Alpha protein kinase 1 inhibitors for the treatment of kidney diseases and kidney-related diseases

Abstract

The present invention provides the use of compounds of formula I and related compositions for treating kidney diseases, disorders and conditions in a subject in need of treatment, where the subject in need of such treatment is a subject having one or more genetic mutations in ALPK1.

Description

Technical Field

[0001] The present invention relates to a method for suppressing ALPK1 kinase activity using a compound of formula I, and related compositions and methods for treatment in the treatment of kidney diseases, disorders, and conditions.

Background Art

[0002] Alpha kinases have little sequence similarity to conventional protein kinases. A total of six alpha kinase members have been identified. These include alpha protein kinase 1 (ALPK1), ALPK2, ALPK3, elongation factor-2 kinase (eEF2K), transient receptor potential cation channel M6, M7 (TRPM6, TRPM7). See Non-Patent Document 1 and Non-Patent Document 2.

[0003] ALPK1 is a cytoplasmic serine threonine protein kinase and plays an important role in activating the innate immune response to bacteria through TRAF interacting proteins with forkhead related domain (TIFA)-dependent inflammatory nuclear factor-κ-B (NFkB) signaling. See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5. TIFA is also activated in vascular endothelial cells by oxidative stress and inflammatory stress, leading to activation of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. See Non-Patent Document 6.

[0004] Inappropriate activation of ALPK1 signaling is involved in diseases and disorders associated with excessive or inappropriate inflammation. For example, ALPK1 is involved in sodium urate monohydrate (MSU)-induced inflammation and gout (Non-Patent Document 7). Increased ALPK1 expression is also associated with lymph node metastasis and tumor growth in oral squamous cell carcinoma (Non-Patent Document 8).

[0005] The rs2074380 and rs2074381 SNPs of ALPK1 are associated with chronic kidney disease in diabetic patients. The rs2074380 and rs2074381 SNPs cause amino acid changes at G870S and N916D. The changes at G870S and N916D have been found to play a role in chronic kidney disease (Non-Patent Document 9). The changes at G870S and N916D reduce the activity of ALPK1 during the progression of chronic kidney disease, and a hypothesis is proposed that an ALPK1 inhibitor can treat patients with chronic kidney disease.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

Means for Solving the Problems

[0007] The present disclosure provides a method for treating a disease, disorder, or condition characterized by excessive or inappropriate ALPK1-dependent inflammatory signaling. In particular, the present disclosure provides a method for treating kidney diseases, disorders, and conditions in a subject in need of such treatment by administering to the subject a compound of Formula I, and subembodiments of Formula I described herein, and pharmaceutically acceptable salts thereof. In embodiments, the related diseases, disorders, and conditions include chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio-renal syndrome, nephrotic syndrome, hepato-renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephrