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; and saturated or unsaturated 7-11 membered spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; and 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, where, each X 1 C is independent 1~6 It is alkylene, Each R 7a and R 8a These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. 3-7 membered heterocyclils, monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls, 7-8 membered cross-linked heterocyclils, 7-11 membered spiroheterocyclils, and 6-11 membered bicyclic heterocyclils are each independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 7gR 8g )and-N(R 7g R 8g ) is replaced with 0 to 2 parts selected from, where, Each R 7g and R 8g Each of these is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0138] In some embodiments, D, E, F, and G in formula XI-B are, respectively, CR 10 CR 14 CR 12 and CR 11 That is the case.

[0139] In some embodiments, F and G in formula XI-B are, respectively, CR 14 and CR 11 And E is N or CR 14 And D is N or CR 10 That is the case.

[0140] In some embodiments, R in formula XI-B 10 and R 11 H and R 12 and R 14 These are independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 R8b ) and -N(R 7b R 8b ) is selected, where each R 7b and R 8b R is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl, 13 The three- to seven-membered heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated seven to eight-membered bridged heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated seven to eleven-membered spiroheterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, wherein the three- to seven-membered heterocyclils, seven to eight-membered bridged heterocyclils, and seven to eleven-membered spiroheterocyclils may be substituted with 0 to 2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0141] In some embodiments, R in formula XI-B 12 and R 14 H is R 10 and R 11 These are independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is selected, where each R 7b and R 8b R is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl, 13 The three- to seven-membered heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated seven to eight-membered bridged heterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated seven to eleven-membered spiroheterocyclils containing one to two heteroatomic ring vertices selected from N, O, and S, wherein the three- to seven-membered heterocyclils, seven to eight-membered bridged heterocyclils, and seven to eleven-membered spiroheterocyclils may be substituted with 0 to 2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0142] In some embodiments, R in formula XI-B 10 , R 11 , R 12 and R 14 All are H, and R 13The 3-7 member heterocyclils, 7-8 member bridged heterocyclils, and 7-11 member spiroheterocyclils are substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0143] In some embodiments, R in formula XI-B 10 , R 11 , R 12 and R 14 These are H and R respectively. 13 These are 3- to 7-membered heterocyclines containing 1-2 heteroatom ring vertices selected from N, O, and S, substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0144] In some embodiments, R in formula XI-B 10 , R 11 , R 12 and R 14 These are H and R respectively. 13 This is a substituted or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, substituted with 0-2 substituents selected from -OH, -COOH, -NH2, =O, -CN, and -C1-C6 alkyl groups.

[0145] In some embodiments, the compound of formula XI-B is represented by the compound of formula XI-B-1 or XI-B-2, and / or its stereoisomer, stable isotope, or pharmaceutically acceptable salt. [ka] Formula XI-B-1 [ka] Formula XI-B-2.

[0146] In some embodiments, the compound of formula XI-B-1 or XI-B-2 is represented by the compounds of formula XI-B-1-a, XI-B-2-a, and / or their stereoisomers, stable isotopes, or pharmaceutically acceptable salts. [ka] Formula XI-B-1-a [ka] Formula XI-B-2-a (In the formula, p, R 2 , R 3 , R 4 and R 5 As defined above, R 16 and R 17 Each is independently selected from halo and C1-C6 alkyl groups. R 15 -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -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 ) is selected, and here, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0147] In some embodiments, R in formula XI-B-1 or XI-B-2 15 C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR 7b R 8b Selected from, Each R 7b and R 8b (These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl).

[0148] In some embodiments, R in formula XI-B-1 or XI-B-2 15 These are C1-C6 alkyl groups.

[0149] In some embodiments, R in formula XI-B-1 or XI-B-2 2 and R 3 Both are methyl groups.

[0150] In some embodiments, R in formula XI-B-1 or XI-B-2 2 and R 3These are, independently, a methyl group or an ethynyl group.

[0151] In some embodiments, XI-B-1-a is represented by formula XI-B-1-aI, and XI-B-2-a is represented by formula XI-B-2-aI. [ka] (XI-B-1-aI) [ka] (XI-B-2-aI) or a pharmaceutically acceptable salt thereof, where R 4 It is a halo.

[0152] In some embodiments, XI-B-1-a is represented by formula XI-B-1-a-II, and XI-B-2-a is represented by formula XI-B-2-a-II. [ka] (XI-B-1-a-II) [ka] (XI-B-2-a-II) or a pharmaceutically acceptable salt thereof.

[0153] 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. [ka] (XI-B-1-a-III) [ka] (XI-B-2-a-III) or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, XI-B-1-a is represented by formula XI-B-1-a-IV, and XI-B-2-a is represented by formula XI-B-2-a-IV. [ka] (XI-B-1-a-IV) [ka] (XI-B-2-a-IV) or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, R in formula XI-B-1 or XI-B-2 5 is either H or methyl.

[0156] This invention discloses a novel heterocyclic compound as an inhibitor of ALPK1. The compound is represented by formula XI-C. [ka] Formula XI-C (In the formula, X, R 2 , R 3 , R 4 and R 5 This is defined in equation XI above, m is an integer from 0 to 6. R 18 H, halo, -OH, -COOH, -NH2, -CN, C1~C6 alkenyl, C1~C6 hydroxyalkyl, C1~C6 haloalkyl, C1~C6 aminoalkyl, C1~C6 alkoxyl, C1~C6 haloalkoxyl, -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)(R7a ), -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 ), selected from saturated or unsaturated C3-C6 cycloalkyls, saturated or unsaturated C3-C6 cycloalkoxyls, saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-11 membered spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, and 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, each X 1 C is independent 1~6 It is alkylene, Each R 7a and R 8aThe following are selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, N, O, and S. A saturated or unsaturated 3-7 membered heterocycline is independently selected from a saturated or unsaturated heterocycline containing one or two selected heteroatom ring vertices, and the aryl and the 3-7 membered heterocycline group are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclil, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclil, saturated or unsaturated 7-11 membered spiroheterocyclil, and 6-11 membered bicyclic heterocyclil are each independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclil containing 1-2 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 ) are substituted, where R 7b and R 8b are each independently selected from 0 to 3 moieties selected from H, C1 - C6 alkyl, C1 - C6 alkenyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1 - C6 alkoxyl, saturated or unsaturated C3 - C6 cycloalkyl, and saturated or unsaturated C3 - C6 cycloalkoxyl).

[0157] In some embodiments, the compound of formula XI - C is represented by the compound of formula XI - C - 1 and / or its stereoisomers, stable isotopes or pharmaceutically acceptable salts thereof. [Chemical formula] Formula XI - C - 1 (wherein R 2 , R 3 , R 4 and R 5 are as defined in formula I above, m is an integer from 0 to 6, R 18 is H, halo, -OH, -COOH, -NH2, -CN, C1 - C6 alkenyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1 - C6 alkoxyl, C1 - C6 haloalkoxyl, -R 7a , -X 1 -R 7a , CHR 7a R 8a , -OR 7a , -O-X 1 -R 7a , X 1 -O-X 1 -R 7a , -OC(O)(R 7a ), -O-X 1 -C(O)(R 7a ), -C(O)(R 7a ), -C(O)N(R 7a R 8a , -NR7a (CO)R 8a ,-C(O)O(R 7a ), S(O)2R 7a -S(O)2N(R 7a R 8a ), -N(R 7a R 8a ), selected from saturated or unsaturated C3-C6 cycloalkyls, saturated or unsaturated C3-C6 cycloalkoxyls, saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, monocyclic or bicyclic aryls, 9-10 membered bicyclic heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, saturated or unsaturated 7-11 membered spiroheterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, and 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, each X 1 C is independent 1~6 It is alkylene, Each R 7a and R 8aThe following are selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, N, O, and S. A saturated or unsaturated 3-7 membered heterocycline is independently selected from a saturated or unsaturated heterocycline containing one or two selected heteroatom ring vertices, and the aryl and the 3-7 membered heterocycline group are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclil, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclil, saturated or unsaturated 7-11 membered spiroheterocyclil, and 6-11 membered bicyclic heterocyclil are each independently: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclil containing 1-2 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 ) is replaced by 0 to 3 parts selected from, where each R 7b and R 8b These are independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[0158] In some embodiments, m in formula XI-C or XI-C-1 is 1.

[0159] In some embodiments, R of formula XI-C or XI-C-1 18 H is H.

[0160] In some embodiments, R in each of the formulas described herein 2 and R 3 Both are C1-C6 alkyl groups.

[0161] In some embodiments, in each of the formulas described herein, R 2 is methyl, and R 3 It is CH2OMe.

[0162] In some embodiments, R 2 and R 3 In each of the formulas described herein, each is methyl.

[0163] In some embodiments, R 2 It is methyl, and R 3 is ethynyl in each of the formulas described herein.

[0164] In some embodiments, R 2 It is methyl, and R 3 These are C3-C6 cycloalkyl groups.

[0165] In some embodiments, R 2 is methyl, and R 3 It is phenyl.

[0166] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 It is bonded to the phenyl ring as shown below: [ka] , (In the equation, the wavy line indicates a connection point to the rest of the equation.)

[0167] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 This is a halo bonded to a phenyl ring, as shown below: [ka] , (In the equation, the wavy line indicates a connection point to the rest of the equation.)

[0168] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 This is chlorom bonded to a phenyl ring, as shown below: [ka] , (In the equation, the wavy line indicates a connection point to the rest of the equation.)

[0169] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R 4 This is a methoxy compound bonded to a phenyl ring, as shown below: [ka] , (In the formula, the wavy line represents the bonding point to the remaining part of the formula).

[0170] In some embodiments, R in each of the formulas described herein 5 is H.

[0171] In some embodiments, R in each of the formulas described herein 5 is deuterium.

[0172] In some embodiments, R in each of the formulas described herein 5 is C1-C6 deuterated alkyl. In some embodiments, R in each of the formulas described herein 5 is selected from the group consisting of -CH2D, -CHD2, and -CD3.

[0173] In some embodiments, in each of the formulas described herein, R 2 and R 3 are chiral at the carbon atom to which they are attached. In such embodiments, it is understood that R 2 and R 3 are not the same. In some embodiments, in each of the formulas described herein, R 2 and R 3 are attached to a carbon atom that is the S isomer, referring to the absolute stereochemistry at this carbon atom. In some embodiments, in each of the formulas described herein, R 2 and R 3 are attached to a carbon atom that is the R isomer, referring to the absolute stereochemistry at this carbon atom. In some embodiments, R 2 is methyl and R 3 is ethynyl. In some embodiments, R 2 is methyl and R 3 is C3-C6 cycloalkyl. In some embodiments, R 2 is methyl and R 3 is phenyl. In some embodiments, R 3It is methyl, and R 2 is ethynyl. In some embodiments, R 3 It is methyl, and R 2 is a C3-C6 cycloalkyl group. In some embodiments, R 3 It is methyl, and R 2 It is phenyl.

[0174] In some embodiments, the compound of formula I is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] [ka] , [ka] [ka] , and [ka] Selected from.

[0175] In some embodiments, the compound of formula I is [ka] , [ka] [ka] , [ka] ,

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[0176] In some embodiments, the compound is selected from the examples provided herein.

[0177] Preparation of Compounds of Formula I and Exemplary Compounds Analysis details 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 downfield from TMS, and spectral resolving patterns are referred to as single (s), doublet (d), triplet (t), quadruplet (q), multiplet, unresolved or overlapping signal (m), and broad signal (br). Deuterated solvents are indicated 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.

[0178] LC-MS: Shimadzu20A-2010MS Detection: SPD-M20A Column: MERCK, RP-18e 25~2mm; Wavelength: UV 220nm, 254nm; Column temperature: 50°C; MS ionization: ESI Mobile phase: 1.5 ml / 4 LTFA in water (solvent A) and 0.75 ml / 4 LTFA in acetonitrile (solvent B), with an elution gradient of 5% to 95% (solvent B), were used over 0.7 minutes, and the mixture was held at 95% for 0.4 minutes at a flow rate of 1.5 ml / min.

[0179] Flash column chromatography system System: CombiFlash Rf+ Column: Santai Technologies, Inc., SEPAFLASH (registered trademark) The samples were typically adsorbed onto the isolute. HPLC separation conditions System: TRILUTION LC 4.0 Detection: Gilson 159 UV-VIS Condition 1: Column: Phenomenex Gemini-NX 80*40mm×3um Eluent A: Water (0.05%NH3H2O+10mM NH4HCO3) Eluent B: CH3CN Start B: 20-45%, End B: 80-20%, Gradient time (minutes): 8 Condition 2: Column: Xtimate C 18 10μ 250 mm*50 mm; Eluent A: Water (0.04%NH3H2O+10mM NH4HCO3) Eluent B: CH3CN 50%~80%; Gradient time (minutes): 8 SFC Chiral Separation Conditions Mobile phase: [0.1%NH3H2O ​​ETOH]; B%: 30%-30%, 35%-35%, or 45%-45% Column: DAIEL CHIRALCEL OJ-H (250mm*30mm, 5um); Mobile phase [0.1%NH3H2O ​​ETOH];B%:30%-30%, 40%-40%; Column: DAIEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase [0.1%NH3H2O ​​ETOH];B%:35%-35%; Column: DAIEL CHIRALPAK AS (250mm*30mm, 10um); Mobile phase [0.1%NH3H2O ​​ETOH];B%:35%-35%

[0180] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art.

[0181] The following is an abbreviation table for chemistry. [Table 1-1-1] [Table 1-1-2] [Table 1-2] Reaction scheme 1: [ka]

[0182] A properly substituted compound M1 was obtained (wherein R is a suitable 1 to 3 groups such as a halo or C1-C6 alkyl, and R1 and R2 are suitable groups independently selected from H, C1-C6 alkyl and C2-C6 alkynyl, which are converted to an acid chloride using SOCl2 or (COCl)2 at heating or at room temperature). The Weinreb amide was formed by the reaction of N,O-dimethylhydroxylamine hydrochloride with an acid chloride at 0°C. A Grignard reagent in THF was added to the Weinreb amide at 0°C to obtain a ketone, which was converted to M5 by bromination. Cyclization with thiourea under basic conditions yielded intermediate M6. Example 1: Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-amine (intermediate 1) [ka]

[0183] Step 1. Preparation of compound 2-(4-bromophenyl)-2-methylpropanoyl chloride [ka]

[0184] Compound 2-(4-bromophenyl)-2-methylpropanoic acid (100 g, 411 mmol, 1.0 equivalent) was heated under reflux for 2 hours in SOCl2 (175 mL, 6 equivalents). The solution was then cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a dry acid chloride (yellow oily substance), which was used in the next step without further purification.

[0185] Step 2. Preparation of compound 2-(4-bromophenyl)-N-methoxy-N,2-dimethylpropanamide [ka]

[0186] A solution of compound N,O-dimethylhydroxylamine HCl salt (48.2 g, 49 mmol, 1.2 equivalents) in DCM (300 mL) was cooled to 0°C. Then, the crude acid chloride (1.0 equivalent) obtained from step 1 in DCM (200 mL) and TEA (114 mL, 2 equivalents) was added to the mixture, 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 x 3), the combined organic layers were washed with water (200 mL x 3) and brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated to obtain the residue. The desired compound (108 g, pure) was obtained as a pale yellow oily substance, which was used in the next step without further purification.

[0187] 1 H NMR(400 MHz,CDCl3)δ 7.42(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).

[0188] Step 3. Preparation of compound 3-(4-bromophenyl)-3-methylbutane-2-one [ka]

[0189] The compound obtained in step 2 above (54 g, 189 mmol, 1 equivalent) was cooled to 0°C in a 500 mL solution of dry THF. CH3MgBr (3 M in THF, 253 mL, 757.8 mmol, 4 equivalents) 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 x 2). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. The desired compound (90.4 g, pure) was obtained as a pale yellow oily substance, which was used in the next step without further purification.

[0190] 1 H NMR(400 MHz,CDCl3)δ 7.45(d,J=8.4 Hz,2H),7.11(d,J=8.4 Hz,2H),1.90(s,3H),1.44(s,6H).

[0191] Step 4. Preparation of compound 1-bromo-3-(4-bromophenyl)-3-methylbutan-2-one [ka]

[0192] To a DCM / EtOH (250 mL / 250 mL) solution of the compound obtained from step 3 above (46 g, 191 mmol, 1 equivalent), Br2 (14.7 mL, 286 mmol, 1.5 equivalents) was added dropwise. The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was saturated with Na2SO4. 3( The mixture was quenched with 150 mL of brine. The mixture was extracted with DCM (300 mL x 2), the combined organic layer was washed with brine (300 mL x 2), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The desired compound (118.8 g, crude) was obtained as a white solid, which was used in the next step without further purification.

[0193] 1 H NMR(400 MHz,CDCl3)δ 7.48(d,J=8.4 Hz,2H),7.11(d,J=8.4 Hz,2H),3.82(s,2H),1.52(s,6H).

[0194] Step 5. Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-amine [ka]

[0195] To a solution of the compound obtained in step 4 above (50 g, 156 mmol, 1 equivalent) in MeOH (500 mL), thiourea (14.3 g, 188 mmol, 1.2 equivalents) was added. The mixture was stirred at 50°C for 1.5 hours. The mixture was concentrated under reduced pressure. The mixture was extracted with EA (300 mL x 2), the combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by silica gel chromatography by PE / EA = 10:1 to obtain the pure desired compound (34 g, white solid).

[0196] 1 H NMR(400 MHz,DMSO-d6)δ 7.39(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. Example 2: 4-(1-(4-bromophenyl)cyclopentyl)thiazole-2-amine (intermediate 2) [ka]

[0197] Step 1. Preparation of the compound ethyl 1-(4-bromophenyl)cyclopentane-1-carboxylate [ka]

[0198] To a solution of ethyl 2-(4-bromophenyl)acetate (10 g, 41.3 mmol) in DMF (50 mL), NaH (8.3 g, 207 mmol) was slowly added at 0°C, and the reaction mixture was stirred at room temperature for 30 minutes. 1,4-dibromobutane (8.8 g, 41.3 mmol) was slowly added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~5:1). The title compound (7.8 g, yield: 63.8%) was obtained. MS(ESI)m / z(M+H) + =297.0

[0199] Step 2. Preparation of compound 1-(4-bromophenyl)cyclopentane-1-carboxylic acid [ka]

[0200] To a solution of ethyl 1-(4-bromophenyl)cyclopentane-1-carboxylate (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 flash silica gel chromatography (PE:EA = 1:0 to 1:2). The desired compound (5.6 g, yield: 79.4%) was obtained. MS(ESI)m / z(M+H) + =269.0 The synthesis process described below was the same as that for Intermediate 1. Example 3: 4-(2-(5-bromopyridine-2-yl)propan-2-yl)thiazole-2-amine (intermediate 3) [ka]

[0201] Step 1. Preparation of the compound methyl 2-(5-bromopyridine-2-yl)-2-methylpropane [ka]

[0202] A solution of 3-(5-bromopyridine-2-yl)-2-oxopropanoic acid (2 g, 9.26 mmol, 1.0 equivalent) in DMF (20 mL) was mixed with NaH (1.3 g, 32.4 mmol, 3.5 equivalents) at 0°C. The resulting mixture was stirred at 0°C for 20 minutes. CH3I (2 mL, 3.5 equivalents) was added to the mixture at 0°C and stirred for 6 hours. The reaction mixture was quenched with water (50 mL), extracted with EA (25 mL x 2), washed with brine (10 mL x 2), then dried over Na2SO4, filtered, and evaporated to dryness. The resulting residue was purified by silica gel column chromatography to obtain the desired compound (1.95 g, yield: 93%).

[0203] Step 2. Preparation of compound 2-(5-bromopyridine-2-yl)-2-methylpropanoic acid [ka]

[0204] A mixture of 2-(5-bromopyridine-2-yl)-2-methylpropanoate (1.95 g, 7.56 mmol, 1.0 equivalent) and KOH (1.9 mL, 2 M in H2O, 3.0 equivalents) was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, quenched with 0.1 M HCl, extracted with EA, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to obtain the desired compound (1.82 g, yield: 98%).

[0205] The following steps are similar to those described for intermediate 1.

[0206] The following examples were synthesized using appropriate starting materials and thioureas, in the same manner as the procedure for intermediate 1:

[0207] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] Reaction scheme 2: [ka]

[0208] A well-substituted compound M7, in which R is a halo or 1 to 3 suitable groups such as a C1-C6 alkyl group, was acetylated with a lithium base under conditions below -60°C. M9 was obtained by alkyl substitution, such as a C1-C6 alkyl group, of M8 under basic conditions at 50-70°C. After bromination, M10 was obtained. Cyclization of M10 with thiourea under basic conditions yielded the thiazole intermediate M11. A suitable protecting group was introduced to protect the amine. The ester was reduced to an alcohol with LiBH4 at 0°C to obtain M13, which was oxidized to the corresponding aldehyde using the Dess-Martin periodinane (DMP) reagent. The alkynylthiazoleamine intermediate M15 was obtained by the Seyfers-Gilbert chain extension reaction by treating M14 with 1-diazo-1-dimethoxyphosphoryl-propan-2-one under basic conditions at RT. Final deprotection yielded the intermediate M16. Example 4: Preparation of 4-(2-(4-chlorophenyl)buta-3-in-2-yl)thiazole-2-amine (intermediate 27) [ka]

[0209] Step 1. Preparation of the compound methyl 2-(4-chlorophenyl)-3-oxobutanoate [ka]

[0210] To a solution of the compound methyl 2-(4-chlorophenyl)acetate (10 g, 54.2 mmol, 8.77 mL) in THF (80 mL), LiHMDS (1 M, 65.0 mL) was added dropwise at -78°C. The mixture was stirred at -78°C for 20 minutes. Then, acetyl acetate (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 hours. The mixture was quenched with NH4Cl (200 mL) and extracted with EA (100 mL x 3 times). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~5:1). The desired compound (7.47 g, yield: 60.9%) was obtained as a pale yellow oil.

[0211] MS(ESI)m / z(M+H) + =227.1.

[0212] Step 2. Preparation of the compound methyl 2-(4-chlorophenyl)-2-methyl-3-oxobutanoate [ka]

[0213] 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), iodomethane (13.10 g, 92.28 mmol, 5.74 mL) was added. The mixture was stirred at 70°C for 16 hours. The mixture was filtered, and the filtrate was concentrated to obtain the residue. The desired compound (7.79 g, yield: 98.2%) was obtained as a pale yellow oily substance, which was used in the next step without further purification.

[0214] MS(ESI)m / z(M+H) + =241.1.

[0215] Step 3. Preparation of the compound methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutanoate [ka]

[0216] To a solution of the compound obtained from step 2 above (7.79 g, 32.4 mmol) in CHCl3 (80 mL), Br2 (4.66 g, 29.1 mmol, 1.50 mL) was added. The mixture was stirred at 75°C for 16 hours. The reaction mixture was adjusted to pH 6-7 with NaOH (1N), then washed with H2O (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The desired compound (9.91 g, yield: 95.8%) was obtained as a light brown oily substance, which was used in the next step without further purification.

[0217] MS(ESI)m / z(M+H) + =319.0.

[0218] Step 4. Preparation of the compound methyl 2-(2-aminothiazole-4-yl)-2-(4-chlorophenyl)propanoate [ka]

[0219] To a solution of the compound obtained from 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 the residue. The precipitate was triturated in H2O (100 mL) and collected by filtration. The desired compound (8.49 g, yield: 92.3%) was obtained as a brown solid.

[0220] MS(ESI)m / z(M+H) + =297.0.

[0221] Step 5. Preparation of the compound methyl 2-(2-acetamidothiazol-4-yl)-2-(4-chlorophenyl)propanoate [ka]

[0222] To a solution of the compound obtained from step 4 above (3 g, 10.1 mmol) and TEA (1.53 g, 15.2 mmol, 2.11 mL) in DCM (60 mL), acetyl chloride (794 mg, 10.11 mmol, 721 μL) was added at 0°C. The mixture was stirred at 25°C for 1.5 hours. 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 hour. 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 hours. The reaction mixture was quenched with H2O (3 mL), then anhydrous Na2SO4 was added, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~2:1). The desired compound (1.4 g, yield: 32.6%) was obtained as a pale yellow solid.

[0223] MS(ESI)m / z(M+H) + =339.1.

[0224] Step 6: Preparation of compound N-(4-(2-(4-chlorophenyl)-1-hydroxypropan-2-yl)thiazole-2-yl)acetamide [ka]

[0225] To a solution of the compound obtained from 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), then extracted with EA (30 mL x 3 times), the combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~2:3). The desired compound (970 mg, yield: 73.4%) was obtained as a pale yellow solid.

[0226] MS(ESI)m / z(M+H) + =311.1.

[0227] Step 7. Preparation of compound N-(4-(2-(4-chlorophenyl)-1-oxopropan-2-yl)thiazole-2-yl)acetamide [ka]

[0228] To a solution of the compound obtained from step 6 above (970 mg, 3.12 mmol) in DCM (30 mL), DMP (1.72 g, 4.06 mmol) from DCM (20 mL) was partially added. The mixture was stirred at 25°C for 2 hours. DMP (1.72 g, 4.06 mmol) from DCM (20 mL) was added, and the mixture was stirred at 25°C for 1 hour. DMP (1.06 g, 2.50 mmol) from DCM (20 mL) was added, and the mixture was stirred 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), separated the organic layer, extracted the aqueous layer with DCM (60 mL), washed the combined organic layers with saturated Na2S2O3 / saturated NaHCO3 (1 / 1, 100 mL), water (200 mL x 2), and brine (200 mL x 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, which was used in the next step without further purification.

[0229] Step 8. Preparation of compound N-(4-(2-(4-chlorophenyl)buta-3-in-2-yl)thiazole-2-yl)acetamide [ka]

[0230] To a solution of the compound obtained from step 7 above (1.03 g, 3.34 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-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 obtain a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 to 1:1). The residue was purified by preparative HPLC (column: Venusil ASB Phenyl 150 × 30 mm × 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 9 min). The desired compound (219 mg, yield: 21.54%) was obtained as a white solid.

[0231] 1 H NMR(400MHz,CDCl3)δ 9.98(br s,1H),7.45(d,J=8.5 Hz,2H),7.30(d,J=8.5 Hz,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.

[0232] Step 9. Preparation of compound 4-(2-(4-chlorophenyl)buta-3-in-2-yl)thiazole-2-amine [ka]

[0233] To a solution of the compound obtained from step 8 above (180 mg, 591 μL) 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 9-10 with solid NaHCO3 and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0-2:1). The desired compound (137 mg, yield: 88.3%) was obtained as a pale yellow solid.

[0234] 1 H NMR(400MHz,CDCl3)δ 7.39-7.32(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.

[0235] The following examples were synthesized using appropriate starting materials and thioureas, in the same manner as in Example 4 (Intermediate 27):

[0236] [Table 3] Example 5: 4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazole-2-amine (intermediate 33) [ka]

[0237] Step 1. Preparation of compound N-(4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazole-2-yl)acetamide [ka]

[0238] To a solution of N-(4-(2-(4-bromophenyl)-1-hydroxypropan-2-yl)thiazole-2-yl)acetamide (200 mg, 563 μmol, synthesized by the same method as described in Intermediate 46) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (603 mg, 2.81 mmol) in DCM (10 mL), trimethyloxonium tetrafluoroborate (416 mg, 2.8 mmol) was added at 0°C. The mixture was stirred at 25°C for 16 hours. 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 obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 to 1:1). The desired compound (41 mg, yield: 19.72%) was obtained as a white solid.

[0239] 1 H NMR(400 MHz,CDCl3)δ 8.69(br s,1H),7.39(d,J=8.5 Hz,2H),7.10(d,J=8.5 Hz,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.

[0240] Step 2. Preparation of compound 4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazole-2-amine [ka]

[0241] The synthesis was similar to that described in Intermediate 44. The desired compound (20 mg, yield: 90.3%) was obtained as a white solid.

[0242] 1H NMR(400 MHz,CDCl3)δ 7.42-7.36(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.

[0243] The following intermediates were synthesized using appropriate starting materials and thioureas in the same manner as in Example 5 (intermediate 33):

[0244] [Table 4] Example 6: 1-(2-aminothiazole-4-yl)-1-(4-bromophenyl)ethane-1-ol (intermediate 38) [ka]

[0245] Step 1. Preparation of compound 1-(4-bromophenyl)propane-1,2-dione [ka]

[0246] To a solution of compound 1-(4-bromophenyl)propan-2-one (2.0 g, 9.4 mmol, 1.0 equivalent) in dioxane (20 mL), SeO2 (3.12 g, 28.1 mmol, 3.0 equivalents) was added. The mixture was stirred at 110°C for 4 hours. After cooling, the reaction mixture was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (PE:EA = 96%:4%). The desired compound (960 mg, yield: 45%) was obtained as a yellow oil.

[0247] Step 2. Preparation of compound 3-bromo-1-(4-bromophenyl)propane-1,2-dione [ka]

[0248] To a solution of the compound obtained from step 1 above (960 mg, 4.23 mmol, 1.0 equivalent) in CH3Cl (20 mL), Br2 (1.05 g, 6.34 mmol, 1.5 equivalents) 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 x 2), washed with brine (15 mL), then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE:EA = 94%:6%). The desired compound (800 mg, yield: 74%) was obtained as a yellow oil.

[0249] Step 3. Preparation of the compound (2-aminothiazole-4-yl)(4-bromophenyl)methanone [ka]

[0250] To the solution of the compound obtained from step 2 above (800 mg, 2.62 mmol, 1.0 equivalent) in MeOH (8 mL), add thiourea (200 mg, 2.62 mmol, 1.0 equivalent) and NaHCO₃⁻. 3を添加した。 The mixture was stirred at 50°C for 1.5 hours. The mixture was concentrated under reduced pressure and extracted with EA (15 mL x 2). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. This residue was purified by flash silica gel chromatography (PE:EA = 3:1) to obtain the desired group (680 mg, yield: 90%).

[0251] Step 4. Preparation of compound 1-(2-aminothiazole-4-yl)-1-(4-bromophenyl)ethane-1-ol [ka]

[0252] A solution of the compound (2-aminothiazole-4-yl)(4-bromophenyl)methanone (200 mg, 0.71 mmol, 1.0 equivalent) in dry THF (4 mL) was cooled to 0°C, and CH3MgBr (3 M in THF, 1.6 mL, 4.9 mmol, 7.0 equivalents) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl (200 mL), the mixture was extracted with EA (20 mL x 2), the combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. The obtained residue was purified by preparative TLC to obtain the desired compound (40 mg, yield: 20%).

[0253] 1 H NMR(400 MHz,DMSO)δ 7.45-7.38(m,2H),7.22(t,J=7.5 Hz,2H),7.12(t,J=7.3 Hz,1H),6.77(s,2H),6.30(s,1H),5.37(s,1H),1.67(s,3H).

[0254] MS(ESI)m / z(M+H) + =221.0 Example 7.4-(2-(4-chlorophenyl)buta-3-in-2-yl)thiazole-5-d-2-amine [ka]

[0255] Step 1. Preparation of compound N-(5-bromo-4-(2-(4-chlorophenyl)buta-3-in-2-yl)thiazole-2-yl)acetamide [ka]

[0256] A mixture of N-[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-yl]acetamide (1 g, 3.28 mmol) and NBS (700.74 mg, 3.94 mmol) in DMF (10 mL) was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, then diluted with H2O (50 mL), extracted with Âtiol (30 mL x 3), the organic phases were combined, washed with brine (50 mL x 3), and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~3:1). The desired compound (800 mg, yield: 52.6%) was obtained as a yellow solid.

[0257] 1 H NMR(400MHz,CDCl3)δ 8.89(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.

[0258] Step 2. Preparation of compound 4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]-5-duteriothiazole-2-amine [ka]

[0259] A mixture of the compound obtained from step 1 (600 mg, 1.56 mmol) and MsOH (751.43 mg, 7.82 mmol) in CD3OD (8 mL) was stirred at 80°C for 16 hours. The reaction product was adjusted to pH 8-9 with saturated NaHCO3 aqueous solution, then extracted with RINKAN (30 mL x 3), the organic phases were combined, washed with brine (30 mL), and concentrated to obtain the residue. The residue was purified by silica gel chromatography (PE:EA = 1:0-3:1) to obtain the product, which was then re-purified by pre-TLC (PE:EA = 3:1). The desired compound (100 mg, yield: 20.8%) was obtained as a yellow oily substance.

[0260] 1 H NMR(400MHz,CDCl3)δ 8.89(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.

[0261] Simultaneously, the by-product 5-bromo-4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-amine (300 mg, yield: 52.2%) was obtained as a yellow solid.

[0262] MS(ESI)m / z(M+H) + =343.1.

[0263] General method I To a solution of thiazoleamine (1 equivalent), NaH (1.2–1.5 equivalents) was added in a suitable organic solvent such as DMF at 0–10°C, and the resulting mixture was stirred for 5–30 minutes. The activated amine was added to the mixture by CDI, and the mixture was stirred for 4–16 hours. After the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by tritulation / preparative TLC / chromatography / preparative HPLC to obtain the product. Example 8: Preparation of tert-butyl 4-(4-((3-(4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate [ka]

[0264] To a solution of 4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazole-2-amine (40 mg, 0.15 mmol, 1 equivalent) in DMF (5 mL), NaH (7 mg, 0.3 mmol, 2 equivalents) was added at 10°C. The resulting mixture was stirred for 5 minutes. Tert-butyl 4-(4-((1H-imidazole-1-carboxamide)methyl)phenyl)piperazine-1-carboxylate (58 mg, 0.15 mmol, 1 equivalent) was added to the mixture and stirred overnight. The reaction product was quenched with water, extracted with EA, washed with brine, then dried with (Na2SO4), filtered, and evaporated to dryness. The resulting residue was purified by preparative TLC (PE:EA = 3:1) to obtain 35 mg (0.06 mmol) of the title compound in 40% yield. MS(ESI)m / z(M+H) + = 588.2

[0265] General method II To a solution of amine fragment (1 equivalent) and pyridine in a suitable solvent such as dry DCM, phenyl carbonochloride (2 equivalents) was slowly added at a temperature below 20°C. The mixture was stirred at room temperature for 4-6 hours. After the reaction was complete, the resulting reaction product was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product. Example 9: Preparation of tert-butyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)pyrimidine-2-yl)piperazine-1-carboxylate [ka]

[0266] Phenyl carbonochloride (336 mg, 2.2 mmol, 269.0 μL) was added at -20°C to a mixture of tert-butyl 4-(5-(aminomethyl)pyrimidine-2-yl)piperazine-1-carboxylate (600 mg, 2.1 mmol) and pyridine (194 mg, 2.5 mmol, 198 μL) in CH3CN (15 mL). After addition, the mixture was heated to 25°C and stirred at 25°C for 0.25 hours. The solvent was removed under vacuum. The residue was triturated with ice water (15 mL). A white solid precipitated from the mixture. The mixture was filtered, the solid was collected, and dried under vacuum. Tert-butyl 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidine-2-yl)piperazine-1-carboxylate (420 mg, yield: 38.2%) was obtained as a white solid. MS(ESI)m / z(M+H) + =414.2.

[0267] A mixture of tert-butyl 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidine-2-yl)piperazine-1-carboxylate (139 mg, 336 μmol) and 4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-amine (50 mg, 168 μmol) in DCE (10 mL) was mixed with DMAP (41.0 mg, 337.0 μmol, 2 equivalents). The mixture was stirred at 85°C for 16 hours. 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 (60 mg, yield: 57.7%) was obtained as a white solid.

[0268] MS(ESI)m / z(M+H) + =616.2.

[0269] General method III Two equivalents of phenyl carbonochloride were slowly added to a solution of a substituted thiazole-2-amine and a Huenig base or pyridine in a suitable solvent such as DCM, CH3CN, or DCM / water at 0°C to room temperature. The mixture was stirred at room temperature for 2 to 4 hours, the resulting reaction product was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by chromatography to obtain the substituted thiazole-2-amine carbamate.

[0270] A mixture of substituted thiazole-2-amine carbamate, amine, and DMAP in a suitable solvent such as THF was heated under reflux for 1-2 hours. After cooling, the resulting reaction product was evaporated, diluted with a suitable organic solvent such as EA, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product. Example 10: Preparation of 1-(4-(4-((tert-butyldimethylsilyl)oxy)piperidine-1-yl)benzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)urea [ka]

[0271] To a solution of 4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-amine (100 mg, 0.34 mmol, 1 equivalent) and triethylamine in 5 mL of dry DCM, phenyl carbonochloride (106 mg, 0.68 mmol, 2 equivalents) was slowly added at 0°C to RT, and the mixture was stirred at room temperature for 4 hours. The mixture was quenched with brine, extracted with EA, washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography to obtain phenyl(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)carbamate (112 mg).

[0272] A mixture of phenyl(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)carbamate (112 mg, 0.27 mmol, 1 equivalent), tert-butyl((1-(4-(aminomethyl)phenyl)piperidine-4-yl)methyl)carbamate (24 mg, 0.27 mmol, 1 equivalent), and DMAP (52 mg, 0.4 mmol, 1.5 equivalents) in THF (5 mL) was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was placed between H2O (15 mL) and EA (10 mL x 2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain tert-butyl((1-(4-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)phenyl)piperidine-4-yl)methyl)carbamate (42 mg) as a white powder.

[0273] General method IV A mixture of amine and isocyanate-alkane in THF was stirred overnight at room temperature. Once the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by trituration / preparative TLC / preparative HPLC to obtain the product. Example 11: Preparation of 1-ethyl-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)urea [ka]

[0274] To a solution of 4-(2-(4-methoxyphenyl)propan-2-yl)thiophene-2-amine (200 mg, 0.67 mmol) in THF (5 mL), isocyanatoethane (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 siRNA, washed with brine, dried, filtered, and evaporated to dryness. The resulting residue was purified by preparative TLC to obtain the desired compound (164 mg, yield: 65.4%) as a pale yellow solid. MS(ESI)m / z(M+H) + =367.1.

[0275] General method of De-BOC

[0276] The Boc compound was dissolved in HCl / MeOH, and the reaction mixture was stirred at room temperature for 1-2 hours. The solution was concentrated to dryness to obtain the final compound. Example 12: Preparation of compound 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)-3-((6-(piperazine-1-yl)pyridine-3-yl)methyl)urea hydrochloride [ka]

[0277] To a solution of tert-butyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)pyridine-2-yl)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 (47.0 mg, yield: 74.1%, HCl) was obtained as a white solid.

[0278] 1H NMR(400MHz,DMSO-d6)δ 10.90(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.

[0279] The following examples were synthesized using appropriate intermediates and corresponding fragments, in the same manner as the procedures in Examples 8, 9, 10, 11, and 12.

[0280] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23 Table 5-24 Table 5-25 Table 5-26 Table 5-27 Table 5-28 Table 5-29 Table 5-30 Table 5-31 Table 5-32 Table 5-33 Table 5-34 Table 5-35 Table 5-36 Table 5-37 Table 5-38 Table 5-39 Table 5-40 Table 5-41 Table 5-42 Table 5-43 Table 5-44 Table 5-45 Table 5-46 Table 5-47 Table 5-48 Table 5-49 Table 5-50 Table 5-51 Table 5-52 Table 5-53 Table 5-54 Table 5-55 Table 5-56 Table 5-57 Table 5-58 Table 5-59 Table 5-60 Table 5-61 Table 5-62 Table 5-63 Table 5-64 Table 5-65 Table 5-66 Table 5-67 Table 5-68 Table 5-69 Table 5-70 Table 5-71 Table 5-72 Table 5-73 Table 5-74 Table 5-75 Table 5-76 Table 5-77 Table 5-78 Table 5-79 Table 5-80 Table 5-81 Table 5-82 Table 5-83 Table 5-84 Table 5-85 Table 5-86 Table 5-87 Table 5-88 Table 5-89 Table 5-90 Table 5-91 Table 5-92 Table 5-93 Table 5-94 Table 5-95 Table 5-96 Table 5-97 Table 5-98 Table 5-99 Table 5-100 Table 5-101 Table 5-102 Table 5-103 Table 5-104 Table 5-105 Table 5-106 Table 5-107 Table 5-108 Table 5-109 Table 5-110 Table 5-111 Table 5-112 Table 5-113 Table 5-114 Table 5-115 Table 5-116 Table 5-117 Table 5-118 Table 5-119 Table 5-120 Table 5-121 Table 5-122 Table 5-123 Table 5-124 Table 5-125 Table 5-126 Table 5-127 Table 5-128 Table 5-129 Table 5-130 Table 5-131 Table 5-132 Table 5-133 Table 5-134 Table 5-135 Table 5-136 Table 5-137 Table 5-138 Table 5-139 Table 5-140 Table 5-141 Table 5-142 Table 5-143 Table 5-144 Table 5-145 Table 5-146 Table 5-147 Table 5-148 Table 5-149 Table 5-150 Table 5-151 Table 5-152 Table 5-153 Table 5-154 Table 5-155 Table 5-156 Table 5-157 Table 5-158 Table 5-159 Table 5-160 Table 5-161 Table 5-162 Table 5-163 [Table 5-164] [Table 5-165] [Table 5-166] Example 13: Preparation of tert-butyl 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazole-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate [ka]

[0281] To a solution of tert-butyl 4-(4-((3-(4-(1-(4-bromophenyl)vinyl)thiazole-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate (120 mg) in MeOH (5 mL), Pd / C (12 mg) was added, and the mixture was stirred overnight at room temperature under hydrogen pressure. After filtration and evaporation, the resulting residue was purified by silica gel column chromatography to obtain tert-butyl 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazole-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate (73 mg). Example 14: Preparation of tert-butyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)ureidomethyl)-3-fluoropyridine-2-yl)piperazine-1-carboxylate [ka]

[0282] A suspension of 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)-3-((6-chloro-5-fluoropyridine-3-yl)methyl)urea (174 mg, 0.4 mmol), tert-butylpiperazine-1-carboxylate (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 an N2 atmosphere. The reaction mixture was cooled to room temperature, 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 obtain the crude product, which was purified by flash column to obtain the desired product (67 mg, yield 25%). Example 15: Preparation of 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)-2-(3-methylpiperazine-1-yl)benzamide [ka]

[0283] Preparation of Step 12-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)-5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)ureidomethyl)benzoic acid [ka]

[0284] A mixture of tert-butyl 4-(2-(methoxycarbonyl)-4-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)phenyl)-2-methylpiperazine-1-carboxylate (270 mg, 0.42 mmol, 1 equivalent) and KOH (23.5 mg, 0.42 mmol, 1 equivalent) was heated under reflux for 0.5 hours. After cooling, the reaction product was quenched with saturated NH4Cl (aqueous solution), extracted with EA, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The resulting residue was purified by preparative TLC to obtain the desired compound (215 mg).

[0285] Step 2: Preparation of tert-butyl 4-(2-carbamoyl-4-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)phenyl)-2-methylpiperazine-1-carboxylate [ka]

[0286] A mixture of 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)ureidomethyl)benzoic acid (215 mg, 0.34 mmol, 1 equivalent), EDCI (132 mg, 0.69 mmol, 2 equivalents), HOBt (93 mg, 0.69 mmol, 2 equivalents), and DIEA (133 mg, 1.03 mmol, 3 equivalents) was dissolved in THF (0.1 M) and stirred at room temperature for 15 minutes. Then, NH4Cl (36.9 mg, 0.69 mmol, 2 equivalents) was added all at once, and the reaction was stirred at room temperature. Once the reaction was determined to be complete by TLC analysis, the resulting suspension was diluted with SiO2, washed with brine, dried, filtered, and evaporated to dryness. The resulting residue was purified by trituration or preparative TLC to obtain the desired product (201 mg). Example 16: Preparation of 1-((6-((2-hydroxyethyl)amino)pyridine-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)urea [ka]

[0287] A mixture of 1-((6-fluoropyridine-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)urea (50 g, 0.13 mmol, 1.0 equivalent) and 2-aminoethanol (11.9 mg, 0.19 mmol, 1.5 equivalents) in EtOH was heated to 90°C for 14 hours. After the reaction mixture was cooled to room temperature, it was concentrated to obtain a residue, which was purified by silica gel column chromatography to obtain 1-((6-((2-hydroxyethyl)amino)pyridine-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)urea (21 mg). Example 17: Preparation of 1-(4-(2-(4-methoxyphenyl)buta-3-in-2-yl)thiazole-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea [ka]

[0288] Step 1. Preparation of methyl 2-(4-methoxyphenyl)acetate [ka]

[0289] To a mixture of 2-(4-methoxyphenyl)acetic acid (20.0 g, 120.4 mmol) in MeOH (100 mL), H2SO4 (1.2 g, 12.0 mmol, 642 μL) was added at 15°C. The mixture was stirred at 85°C for 12 hours. The mixture was diluted with EA (400 mL), washed with saturated NaHCO3 aqueous solution (100 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica column chromatography (ethyl acetate in petroleum ether = 0-15%). The desired product (21.6 g, yield: 99.7%) was obtained as a yellow oily substance.

[0290] 1 H NMR(400 MHz,CDCl3)δ 7.21(d,J=8.8 Hz,2 H)6.87(d,J=8.8 Hz,2 H),3.80(s,3 H),3.69(s,3 H),3.58(s,2 H)

[0291] Step 2. Preparation of the compound methyl 2-(4-methoxyphenyl)-3-oxobutanoate

[0292] [ka]

[0293] To a solution of the compound obtained from step 1 above (23.8 g, 132.2 mmol) in THF (200 mL), LiHMDS (1 M, 159 mL) was added at -78°C. The mixture was stirred at -78°C for 20 minutes. Acetyl acetate (13.5 g, 132.2 mmol) was added to the solution. The mixture was then heated to 0°C and stirred at 0°C for 2 hours. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0-15%) to obtain the desired compound (14.23 g, yield: 48.4%) as a yellow oil.

[0294] 1H NMR(400 MHz,CDCl3)δ 12.97(s,1 H),7.25-7.23(m,1.5 H),7.07-7.03(m,2 H),6.87-6.85(m,2 H),4.63(s,0.5 H),3.80(s,3 H),3.78(s,1.5 H),3.73(s,1.5 H),3.67(s,3 H),2.15(s,1.5 H),1.83(s,3 H).MS(ESI)m / z(M+H) + =223.1

[0295] Step 3. Preparation of the compound methyl 2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate [ka]

[0296] CH3I (26.0 g, 183.3 mmol) was added at 15°C to a mixture of the compound obtained from step 2 above (14.5 g, 65.4 mmol) and 2CO3 (45.2 g, 326.9 mmol) in acetone (100 mL). The mixture was stirred at 70°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica column chromatography (ethyl acetate in petroleum ether = 0-15%). The desired compound (9.76 g, yield: 63.2%) was obtained as a colorless oil.

[0297] 1 H NMR(400 MHz,CDCl3)δ 7.25-7.19(m,2 H),6.95-6.86(m,2 H),3.82(s,3 H),3.79(s,3 H),2.10(s,3 H),1.77(s,3 H)

[0298] Step 4. Preparation of the compound methyl 4-bromo-2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate [ka]

[0299] To a solution of the compound obtained in step 3 above (1 g, 4.2 mmol) in CHCl3 (20 mL), Br2 (676 mg, 4.2 mmol) was added 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) was obtained as a colorless oil. The crude product was used directly in the next step without further purification.

[0300] MS(ESI)m / z(M+H) + =315.1

[0301] Step 5. Preparation of the compound methyl 2-(2-aminothiazole-4-yl)-2-(4-methoxyphenyl)propanoate [ka]

[0302] The mixture of 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 triturated with H2O (20 mL) at 15°C for 10 minutes, filtered, and the cake was concentrated under vacuum to obtain the residue. The desired product (0.79 g, yield: 82.68%) was obtained as a yellow solid.

[0303] 1 H NMR(400 MHz,CDCl3)δ 7.20-7.18(m,2 H),6.97-6.92(m,2 H),6.88-6.86(m,2 H),5.95(s,1 H),3.73(s,3 H),3.61(s,3 H),1.77(s,3 H).

[0304] Step 6. Preparation of the compound methyl 2-(4-methoxyphenyl)-2-(2-((phenoxycarbonyl)amino)thiazole-4-yl)propanoate [ka]

[0305] A mixture of the compound obtained from step 5 above (300 mg, 1.03 mmol) and pyridine (97.4 mg, 1.23 mmol) in CH3CN (3 mL) was mixed with phenyl carbonochloride (169 mg, 1.08 mmol) 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 column (ethyl acetate in petroleum ether = 0-30%) to obtain the desired compound (330 mg, yield: 77.97%) (obtained as a yellow oily substance).

[0306] MS(ESI)m / z(M+H) + =413.0

[0307] Step 7. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(1-methoxy-2-(4-methoxyphenyl)-1-oxopropan-2-yl)thiazole-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate [ka]

[0308] A mixture of the compound obtained from step 6 above (330 mg, 800 μmol) and tert-butyl 4-[4-(1-aminoethyl)phenyl]piperazine-1-carboxylate (269 mg, 880 μmol) in THF (2 mL) was stirred under microwave at 100°C for 1 hour. The mixture was concentrated directly under vacuum to obtain a residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-80%). The desired compound (441 mg, yield: 88.37%) was obtained as a yellow oily substance.

[0309] MS(ESI)m / z(M+H) + =646.2

[0310] Step 8. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(1-hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate [ka]

[0311] To a solution of the compound obtained in step 7 above (370 mg, 593 μmol) in THF (10 mL), LiBH4 (26 mg, 1.2 mmol) was added 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 column (ethyl acetate in petroleum ether = 0-100%) to obtain the desired compound (307 mg, yield: 87.0%) (obtained as a yellow solid).

[0312] 1 H NMR(400 MHz,CDCl3)δ 7.17(d,J=8.4 Hz,2 H),7.09-7.06(m,2 H),6.86-6.80(m,4 H),6.45(s,1 H),4.94-4.91(m,1 H),4.05-4.00(m,1 H),3.81-3.77(m,4 H),3.56-3.54(m,4 H)3.09-3.07(m,4 H),1.56(d,J=1.6 Hz,3 H),1.49(s,9 H),1.46(d,J=6.8 Hz,3 H).

[0313] Step 9. Preparation of compound 1-(4-(1-hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)-3-(1-(4-(piperazine-1-yl)phenyl)ethyl)urea hydrochloride [ka]

[0314] To a solution of the compound obtained from step 8 above (50 mg, 83.93 μmol) in DCM (2 mL), HCl / Â (4 M, 2 mL) was added at 15°C. The mixture was stirred at 15°C for 12 hours. When the mixture was concentrated under vacuum, the desired compound (34 mg, yield: 76.1%) was obtained as a yellow solid.

[0315] 1 H NMR(400 MHz,DMSO)δ 10.47(br s,1 H),9.11(br s,2 H),7.36-7.23(m,1 H),7.19(d,J=8.8 Hz,2 H),7.10(d,J=8.8 Hz,2 H),6.95(d,J=8.8 Hz,2 H),6.75(d,J=8.0 Hz,2 H),6.69(s,1 H),4.77-4.73(m,1 H),3.80-3.76(m,1 H),3.70(s,3 H)3.34-3.31(m,4 H),3.24-3.16(m,4 H),2.07(s,1 H),1.55(s,3 H),1.33(d,J=6.8 Hz,3 H).MS(ESI)m / z(M+H) + =496.2

[0316] Step 10: Preparation of compound tert-butyl 4-(4-(1-(3-(4-(2-(4-methoxyphenyl)-1-oxopropan-2-yl)thiazole-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate [ka]

[0317] To a solution of oxalyl dichloride (68.2 mg, 537.14 μmol) in DCM (2 mL), DMSO (66 mg, 839 μmol) was added at -78°C. After 10 minutes, the compound obtained from step 9 above (100 mg, 168 μmol) in DCM (2 mL) was added and stirred at -78°C for 1 hour. Et3N (170 mg, 1.68 mmol) was added and stirred for a further 10 minutes, then heated to 15°C and stirred for a further 1 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) was obtained as a yellow oil. The crude product was used directly in the next step without further purification.

[0318] Step 11: Preparation of compound tert-butyl 4-(4-(1-(3-(4-(2-(4-methoxyphenyl)buta-3-in-2-yl)thiazole-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate [ka] 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 in MeOH (5 mL)) were 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%~95%, 10 min) to obtain the desired compound (50 mg, yield: 50.34%) as a yellow oil.

[0319] MS(ESI)m / z(M+H) + =590.3

[0320] Step 12. Preparation of compound 1-(4-(2-(4-methoxyphenyl)buta-3-in-2-yl)thiazole-2-yl)-3-(1-(4-(piperazine-1-yl)phenyl)ethyl)urea [ka]

[0321] The desired compound (39 mg, yield: 87.4%) was obtained as a yellow solid using the De-BOC method.

[0322] 1 1H NMR (400 MHz, DMSO-d6)δ 10.50(br s,1 H),9.22(br s,2 H),7.31(d,J=8.8 Hz,2 H),7.19(d,J=8.4 Hz,3 H),6.95(d,J=8.4 Hz,2 H),6.85(dd,J=8.4,1.2 Hz,2 H),6.81-6.79(m,1 H),4.76-4.73(m,1 H),3.71(s,3 H),3.39(s,1 H),3.35-3.32(m,4 H)3.24-3.16(m,4 H),1.82(d,J=2.4 Hz,3 H),1.33(d,J=6.8 Hz,3 H).

[0323] MS(ESI)m / z(M+Na) + = 512.3 Example 18: Preparation of 1-(4-(2-(4-cyclopropylphenyl)propan-2-yl)thiazole-2-yl)-3-(4-(piperazine-1-yl)benzyl)urea [ka]

[0324] Step 1: Preparation of tert-butyl 4-(4-((3-(4-(2-(4-cyclopropylphenyl)propan-2-yl)thiazole-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate [ka]

[0325] To a solution of the compound obtained from step 1 (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 an N2 atmosphere. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was filtered through a Celite pad 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 obtain the desired compound (45 mg, yield: 60.2%) as a white solid.

[0326] Step 2. Preparation of compound 1-(4-(2-(4-cyclopropylphenyl)propan-2-yl)thiazole-2-yl)-3-(4-(piperazine-1-yl)benzyl)urea [ka]

[0327] The desired compound was obtained as a white solid (40 mg, HCl salt, yield: 100%) using the procedure described in Example 9. MS(ESI)m / z(M+H) + =476.2. Example 19: 1-(4-(2-(4-chlorophenyl)buta-3-in-2-yl)thiazole-2-yl)-3-(2-hydroxyethyl-2,2-d2)urea [ka]

[0328] Step 1. Preparation of the compound tert-butyl N-(2,2-diduterio-2-hydroxy-ethyl)carbamate [ka]

[0329] To a solution of methyl 2-((tert-butoxycarbonyl)amino)acetate (1 g, 5.29 mmol) in THF (20 mL), LiAlD4 (364.8 mg, 7.93 mmol) was added at 0°C, and the mixture was then stirred at 80°C for 3 hours. After adding EA (20 mL) and H2O (5 mL) dropwise, the mixture was extracted with EA (100 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The desired compound (610 mg, yield: 70.7%) was obtained as a yellow oily substance, which was used in the next step without further purification.

[0330] 1 H NMR(400MHz,CDCl3)δ 5.17(br s,1H),3.24(d,J=5.6 Hz,2H),3.08(br s,1H),1.42(s,9H).

[0331] Step 2. Preparation of compound 2-amino-1,1-diduterioethanol [ka]

[0332] The mixture of the compound obtained from step 1 (610 mg, 3.74 mmol) in HCl / MeOH (4 M, 5 mL) was stirred at 25°C for 3 hours. The reaction mixture was concentrated under vacuum. The desired compound (520 mg, crude, HCl) was obtained as a yellow oily substance, which was used in the next step without further purification.

[0333] 1 H NMR(400MHz,DMSO-d6)δ 2.80(q,J=5.7 Hz,2H).

[0334] Step 3. Preparation of the compound phenyl N-[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-yl]carbamate [ka]

[0335] To a solution of 4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-amine (500 mg, 1.90 mmol) and pyridine (752.60 mg, 9.51 mmol) in MeCN (20 mL), phenyl carbonochloride (327.7 mg, 2.09 mmol) was added at 0°C, 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 x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The desired compound (830 mg, crude) was obtained as a yellow oily substance, which was used in the next step without further purification.

[0336] MS(ESI)m / z(M+H) + =383.0

[0337] Step 4. Preparation of compound 1-[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-yl]-3-(2,2-diduterio-2-hydroxyethyl)urea [ka]

[0338] A mixture of the compound obtained in step 3 (400 mg, 1.04 mmol), the compound obtained in step 2 (98.9 mg, 1.57 mmol), and DMAP (12.8 mg, 104.48 µl) in DCE (20 mL) was stirred at 80°C for 5 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Xtimate C18 150*40 mm*5 µm; mobile phase: [water (HCl)-ACN]; B%: 28%~58%, 10 min). The desired compound (90 mg, yield: 24.5%) was obtained as a white solid.

[0339] MS(ESI)m / z(M+H) + =352.1.

[0340] SFC: Column: ChiralPak IG-3 100×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5.5 mins to 40% B and hold at 40% for 3 minutes, then hold at 5% B for 1.5 minutes, Flow rate: 2.5 mL / min, Column temperature: 40°C (P1: Rf = 4.159 mins, P2: Rf = 4.831 mins).

[0341] Step 5. Preparation of compound 1-[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-yl]-3-(2,2-diduterio-2-hydroxyethyl)urea [ka]

[0342] The compound obtained in step 4 above (90 mg, 255.79 μm) was separated by SFC (column: DAIEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 40%-40%, min). Chiral isomer 1 (26.85 mg, yield: 29.8%) was obtained as a white solid.

[0343] 1 H NMR(400MHz,CDCl3)δ 7.34-7.28(m,2H),7.22-7.19(m,2H),6.69(s,1H),3.23(d,J=5.5 Hz,2H),2.48(s,1H),1.84(s,3H).MS(ESI)m / z(M+H) + =351.9.SFC Rf=4.151 minutes.

[0344] Chiral isomer 2 (27.90 mg, yield: 31.0%) was obtained as a white solid.

[0345] 1H NMR(400MHz,CDCl3)δ 7.43-7.35(m,2H),7.31-7.27(m,2H),6.76(s,1H),3.31(d,J=5.5 Hz,2H),2.55(s,1H),1.92(s,3H).MS(ESI)m / z(M+H) + =351.9.SFC:Rf=4.815 minutes. General method A

[0346] HOBt (2 equivalents), DIEA (3 equivalents), a carboxylic acid (1 equivalent) containing or not containing pyridine / DMAP, and EDCI (2-2.5 equivalents) were dissolved in THF / DMF and stirred at room temperature for 15-30 minutes. Then, an amine (1 equivalent) was added all at once, and the reaction mixture was stirred at room temperature to 70°C for 2-16 hours. After the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by tritulation / preparative TLC / chromatography / preparative HPLC to obtain the product. Example 20: Preparation of compound 4-((2-hydroxyethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)benzamide [ka]

[0347] To a solution of 4-((2-hydroxyethyl)amino)benzoic acid (200 mg, 1.10 mmol) and 4-[1-(4-methoxyphenyl)-1-methyl-ethyl]thiazole-2-amine (261.98 mg, 919.85 µl, HCl) in Py (8 mL), EDCI (440.84 mg, 2.30 mmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (column: Agela ASB 150 × 25 mm × 5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 48%-78%, 10 min). The desired compound (52 mg, yield: 13.57%) was obtained as a pale yellow solid.

[0348] 1H NMR(400MHz,DMSO-d6)δ 12.06(br s,1H),7.87(d,J=8.8 Hz,2H),7.12(d,J=8.8 Hz,2H),6.86(s,1H),6.82(d,J=8.8 Hz,2H),6.62(d,J=8.8 Hz,2H),3.70(s,3H),3.54(t,J=5.9 Hz,2H),3.16(t,J=5.9 Hz,2H),1.62(s,6H).MS(ESI)m / z(M+H) + =412.5. General method B

[0349] Acid chlorides were obtained by using SOCl2 in a suitable solvent such as DCM. TEA or pyridine (3 equivalents) and amine (1 equivalent) in DCM were slowly added to an acyl chloride solution under N2 at 0°C, and the mixture was stirred at room temperature for 0.5–2 hours. Once the reaction was complete, the mixture was quenched with H2O, extracted with EA, washed with brine, dried (Na2SO4), filtered, and evaporated to dryness. The resulting residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product. Example 21 [ka]

[0350] To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (150 mg, 438.16 ml) in DCM (6 mL), SOCl2 (31.8 μL, 438.16 ml) was added. 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. Then, 4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]thiazole-2-amine (115.07 mg, 437.94 ml) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 to 1:1). The desired compound (152 mg, yield: 54.4%) was obtained as a colorless oil.

[0351] MS(ESI)m / z(M+H) + =587.1. Example 22: Preparation of compound N-(4-(2-(4-chlorophenyl)buta-3-in-2-yl)-1H-imidazole-2-yl)-2,6-difluoro-4-(piperazine-1-yl)benzamide

[0352] [ka]

[0353] Step 1. Preparation of the compound methyl 2-(4-chlorophenyl)-2-(imidazo[1,2-a]pyrimidine-2-yl)propanoate [ka]

[0354] A mixture of pyrimidine-2-amine (1.0 g, 10.5 mmol) and methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutanoate (3.36 g, 10.5 mmol) in EtOH (20 mL) was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, 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 / 0~0 / 1) to obtain methyl 2-(4-chlorophenyl)-2-imidazo[1,2-a]pyrimidine-2-ylpropanoate (1.48 g, yield: 40.1%) as a white solid.

[0355] MS(ESI)m / z(M+H) + =316.0.

[0356] Step 2. Preparation of the compound methyl 2-(2-amino-1H-imidazole-4-yl)-2-(4-chlorophenyl)propanoate [ka]

[0357] A solution of methyl 2-(4-chlorophenyl)-2-imidazo[1,2-a]pyrimidine-2-ylpropanoate (600 mg, 1.90 mmol) in dioxane (5 mL) contains NH2NH2 . H2O (650 mg, 11.04 mmol, purity 85%) 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 obtain methyl 2-(2-amino-1H-imidazole-4-yl)-2-(4-chlorophenyl)propanoate (60 mg, yield: 33.9%) as a white solid.

[0358] MS(ESI)m / z(M+H) + =280.1.

[0359] 1 H NMR(400MHz,CD3OD)δ 7.29(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).

[0360] Step 3. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-1-methoxy-1-oxopropan-2-yl)-1H-imidazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0361] SOCl2 (92 mg, 772 umol) was added to a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (220 mg, 644 umol) in DCM (10 mL), then DMF (13 mg, 172 umol) was added, and the reaction mixture was stirred at 25°C for 1 hour. Subsequently, Py (204 mg, 2.57 mmol) was added to the reaction mixture and stirred at 25°C for 10 minutes. Then, methyl 2-(2-amino-1H-imidazole-4-yl)-2-(4-chlorophenyl)propanoate (120 mg, 429 umol) 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 obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]-1H-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (120 mg, yield: 38.9% yield, purity 84%) as a colorless, rubbery substance.

[0362] MS(ESI)m / z(M+H) + =604.1.

[0363] Step 4. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-1-hydroxypropan-2-yl)-1H-imidazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0364] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]-1H-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (120 mg, 199 umol) in THF (8 mL), LiBH4 (4 M, 248 uL) was added at 0°C. After the 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 toluene (8 mL x 2). The extract was washed with water (8 mL x 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-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (110 mg, crude) as a light brown, rubbery substance, which was used in the next step without purification.

[0365] MS(ESI)m / z(M+H) + =576.1.

[0366] Step 5. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-1-oxopropan-2-yl)-1H-imidazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0367] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-hydroxy-1-methyl-ethyl]-1H-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (170 mg, 295 ml) in DCM (10 mL), DMP (500 mg, 1.18 mmol) was added, and the reaction mixture was stirred at 25°C for 4 hours after the addition. 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-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (150 mg, crude) as a light brown, rubbery substance, which was used in the next step without purification.

[0368] Step 6. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)buta-3-in-2-yl)-1H-imidazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0369] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-2-oxo-ethyl]-1H-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (150 mg, 261 umol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (75.3 mg, 392 umol) in MeOH (8 mL), K2CO3 (72.2 mg, 522.63 umol) was added. 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 10 mL of water, extracted with siRNA (10 mL x 2), the combined extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (FA conditions) to obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]-1H-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (12 mg, yield: 8.1%) as a grayish-white solid.

[0370] Step 7. Preparation of compound N-(4-(2-(4-chlorophenyl)buta-3-in-2-yl)-1H-imidazole-2-yl)-2,6-difluoro-4-(piperazine-1-yl)benzamide [ka]

[0371] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]-1H-imidazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (12 mg, 21.05 umol) in MeOH (0.3 mL), HCl / dioxane (4 M, 900 uL) 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 obtain N-[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]-1H-imidazole-2-yl]-2,6-difluoro-4-piperazine-1-yl-benzamide (5 mg, yield: 40.2% yield, 2HCl salt) as a light brown solid.

[0372] MS(ESI)m / z(M+Na) + =492.3.

[0373] 1 H NMR(400MHz,CD3OD)δ 7.52(br d,J=8.4 Hz,2H),7.40(br d,J=8.4 Hz,2H),7.22(s,1H),6.76(br d,J=12.4 Hz,2H),3.65-3.59(m,4H),3.39-3.32(m,4H),3.20(s,1H),1.97(s,3H). Example 23: Preparation of N-(4-(2-(4-chlorophenyl)buta-3-in-2-yl)oxazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide

[0374] [ka] Step 1. Preparation of the compound methyl 2-(2-aminooxazol-4-yl)-2-(4-chlorophenyl)propanoate [ka]

[0375] To a solution of methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutanoate (1.00 g, 3.13 mmol) in EtOH (30 mL), urea (282 mg, 4.69 mmol) was added, and the mixture was stirred at 80°C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain methyl 2-(2-aminooxazole-4-yl)-2-(4-chlorophenyl)propanoate (50.0 mg, yield: 4.2%) as a yellow solid.

[0376] MS(ESI)m / z(M+H) + =281.1.

[0377] 1 H NMR(400MHz,CD3OD)δ 7.31(s,4H),6.98(s,1H),3.71(s,3H),1.85-1.79(m,3H).

[0378] Step 2. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-1-methoxy-1-oxopropan-2-yl)oxazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0379] SOCl2 (38.0 mg, 321 umol) was added to a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluorobenzoic acid (91.0 mg, 267 umol) in DCM (5 mL). DMF (5.0 mg, 71.3 umol) was added, and the reaction mixture was stirred at 25°C for 1 hour. Next, Py (85.0 mg, 1.07 mmol) was added to the reaction mixture, and it was stirred at 25°C for 10 minutes. Then, methyl 2-(2-aminooxazole-4-yl)-2-(4-chlorophenyl)propanoate (50.0 mg, 178 umol) was added to the reaction mixture, and it 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 obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]-oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (42.0 mg, yield: 30%) as a colorless, rubbery substance.

[0380] MS(ESI)m / z(M+H) + =605.1.

[0381] Step 3. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-1-hydroxypropane-2-yl)oxazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0382] A solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-methoxy-1-methyl-2-oxo-ethyl]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (40.0 mg) in 2 mL of THF was added to a solution of LiBH4 (4 M, 83 μL) in 3 mL of THF under 0°C and a N2 atmosphere. After the 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 toluene (8 mL x 2). The extract was washed with water (8 mL x 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]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (28.0 mg, crude) as a white solid, which was used in the next step without purification.

[0383] Step 4. Preparation of the compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-1-oxopropan-2-yl)oxazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0384] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-2-hydroxy-1-methyl-ethyl]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (28.0 mg, crude) in DCM (5 mL), DMP (41.0 mg, 97.05 umol) was added, and the reaction mixture was stirred at 25°C for 3 hours after the addition. 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 obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-2-oxo-ethyl]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (30.0 mg, crude) as a light brown solid, which was used in the next step without purification.

[0385] MS(ESI)m / z(M+H) + =575.1.

[0386] Step 5. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)buta-3-in-2-yl)oxazole-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka]

[0387] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-2-oxo-ethyl]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (30.0 mg, crude) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (15.0 mg, 78.3 umol) in MeOH (4 mL), K2CO3 (14.0 mg, 104 umol) was added. After the 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 siRNA (5 mL x 3), the combined extract was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (28.0 mg, crude) as a light brown, rubbery substance.

[0388] MS(ESI)m / z(M+H) + =571.1.

[0389] Step 6. Preparation of compound N-(4-(2-(4-chlorophenyl)buta-3-in-2-yl)oxazol-2-yl)-2,6-difluoro-4-(piperazine-1-yl)benzamide [ka]

[0390] To a solution of tert-butyl 4-[4-[[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]oxazole-2-yl]carbamoyl]-3,5-difluorophenyl]piperazine-1-carboxylate (25.0 mg, crude) in DCM (2 mL), TFA (2 mL) 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 (FA conditions) to obtain N-[4-[1-(4-chlorophenyl)-1-methyl-propa-2-inyl]oxazole-2-yl]-2,6-difluoro-4-piperazine-1-yl-benzamide (7.5 mg, yield: 28.7%, TFA salt) as a light brown solid.

[0391] MS(ESI)m / z(M+H) + =471.3.

[0392] 1 1H NMR (400MHz, CD3OD) δ 7.64(s,1H),7.58(br d,J=8.0 Hz,2H),7.39-7.29(m,2H),6.72(br d,J=11.8 Hz,2H),3.65-3.54(m,4H),3.42-3.35(m,4H),2.98(s,1H),1.90(s,3H). General method C

[0393] A carboxylic acid (1 equivalent), HATU (1.2 equivalents) or HBTU or PyBOP, and TEA or DIEA (3 equivalents) were dissolved in a suitable organic solvent such as THF or DMF and stirred at room temperature for 15-30 minutes. Then, an amine (1-1.5 equivalents) was added all at once, and the reaction mixture was stirred at room temperature to 100°C for 4-16 hours. After the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the resulting residue was purified by tritulation / preparative TLC / chromatography / preparative HPLC to obtain the product. Example 24: Preparation of the compound methyl N-(4-(2-(4-bromophenyl)buta-3-in-2-yl)thiazole-2-yl)-3-((tert-butyldiphenylsilyl)oxy)cyclobutan-1-carboxamide [ka]

[0394] A solution of 3-[tert-butyl(diphenyl)silyl]oxycyclobutanecarboxylic acid (1.36 g, 3.84 mmol) in DCM (10 mL) was mixed with PyBOP (2.00 g, 3.84 mmol) at 25°C. After stirring for 10 minutes, methyl 2-(2-aminothiazole-4-yl)-2-(4-bromophenyl)propanoate (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 hours. 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 resulting residue was purified by silica column (ethyl acetate in petroleum ether = 0-25%). The desired compound (1.4 g, crude) was obtained as a yellow oily substance. MS(ESI)m / z(M+H) + =643.1

[0395] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] Table 6-7 Table 6-8 Table 6-9 Table 6-10 Table 6-11 Table 6-12 Table 6-13 Table 6-14 Table 6-15 Table 6-16 Table 6-17 Table 6-18 Table 6-19 Table 6-20 Table 6-21 Table 6-22 Table 6-23 Table 6-24 Table 6-25 Table 6-26 Table 6-27 Table 6-28 Table 6-29 Table 6-30 Table 6-31 Table 6-32 Table 6-33 Table 6-34 Table 6-35 Table 6-36 Table 6-37 Table 6-38 Table 6-39 Table 6-40 Table 6-41 Table 6-42 Table 6-43 Table 6-44 Table 6-45 Table 6-46 Table 6-47 Table 6-48 Table 6-49 Table 6-50 Table 6-51 Table 6-52 Table 6-53 Table 6-54 Table 6-55 Table 6-56 Table 6-57 Table 6-58 Table 6-59 Table 6-60 Table 6-61 Table 6-62 Table 6-63 Table 6-64 Table 6-65 Table 6-66 Table 6-67 Table 6-68 Table 6-69

[0396] Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Table 7-16 Table 7-17 Table 7-18 Table 7-19 Table 7-20 Table 7-21 Table 7-22 [Table 7-23] [Table 7-24] [Table 7-25] [Table 7-26] [Table 7-27] [Table 7-28] [Table 7-29] [Table 7-30]

[0397] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] Example 25: 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)nicotinamide [ka]

[0398] Step 1. Preparation of compound 6-chloro-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)nicotinamide [ka]

[0399] A mixture of compound 4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-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) in pyridine (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 2:1). The desired compound (63 mg, yield 46.26%) was obtained as a yellow oil. MS(ESI)m / z(M+H) + =388.0

[0400] Step 2. Preparation of compound 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)nicotinamide [ka]

[0401] The mixture of the compound obtained from step 1 (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) in DMF (5 mL) was stirred at 65°C for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (water (0.05% HCl)-ACN). The desired compound (25.01 mg, yield 35.0%) was obtained as a yellow solid.

[0402] 1H NMR(400MHz,MeOD)δ 8.43-8.32(m,1H),8.18-8.11(m,1H),7.35(s,1H),7.23-7.14(m,3H),6.83(d,J=8.8 Hz,2H),6.79(s,1H),3.76(m,4H),1.70(s,6H).

[0403] MS(ESI)m / z(M+H) + =440.2 Example 26: Preparation of compound 6-((4-(2-hydroxyethyl)piperazine-1-yl)methyl)-N-(4-(2-(p-tolyl)propan-2-yl)thiazole-2-yl)nicotinamide [ka]

[0404] To a solution of compound 6-(piperazine-1-ylmethyl)-N-(4-(2-(p-tolyl)propan-2-yl)thiazole-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 equivalents) and K2CO3 (19 mg, 137.8 μmol, 2 equivalents) were added. The reaction mixture was then stirred at 80°C for 16 hours. The reaction product was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (water (0.225% FA)-ACN; B%: 15%~45%, 7.5 min). The compound (2.3 mg, yield: 6.9%) was obtained as a white solid.

[0405] 1 H NMR(400MHz,CDCl3)δ 9.09-9.05(m,1H),8.33-8.28(m,1H),7.75(br d,J=8.8 Hz,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. Example 27: (1r,3r)-N-(4-(2-(4-bromophenyl)buta-3-in-2-yl)thiazole-2-yl)-3-(hydroxymethyl)cyclobutan-1-carboxamide [ka]

[0406] Step 1. Preparation of the compound methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylate [ka]

[0407] To a solution of methyl 3-(hydroxymethyl)cyclobutane carboxylate (200 mg, 1.39 mmol) and imidazole (189 mg, 2.77 mmol) in DCM (5 mL), TBDPSCl (458 mg, 1.66 mmol, 427 μL) was added 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 obtain the residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-20%). The desired compound (420 mg, yield: 79.1%) was obtained as a yellow oil.

[0408] MS(ESI)m / z(M+H) + =383.1

[0409] Step 2. Preparation of compound 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylate [ka]

[0410] A mixture of the compound obtained from step 1 (412 mg, 1.08 mmol) in THF (1.5 mL) / MeOH (0.5 mL) / H2O (0.5 mL) was to which LiOH·H2O (90.6 mg, 2.16 mmol) was added at 0°C. The mixture was stirred at 25°C for 3 hours. The mixture was diluted with H2O (15 mL) to adjust the pH to 6-7 and extracted with EA (15 mL x 3 times). The combined organic layer was 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.

[0411] MS(ESI)m / z(M+Na) + =391.1

[0412] Step 3. Preparation of the compound methyl 2-(4-bromophenyl)-2-(2-((1R,3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide)thiazole-4-yl)propanoate [ka]

[0413] A solution of the compound obtained from step 2 (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 minutes. Methyl 2-(2-aminothiazole-4-yl)-2-(4-bromophenyl)propanoate (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 hours. 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 obtain the residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-20%). The desired compound (194 mg, crude) was obtained as a yellow oily substance. Another desired compound B (186 mg, crude) was obtained as a yellow oily substance. The crude product was used directly in the next step without further purification. The chirality of the product was confirmed in the final step.

[0414] Step 4. Preparation of the compound (1R,3R)-N-(4-(2-(4-bromophenyl)-1-hydroxypropane-2-yl)thiazole-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide [ka]

[0415] To a solution of the compound obtained in step 3 above (194 mg, 280.4 μmol) in THF (5 mL), LiBH4 (31 mg, 1.40 mmol) was added 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 x 3 times). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-30%). The desired compound (77 mg, yield: 41.4%) was obtained as a yellow oil.

[0416] MS(ESI)m / z(M+H)+ =663.1

[0417] Step 5. Preparation of the compound (1R,3R)-N-(4-(2-(4-bromophenyl)-1-oxopropan-2-yl)thiazole-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide [ka]

[0418] A solution of the compound obtained from step 4 above (77 mg, 132 μmol) in DCM (2 mL) was added at 20°C to a mixture of Dess-Martin (73 mg, 171.2 μmol, 53 μL) in DCM (2 mL). 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 x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 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.

[0419] Step 6. Preparation of the compound (1R,3R)-N-(4-(2-(4-bromophenyl)buta-3-in-2-yl)thiazole-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide [ka]

[0420] A solution of the compound obtained from step 5 above (77 mg, 116 μmol), 1-diazo-1-dimethoxyphosphoryl-propan-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 obtain a residue. The residue was purified by silica column chromatography (ethyl acetate in petroleum ether = 0-15%). The desired compound (37 mg, yield: 48.3%) was obtained as a yellow oily substance.

[0421] MS(ESI)m / z(M+H) + =657.1

[0422] Step 7. Preparation of the compound (1R,3R)-N-(4-(2-(4-bromophenyl)buta-3-in-2-yl)thiazole-2-yl)-3-(hydroxymethyl)cyclobutanecarboxamide [ka]

[0423] To a solution of the compound obtained in step 6 above (37 mg, 56.3 μmol) in THF (2 mL), TBAF (1 M, 0.1 mL) was added at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with EA (50 mL), washed with H2O (10 mL x 3) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-15%). The desired compound (12.61 mg, yield: 53.5%) was obtained as a yellow solid.

[0424] 1 1H NMR (400MHz, CDCl3)δ 13.28(br s,1 H),7.56-7.48(m,4 H),6.91(s,1 H),3.65(d,J=4.4 Hz,2 H),3.34-3.30(m,1 H),2.77(s,1 H),2.63-2.61(m,1 H),2.52-2.43(m,2 H),2.34-2.32(m,2 H),2.15(s,3 H).MS(ESI)m / z(M+H) + =419.0.

[0425] Other isomers were synthesized using the same procedure as described above. Example 28: 4-((4-(2-hydroxyethyl)piperazine-1-yl)methyl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)benzamide [ka]

[0426] To a solution of the compounds 4-formyl-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-yl)benzamide (120 mg, 0.32 mmol) and 2-(piperazine-1-yl)ethane-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 obtain the residue. The residue was purified by flash silica gel chromatography (DCM:MeOH = 1:0~10:1). The desired compound (80 mg, yield: 51.4%) was obtained as a white solid.

[0427] MS(ESI)m / z(M+H) + =495.2

[0428] How to use ALPK1 is an intracellular serine-threonine protein kinase that plays a crucial role in activating the innate immune response. ALPK1 binds to the bacterial pathogen-associated molecular pattern metabolite (PAMP), ADP-D-glycero-β-D-mannoheptose (ADP-heptose). ALPK1-ADP-heptose binding occurs via a direct interaction at the ALPK1 N-terminal domain. This interaction stimulates the kinase activity of ALPK1 as well as its phosphorylation and activation of the TRAF-interacting protein with its forkhead-associated domain (TIFA). TIFA activation then induces pro-inflammatory NFκB signaling, including the expression and / or secretion of pro-inflammatory cytokines and chemokines. Therefore, the compounds disclosed herein are generally useful as inhibitors of ALPK1 kinase activity and downstream activation of pro-inflammatory NFκB signaling.

[0429] This disclosure provides the use of compounds of Formula I described herein or their lower embodiments for inhibiting ALPK1 kinase activity and reducing inflammation in target tissues. The method also encompasses the use of compounds of Formula I described herein or their lower embodiments for treating diseases, disorders, or conditions characterized by excessive or inadequate ALPK1-dependent pro-inflammatory signaling. In embodiments, the disease, disorder, or condition is selected from sepsis, cancer, sweat adenoma, spiral gland carcinoma, “retinal dystrophy, optic edema, splenomegaly, anhidrosis, and migraine” (“ROSAH”) syndrome and “periodic fever, aphthous stomatitis, pharyngitis, and adenitis” (“PFAPA”) syndrome. In embodiments, cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma. In embodiments, cancer is oral squamous cell carcinoma.

[0430] In embodiments, the Disclosure provides a method for inhibiting ALPK1 kinase activity in mammalian cells or target tissue by contacting said cells or target tissue with a compound of Formula I or a lower embodiment described herein. In embodiments, the method comprises administering to a subject an amount effective in inhibiting ALPK1 kinase activity in the target cells or tissue. In embodiments, the method comprises reducing inflammation in a target tissue of a subject requiring a treatment that reduces inflammation in the target tissue by administering to a subject a compound of Formula I, or a lower embodiment described herein, or a pharmaceutical composition containing the same.

[0431] In some embodiments, the Disclosure provides a method for treating a subject having a disease or disorder characterized by excessive or inappropriate activation of ALPK1 kinase activity, comprising administering a compound of Formula I or a lower embodiment described herein to the subject. In embodiments, the disease or disorder is selected from sepsis, cancer, sweat adenoma, spiral gland carcinoma, ROSAH syndrome, and PFAPA syndrome.

[0432] In the embodiments, the disease or disorder is sweat adenoma or spiral carcinoma, and the method comprises administering a compound of formula I or a lower embodiment described herein to a subject requiring such treatment. In the embodiments, the subject requiring treatment is a subject diagnosed with sweat adenoma or spiral carcinoma and having one or more gene mutations in ALPK1. In the embodiments, at least one of the gene mutations is an activating mutation. In the embodiments, the gene mutation in ALPK1 is p.V1092A, described in Rashid et al., Nature Communications (2019).

[0433] In the embodiments, the disease or disorder is ROSAH, and the method comprises administering a compound of formula I or a lower embodiment described herein to a subject requiring such treatment. In the embodiments, the subject requiring treatment is a subject diagnosed with ROSAH and having one or more gene mutations in ALPK1. In the embodiments, at least one of the gene mutations is an activating mutation. In the embodiments, the gene mutations in the ALPK1 gene are c.710C>T, p.T237M, as described in Williams et al., Genetics in Medicine 21:2103-2115 (2019).

[0434] In the embodiments, the disease or disorder is PFAPA, and the method comprises administering a compound of formula I or a lower embodiment described herein to a subject requiring such treatment. In the embodiments, the subject requiring treatment is a subject diagnosed with or having clinical symptoms of PFAPA and possessing one or more gene mutations in ALPK1. In the embodiments, at least one of the gene mutations is an activating mutation. In the embodiments, the gene mutation in the ALPK1 gene is 2770T>C, p.(S924P) as described in Sangiorgi et al. Eur.J. Human Genetics (2019).

[0435] In the embodiment, the disease or disorder is a cancer selected from lung cancer, colon cancer, and oral squamous cell carcinoma. In the embodiment, the cancer is oral squamous cell carcinoma. In the embodiment, the subject requiring treatment is a subject diagnosed with cancer, and the cancer cells have at least one activating mutation in ALPK1, or the cancer cells express ALPK1 mRNA or protein at elevated levels compared to the non-cancer cells of the subject.

[0436] In embodiments, the disclosure further provides a method for identifying a disease, disorder, or condition for treatment of a compound of formula I or a disease, disorder, or condition according to a lower embodiment described herein, comprising assaying a biological sample from a subject diagnosed with a disease, disorder, or condition for one or more activating mutations in ALPK1 and overexpression of ALPK1 mRNA or protein in cells or tissues involved in the disease, disorder, or condition, compared to reference cells or tissue not involved in the disease, disorder, or condition. In embodiments, the activating mutation in ALPK1 is 2770T>C,p(S924P).

[0437] In the context of the methods described herein, the term “to treat” may mean the improvement or stabilization of one or more symptoms associated with the disease, disorder, or condition being treated. The term “to treat” may also encompass the management of a disease, disorder, or condition, where the subject is derived from a treatment but does not result in a cure of the underlying disease, disorder, or condition.

[0438] In embodiments in which a therapeutically effective dose of the compounds described herein is administered to a target, the therapeutically effective dose is an amount sufficient to achieve a desired therapeutic outcome, such as improvement or stabilization of one or more symptoms of the disease, disorder, or condition being treated.

[0439] In this embodiment, the therapeutically effective dose is the amount required to achieve at least the same therapeutic effect as a standard treatment. An example of a standard treatment is an FDA-approved drug indicated for treating the same disease, disorder, or condition.

[0440] In connection with 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, a cat, a rodent (e.g., a mouse, a rat, a rabbit), a horse, a cow, a sheep, a goat, or any other non-human mammal.

[0441] In some embodiments, the human subjects are selected from adult, child, or elderly individuals, and these terms are understood by the physician as defined, for example, by the U.S. Food and Drug Administration.

[0442] Pharmaceutical composition In embodiments, this disclosure provides pharmaceutical compositions comprising a compound of Formula I described herein or a lower embodiment thereof, and one or more carriers or excipients, preferably pharmaceutically acceptable carriers or excipients. As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, carrier and / or dosage form suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio, within the bounds of sound medical judgment. Excipients for preparing pharmaceutical compositions are generally known to be safe and non-toxic when administered to the human or animal body. 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 above. The specific excipients used in a composition depend on various factors, including the chemical stability and solubility of the compound being formulated and the intended route of administration.

[0443] Pharmaceutical compositions can be supplied in bulk or in unit dosage forms. Formulating pharmaceutical compositions in unit dosage forms is particularly advantageous for ease of administration and uniformity of dosage. The term "unit dosage form" refers to a physically distinct unit suitable as a unit dose for the target being treated, each unit containing a predetermined amount of the active compound calculated to associate with the required pharmaceutical carrier to produce the desired therapeutic effect. Unit dosage forms may be ampoules, vials, suppositories, sugar-coated tablets, tablets, capsules, IV bags, or single pumps on aerosol inhalers.

[0444] For therapeutic use, the dose may vary depending on the chemical and physical properties of the active compound, as well as the clinical characteristics of the subject, including, for example, age, weight, and comorbidities. Generally, the dose should be a therapeutically effective dose. An effective dose of a pharmaceutical composition is the amount that provides an objectively identifiable improvement, as noted by a clinician or other qualified observer, such as alleviating the symptoms of a disorder, disease, or condition.

[0445] The pharmaceutical compositions described herein may take any suitable form (e.g., liquid, aerosol, solution, inhalant, mist, spray; or solid, powder, ointment, paste, cream, lotion, gel, patch, etc.) for administration via any desired route (e.g., lung, inhalation, intranasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, percutaneous, transmucosal, rectal, etc.). In embodiments, the pharmaceutical compositions may take the form of orally acceptable dosage forms, including, but not limited to, capsules, tablets, buccal forms, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions, or solutions. Capsules may contain excipients such as inert fillers and / or starches (e.g., corn, potato, or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), wheat flour, gelatin, gum, etc., as diluents. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added.

[0446] In embodiments, the pharmaceutical composition is in the form of a tablet. The tablet may contain a unit dose of the compound described herein together with an inert diluent or carrier, such as a sugar or sugar alcohol, such as lactose, sucrose, sorbitol, or mannitol. The tablet may further contain a non-sugar diluent such as sodium carbonate, calcium phosphate, or calcium carbonate, or cellulose or its derivatives such as methylcellulose, ethylcellulose, or hydroxypropylmethylcellulose, and starch such as corn starch. The tablet may further contain a binder and granulator such as polyvinylpyrrolidone, a disintegrant (e.g., a swellable crosslinked polymer such as crosslinked carboxymethylcellulose), a lubricant (e.g., stearate), a preservative (e.g., paraben), an antioxidant (e.g., butylated hydroxytoluene), a buffer (e.g., phosphate buffer or citrate buffer), and a foaming agent such as a citrate / bicarbonate mixture. The tablet may be a coated tablet. The coating may be a protective film coating (e.g., wax or varnish) or a coating designed to control the release of the active compound, such as delayed release (release of the active substance after a predetermined delay time following ingestion) or release at a specific location within the gastrointestinal tract. The latter can be achieved using enteric film coatings, such as those sold under the trade name Eudragit®.

[0447] Tablet formulations may be prepared by conventional compression, wet granulation, or dry granulation methods and may utilize 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 carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starch, and powdered sugars). Preferred surface modifiers include nonionic and anionic surface modifiers. Typical examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsified wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine.

[0448] In the embodiments, the pharmaceutical composition is in the form of a hard or soft gelatin capsule. According to this formulation, the compound of the present invention may be in the form of a solid, semi-solid, or liquid.

[0449] In embodiments, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for parenteral administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-sacral, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques.

[0450] In embodiments, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for administration by direct injection or addition to a sterile infusion solution 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 can be prepared in water using a cosolvent or surfactant. Examples of suitable surfactants include polyethylene glycol (PEG) fatty acids and PEG fatty acid mono and diesters, PEG glycerol esters, alcohol-oil transesterification products, polyglyceryl fatty acids, propylene glycol fatty acid esters, sterols and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugars and their derivatives, polyethylene glycol alkylphenols, polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, sorbitan fatty acid esters, ionic surfactants, lipid-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.

[0451] This disclosure also provides packaging and kits comprising pharmaceutical compositions for use in the methods described herein. The kit may include one or more containers selected from the group consisting of bottles, vials, ampoules, blister packs, and syringes. The kit may further include one or more of the following: instructions for use, one or more syringes, one or more applicators, or sterile solutions suitable for reconstituting the compounds or compositions described herein.

[0452] All percentages and ratios used herein are based on weight unless otherwise specified.

[0453] The present invention will be further explained and illustrated by the following non-limiting embodiments. Examples

[0454] In embodiments, the compound of formula I or the subembodied embodiments described herein is an inhibitor of ALPK1 measured, for example, in an in vitro kinase assay or an assay designed to measure the activation of downstream targets of ALPK1 pathway activation, such as NFκB transcriptional activation and the secretion of pro-inflammatory cytokines and chemokines, such as IL-8, also known as CXCL-8. Generally, the computer program XL fit was used for data analysis, including nonlinear regression analysis. The maximum half dose inhibitory concentration (IC50) was used as a measure of the efficacy of the compound in the assay. The IC50 value was determined using the following logistic equation Y = minimum + (maximum - minimum) / (1 + (X / IC50^- Hill slope), where Y is the value at compound concentration X. Concentration response curve fitting was performed using GraphPad Prism version 6.00 software.

[0455] ALPK1 in vitro kinase assay ALPK1 kinase activity was measured in an in vitro assay using ADP-heptose as the ALPK1 ligand, an activator of its kinase activity, and TIFA protein as the ALPK1 phosphorylation substrate. Since phosphorylated TIFA protein oligomers, protein-protein interactions between HA-tagged TIFA proteins were measured using homogeneous time-resolved fluorescence (HTRF) as an indicator of TIFA phosphorylation.

[0456] In short, dose-response studies were performed using HEK293 cells cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Hyclone®) containing the antibiotic (PEN / Strip, G418) in a 384-well assay plate. Each well contained 0.1 mg of TIFA, ALPK1 (final concentration 2 nM in the reaction mixture), and kinase buffer (100 mM HEPES pH 7.4, 4 mM DTT, 40 mM MgCl2, 20 mM β-glycerol disodium phosphate, 0.4 mM Na3VO4, 0.16 mg / mL). Titration of the test compound was prepared in dimethyl sulfoxide (DMSO). The reaction was initiated by the addition of ATP and ADP-heptose.

[0457] For HTRF, Tb cryptotate-labeled anti-HA antibodies were incubated with samples to capture HA-tagged proteins according to the manufacturer's instructions (PerkinElmer®, CisBio®), and the fluorescence signal was quantified (Tecan Infinite F NANO+). The HTRF signal was calculated as the HTRF ratio (ratio of fluorescence measured at 665 nm and 620 nm) × 10⁴ (thus using the signal at 620 nm as the internal standard).

[0458] All compounds showed a dose-dependent decrease in TIFA phosphorylation in this assay. IC50 values ​​were determined using a 3-parameter or 4-parameter logistic equation with GraphPad Prism version 6.00. Reference compound A027 was used as a positive control for each plate. This compound has an IC50 of approximately 50 nanomoles (nM) in this assay. The IC50 values ​​of the test compounds ranged from 1 to 1000 nM and are shown in Tables 4 to 7.

[0459] NFκB gene reporter alkaline phosphatase assay Inhibition of ALPK1-dependent NFκB reporter gene activation was measured using an alkaline phosphatase reporter assay system. Briefly, HEK293 cells (hereinafter referred to as "G9 cells") stably expressing the NF-κB reporter were maintained in DMEM as described above. For the assay, cells were seeded at a density of 10,000 cells / well in Freestyle® 293 expression medium (ThermoFisher) into 96-well plates and allowed to adhere overnight. Cells were pretreated with serial dilution compounds for 30 minutes and then stimulated with D-glycero-D-manno-6-fluoroheptose-1β-S-ADP. This compound is an analog of ADP-heptose that exhibits increased stability in vitro along with a similar ability to activate ALPK1 kinase activity. NFκB gene activation was detected using the chromogenic substrate p-nitrophenyl phosphate (pNPP) according to the manufacturer's protocol (pNPP phosphatase assay, Beyotime Biotechnology). All compounds showed a dose-dependent decrease in NFκB promoter-driven gene expression in this assay. IC50 values ​​ranged from 1 to 10 micromoles (uM), as shown in Tables 4-7.

[0460] Inhibition of activated ALPK1 Activating mutations in ALPK1 are associated with diseases and disorders such as cancer, sweat adenoma, spiral carcinoma, ROSAH syndrome, and PFAPA syndrome. The inventors conducted further experiments to evaluate the ability of representative compounds to inhibit ALPK1 in the context of two activating mutations, T237M and V1092A. In preliminary experiments, the inventors determined that IL-8 protein secretion was elevated in cells transiently transfected with human ALPK1 expression vectors containing each of these activating mutations. Therefore, the inventors used IL-8 secretion as an indicator of activated ALPK1 inhibition in cells expressing these mutations.

[0461] First, in preliminary experiments, the inventors established 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 before transient transfection 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) kinase-dead ALPK1 mutant (hALPK1-T237M-D1194S). Transfection was carried out according to the manufacturer's protocol (Lipofectamine® 3000, ThermoFisher). Transfected cells were selected, seeded in 96-well plates, and treated with serial dilutions of the test compound for 6.5 hours. After treatment, cell viability was determined using a luminescent cell viability assay (cell counting-Lite assay or "CCL assay" from Vazyme Biotech Co., Ltd.), and the cell-free supernatant was collected and analyzed for IL-8 protein by IL-8 ELISA as described above. Figure 1 shows the IL-8 secretion of each test group. As shown in the figure, IL-8 was hardly detected in cells transfected with either an empty vector, hALPK1, or a kinase-dead hALPK1 mutant. In contrast, both activating mutations in hALPK1 induced significant IL-8 secretion.

[0462] Next, the inventors tested a representative series of compounds for inhibiting IL-8 secretion in cells expressing the activated ALPK1 mutants T237M and V1092A, respectively. Table 8 shows the inhibition of IL-8 secretion in cells transfected with T237M, and Table 9 shows the inhibition of IL-8 secretion in cells transfected with the V1092A mutant. For the T237M mutant study, the inventors created a HEK293 cell line ("A2") that stably expresses the T237M hALPK1 mutant. A2 cells were cultured for a total of 40 hours in the presence of the test compounds. Fresh medium and the compounds were added at 24 hours. Cell viability and IL-8 secretion were determined 16 hours after the second addition of the compounds using the CCL assay and IL-8 ELISA as described above. Table 8 shows the maximum half-dose inhibitory concentration (IC50) of IL-8 secretion in A2 cells compared to IL-8 secretion from wild-type HEK293 cells. The results suggest that knockdown of IL-8 levels from wild-type cells is 100% inhibitory.

[0463] [Table 9-1] [Table 9-2]

[0464] For the V1092A mutant test shown in Table 9, HEK293 cells were transiently transfected with either hALPK1-V1092A or hALPK1 (wild-type) expression vectors, and then treated with the test compound for 24 hours. Fresh medium and the compound were added after 18 hours. Cell viability and IL-8 secretion were determined 6 hours after the second addition of the compound using the CCL assay and IL-8 ELISA as described above. Table 9 shows the maximum half-liquid inhibitory concentration (IC50) of IL-8 secretion compared to wild-type HEK293 cells.

[0465] [Table 10-1] [Table 10-2]

[0466] Inhibition of activated ALPK1 in the kidney To investigate the effects of ALPK1 inhibitors on the expression of innate immune genes activated upon ALPK1 activation, SD rats were orally administered ALPK1 inhibitors, followed by intraperitoneal administration of the ALPK1 agonist D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP to activate the innate immune genes. Kidney tissue was collected and gene expression was assayed. Briefly, 20 male Sprague-Dawley (SD) rats were randomly divided into five groups. The normal group was orally administered vehicle (0.5% MC). Two hours later, PBS was administered by intravenous injection. The control group was orally administered vehicle (0.5% MC). Two hours later, D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP (50 μpk) was administered by intravenous 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-heptose-1β-S-ADP (50 μpk) was administered by ip injection. Kidneys from each group were collected after 3 hours of ip injection of D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP (50 μpk). Samples were isolated for RT-PCR, and the expression levels of MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6 mRNA were identified. Total RNA was extracted from the kidneys according to the Rneasy Mini Kit (QIAGEN, Germany) protocol. Messenger RNA was reverse transcribed to cDNA using the HiScript Q RT SuperMix for qPCR Kit (Vazyme, Nanjing, China). Quantitative PCR was performed using the AceQ qPCR SYBR Green Master Mix Kit (Vazyme, Nanjing, China) at QuantStudio 5 applied biosystems (Thermo Scientific, USA). Relative mRNA levels were calculated using the 2-ΔΔCT method, and HPRT was used as the standard for gene expression normalization. The data were presented as gene saturation changes.As shown in Figure 2, A0176 exhibited dose-dependent inhibition of gene expression levels for several innate immune genes, including MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6.

[0467] Efficacy study in an animal model of sepsis-induced acute kidney injury Multiple bacterial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because its progression and characteristics closely resemble those of human sepsis. The effects of the compounds described herein on sepsis were evaluated using a rat CLP model. Briefly, the rat cecum was ligated with sterile silk, the cecum was punctured twice with a needle, gently squeezed to express a small amount of feces, and then the abdominal incision was closed. Compounds C008 and A0176 (20 mg / kg) were administered 2 hours prior to surgery, and survival was recorded over the following 24 hours. Furthermore, 24 hours postoperatively, the kidney was collected for gene expression analysis by Q-PCR, and plasma was collected for measurement of plasma MCP-1 concentration by ELISA. The results are shown in Figures 3, 4, and 5. In short, ALPK1 inhibitors improved animal survival (Figure 3), reduced renal pro-inflammatory gene expression (Figure 4), and improved plasma MCP-1 levels (Figure 5).

[0468] Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the invention described herein by means of routine experiments. Such equivalents are intended to be covered by the following claims.

[0469] All references cited herein are incorporated herein by reference in their entirety, to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated in its entirety by reference in all purposes.

[0470] The present invention is not limited in scope by the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to be included within the scope of the appended claims.

Claims

1. Compounds of formula XI, formula XI-B, or formula XI-C 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, X is -S-, -O-, and -NR ａ - is selected from, and here, R ａ H is, A is azetidinyl, -N(R ６ ) -, -CH ２ -N(R) ６ )-,-CHR ９ -N(R) ６ ) - Selected from, here, R ６ is selected from H, -OH, optionally substituted C １ ~C ６ alkyl, optionally substituted C １ ~C ６ hydroxyalkyl, and C １ ~C ６ aminoalkyl, where R may be substituted. ６ The parts are -OH and -NH ２ It comprises 0 to 3 substituents independently selected from, R ９ C may be substituted. １ ~C ６ It is alkyl, and here, R may be substituted. ９ The part contains 0 to 2 substituents that are -OH. R １ H, and C which may be substituted. １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Hydroxyalkyl, optionally substituted C １ ~C ６ Hydroxydeuterated alkyl, optionally substituted C １ ~C ６ Haloalkyl, optionally substituted C １ ~C ６ aminoalkyl, optionally substituted C １ ~C ６ Alkoxyl, optionally substituted saturated or unsaturated C ３ ~C ６ Selected from cycloalkyls, optionally substituted monocyclic or bicyclic aryls, optionally substituted 5-10 membered heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S; and optionally substituted saturated or unsaturated 6-11 membered bicyclic heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, R may be substituted. １ The parts are -D, halo, -OH, and -NH. ２ , = O, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkyl hydroxydeuterated, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkoxyl, -R ７ａ , -X １ -R ７ａ _CHR ７ａ R ８ａ , -OR ７ａ , -O-X １ -R ７ａ , -X １ -O-X １ -R ７ａ , -O-X １ -C(O)(R ７ａ ), -C(O)(R ７ａ ), -C(O)N(R ７ａ R ８ａ ), S(O) ２ R ７ａ , -S(O) ２ N(R) ７ａ R ８ａ ), -N(R ７ａ R ８ａ ), saturated or unsaturated C ３ ~C ６ A saturated or unsaturated 3-7 membered heterocyclil containing 1-2 heteroatom ring vertices selected from cycloalkyl, N, O, and S; a monocyclic or bicyclic aryl; a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S; and a saturated or unsaturated 7-8 membered bridged heterocyclil containing 1-2 heteroatom ring vertices selected from N, O, and S, comprising 0-4 substituents independently selected from these, Each X １ C is independent １～６ It is alkylene, Each R ７ａ and R ８ａ are independently selected from H, C １ to C ６ alkyl, C １ to C ６ hydroxyalkyl, C １ to C ６ haloalkyl, C １ to C ６ aminoalkyl, C １ to C ６ alkoxyl, monocyclic or bicyclic aryl, 1 to 2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 3- to 7-membered heterocyclyl, and the monocyclic or bicyclic aryl and the 3- to 7-membered heterocyclyl group are halo, -OH, -NH ２ , =O, C １ to C ６ alkyl, C １ to C ６ hydroxyalkyl, C １ to C ６ haloalkyl, C １ to C ６ aminoalkyl, C １ to C ６ alkoxyl, and 0 to 3 substituents selected from saturated or unsaturated C ３ to C ６ cycloalkyl, and are substituted In the substituent of the substituted R1, the saturated or unsaturated C ３ ~C ６ Cycloalkyl, the saturated or unsaturated 3- to 7-membered heterocyclyl, the monocyclic or bicyclic aryl, the 5- to 10-membered heteroaryl, and the saturated or unsaturated 7- to 8-membered cross-linked heterocyclyl are each independently represented as halo, -OH, and -NH. ２ , = O, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Alkoxyl, saturated, or unsaturated C ３ ~C ６ Saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from cycloalkyl, N, O, and S, -CHR ７ｂ R ８ｂ , -OR ７ｂ , -C(O)N(R ７ｂ R ８ｂ ), -S(O) ２ N(R) ７ｂ R ８ｂ ) and -N(R ７ｂ R ８ｂ ) is replaced by 0 to 3 parts selected from, Each R ７ｂ and R ８ｂ These are H and C, independently. １ ~C ６ Selected from alkyl groups, or R １ and R ６ These combine to form a 3-6 member heterocycloalkyl group, R ５ H, deuterium, halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, and C １ ~C ６ Selected from haloalkyls, R ２ and R ３ These are H, OH, and C, respectively, independently. １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ６ Selected from cycloalkyl and the monocyclic or bicyclic aryl, where C １ ~C ６ Alkyl, C ２ ~C ６ Alkinyl, C ３ ~C ６ Cycloalkyl and the monocyclic or bicyclic aryl are, respectively, halo, -OH, and C. １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, and C １ ~C ６ Substituted by 0 to 3 moieties independently selected from the alkoxyl, However, R ２ and R ３ Are both of them not H, or R ２ and R ３ They combine to form C ３ ~C ６ Forming a cycloalkyl ring, Each R ４ is halo, -OH, -NH ２ , C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Alkoxyl, saturated, or unsaturated C ３ ~C ６ Cycloalkyl, CHR ７ｅ R ８ｅ , and OR ７ｅ Selected independently from, here, Each R ７ｅ and R ８ｅ These are H and C, independently. １ ~C ６ Alkyl and C １ ~C ６ Selected from haloalkyls, The subscript p is 1, 2, or 3. D is CR １０ or N, E is CR １４ or N, F is CR １２ or N, G is CR １１ or N, However, if three or fewer of D, E, F, and G are N, R １０ , R １１ , R １２ , and R １４ If present, these are H, halo, -OH, and C, respectively, independently. １ ~C ６ Alkoxyl, -O-X １ -R ７ａ , -C(O)N(R ７ａ R ８ａ ), and selected from saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatom ring vertices selected from N, O, and S, where, Each X １ C is independent １～６ It is alkylene, Each R ７ａ and R ８ａ These are H and C, independently. １ ~C ６ Alkyl and C １ ~C ６ Selected from alkoxyls, R １３ This is a 3-7 member heterocyclil containing 1-2 heteroatomic ring vertices selected from N, O, and S, or a saturated or unsaturated 7-8 member bridged heterocyclil containing 1-2 heteroatomic ring vertices selected from N, O, and S. 3- to 7-membered heterocyclyls and 7- to 8-membered cross-linked heterocyclyls are -OH, C １ ~C ６ Alkyl, C １ ~C ６ Aminoalkyl, -NH ２ , and C １ ~C ６ It may be substituted with 0 to 2 moieties independently selected from the hydroxyalkyl group. m is an integer from 1 to 6. R １８ H is The aforementioned compound, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein X is -S-, X is -O-, or X is -NH-.

3. R ６ However, H, C １ ~C ６ Alkyl and C １ ~C ６ A compound according to claim 1, selected from hydroxyalkyl groups.

4. R ９ CH ３ and CH ２ The compound according to claim 1, selected from OH.

5. R １ However, H and C may be substituted. １ ~C ６ Selected from alkyl groups, C may be substituted. １ ~C ６ Alkyl is a halo, -OH, -NH ２ , = O, -CN, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkoxyls, saturated or unsaturated C ３ ~C ６ Cycloalkyl, -CHR ７ａ R ８ａ , -OR ７ａ , -C(O)(R ７ａ ), -C(O)N(R ７ａ R ８ａ ), -S(O) ２ R ７ａ , -S(O) ２ N(R) ７ａ R ８ａ ) and -N(R ７ａ R ８ａ It comprises 0 to 4 substituents independently selected from ) Each R ７ａ and R ８ａ These are H and C, independently. １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, and C １ ~C ６ Selected from alkoxyls, Or, R １ This may be saturated or unsaturated C, which may be substituted. ３ ~C ６ It is a cycloalkyl, C may be substituted. ３ ~C ６ Cycloalkyls are halo, -OH, -NH ２ , = O, -CN, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxyl, and C １ ~C ６ It contains 0 to 4 substituents independently selected from the haloalkoxyl, Or, R １ It is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S. 5-10 member heteroaryls are halo, -OH, -NH ２ ,-CN,C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ 3-7 membered heterocyclyls containing 1-2 heteroatom ring vertices selected from alkoxyl, N, O, and S, saturated or unsaturated C ３ ~C ６ Cycloalkyl, -CHR ７ａ R ８ａ , -OR ７ａ , -C(O)N(R ７ａ R ８ａ ), -S(O) ２ N(R) ７ａ R ８ａ ) and -N(R ７ａ R ８ａ ) is replaced by 0 to 3 parts selected from, Each R ７ａ and R ８ａ These are H and C, independently. １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, and C １ ~C ６ Selected from alkoxyls, Or, R １ However, the halo is a monocyclic or bicyclic aryl substituted with 0 to 3 substituents selected from a halo, a 3- to 7-membered heterocyclil containing 1 to 2 heteroatomic ring vertices selected from N, O, and S, and a 7- to 8-membered bridged heterocyclil containing 1 to 2 heteroatomic ring vertices selected from N, O, and S, where 3- to 7-membered heterocyclyls or 7- to 8-membered cross-linked heterocyclyls are halos, -OH, -NH ２ , = O, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Alkoxyl, saturated, or unsaturated C ３ ~C ６ Cycloalkyl, -CHR ７ｂ R ８ｂ , -OR ７ｂ , -C(O)N(R ７ｂ R ８ｂ ), -S(O) ２ N(R) ７ｂ R ８ｂ ) and -N(R ７ｂ R ８ｂ ) is replaced by 0 to 3 parts selected from, Each R ７ｂ and R ８ｂ These are H and C, independently. １ ~C ６ Selected from alkyl groups, The compound according to claim 1.

6. R １ However, -OH, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxyl, -S(O) ２ N(R) ７ａ R ８ａ ) and -N(R ７ａ R ８ａ C substituted with 0 to 4 substituents independently selected from ) １ ~C ６ It is alkyl, Each R ７ａ and R ８ａ These are H and C, independently. １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Alkoxyl, and saturated or unsaturated C ３ ~C ６ A compound according to claim 1, selected from cycloalkyl groups.

7. R １ is -OH, C １ ~C ６ Hydroxyalkyl and -S(O) ２ N(R) ７ａ R ８ａ C substituted with 0 to 2 substituents independently selected from ) １ ~C ６ It is alkyl, Each R ７ａ and R ８ａ H and C １ ~C ６ A compound according to claim 1, independently selected from alkyl groups.

8. R １ C may be substituted. １ ~C ６ The compound according to claim 1, wherein it is a hydroxyalkyl compound.

9. R １ However, halo, -OH, -NH ２ ,-CN,C １ ~C ６ A pyridiyl substituted with 0 to 3 moieties selected from a 3 to 7-membered heterocycline containing 1 to 2 heteroatom ring vertices selected from alkyl, N, O, and S, The aforementioned 3- to 7-membered heterocyclyls are halo, -OH, -NH ２ ,-CN,C １ ~C ６ Alkyl and C １ ~C ６ The compound according to claim 1, which is substituted with 0 to 3 substituents selected from haloalkyl groups.

10. R １ However, halo, -OH, -NH ２ , = O, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ A monocyclic or bicyclic aryl substituted with alkoxyls and 0 to 3 moieties selected from 3 to 7-membered heterocyclines containing 1 to 2 heteroatom ring vertices selected from N, O, and S, The aforementioned 3- to 7-membered heterocyclyls are halo, -OH, -NH ２ , = O, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Alkoxyl, saturated, or unsaturated C ３ ~C ６ Cycloalkyl, -CHR ７ｂ R ８ｂ , -OR ７ｂ , -C(O)N(R ７ｂ R ８ｂ ), -S(O) ２ N(R) ７ｂ R ８ｂ ) and -N(R ７ｂ R ８ｂ ) is replaced by 0 to 3 parts selected from, where, Each R ７ｂ and R ８ｂ These are H and C, independently. １ ~C ６ A compound according to claim 1, selected from alkyl groups.

11. R １ However, it is a monocyclic or bicyclic aryl substituted with a halo and 0 to 3 moieties selected from a 3 to 7-membered heterocycline containing 1 to 2 heteroatom ring vertices selected from N, O, and S. The aforementioned 3- to 7-membered heterocyclyls are -OH, -NH ２ ,=O,-CN and-C １ ~C ６ The compound according to claim 1, further substituted with 0 to 3 portions selected from alkyl groups.

12. D, E, F, and G are CR １０ CR １４ CR １２ and CR １１ The compound according to claim 1.

13. F and G are CR １２ and CR １１ And E is N or CR １４ And D is N or CR １０ The compound according to claim 1.

14. R １２ and R １４ H is, R １０ and R １１ These are, independently, Halo, -OH, and C. １ ~C ６ Alkyl and -C(O)N(R) ７ａ R ８ａ ) is selected, and here, Each R ７ａ and R ８ａ These are H and C, independently. １ ~C ６ Alkyl and C １ ~C ６ Selected from alkoxyls, R １３ This is selected from 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, where, The aforementioned 3- to 7-membered heterocyclyl and the aforementioned 7- to 8-membered cross-linked heterocyclyl are -OH, -NH ２ , C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, and C １ ~C ６ The compound according to claim 1, which may be substituted with 0 to 2 moieties independently selected from the aminoalkyl group.

15. A compound according to claim 1 having formula XI-B-1 or XI-B-2, 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, in the formula, R １５ is -OH, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, and C １ ~C ６ Selected from aminoalkyl groups, R １６ and R １７ Each is independently selected from Haro. A compound, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, having formula XI-B-1-a-I or formula IB-2-a-I, 【Transformation 3】 or a pharmaceutically acceptable salt thereof, in the formula R ４ A halo, a compound, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, having formula XI-B-1-a-II or formula XI-B-2-a-II, 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, having formula XI-B-1-a-III or formula XI-B-2-a-III, 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, having formula XI-B-1-a-IV or formula IB-2-a-IV, 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, having formula XI-C-1 【Transformation 7】 。

21. The compound according to claim 1, wherein m is 1.

22. R ２ and R ３ Are both methyl? Or, R ２ is methyl, R ３ Is it ethynyl? Or, R ２ is methyl, R ３ CH ２ OMe is The compound according to claim 1.

23. The subscript p is 1, R ４ The compound according to claim 1, wherein the compound is bonded to a phenyl ring as shown below: 【Transformation 8】 、 (In the equation, the wavy line indicates a connection point to the rest of the equation.)

24. The subscript p is 1, R ４ Is it a chloroform bonded to a phenyl ring as shown below? 【Chemistry 9】 (In the equation, the wavy line indicates a connection point to the rest of the equation.) , or The subscript p is 1, R ４ This is a methoxy compound bonded to a phenyl ring, as shown below: 【Chemistry 10】 (In the equation, the wavy line indicates a connection point to the rest of the equation.) The compound according to claim 1.

25. R ５ Is it H or methyl? Or, R ５ Is it deuterium? Or, R ５ However, -CH ２ D, -CHD ２ and -CD ３ Selected from the group consisting of, The compound according to claim 1.

26. R ２ and R ３ Whether the carbon atom bonded to it is an S isomer, Or, R ２ and R ３ The carbon atom bonded to it is the R isomer. The compound according to claim 1.

27. below: 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 [Chemistry 11-12] [Chemistry 11-13] [Chemistry 11-14] 【Chemistry 11-15】 【Chemistry 11-16】 [Chemistry 11-17] [Chemistry 11-18] [Chemistry 11-19] [Chemistry 11-20] 【Chemistry 11-21】 [Chemistry 11-22] [Chemistry 11-23] [Chemistry 11-24] A compound selected from among them.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier or excipient.

29. A pharmaceutical product comprising a compound according to any one of claims 1 to 27 for inhibiting ALPK1 kinase activity in cells or tissues.

30. A pharmaceutical product comprising a compound according to any one of claims 1 to 27 for inhibiting or reducing inflammation in a target tissue.

31. A pharmaceutical product comprising a compound according to any one of claims 1 to 27, for treating a disease, disorder, or condition characterized by excessive or inadequate ALPK1-dependent pro-inflammatory signaling.

32. The pharmaceutical product according to claim 31, wherein the disease, disorder, or condition is selected from sepsis, cancer, sweat adenoma, spiral gland carcinoma, "retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine" ("ROSAH") syndrome, and "periodic fever, aphthous stomatitis, pharyngitis, and adenitis" ("PFAPA") syndrome.

33. The pharmaceutical product according to claim 31, wherein the cancer is selected from lung cancer, colon cancer, and oral squamous cell carcinoma.

34. Is the aforementioned disease or disorder ROSAH? Or, whether the disease or disorder is PFAPA, Or, whether the disease or disorder is a sweat adenoma or spiral gland carcinoma, Or, the disease or disorder is sepsis. The pharmaceutical product according to claim 31.

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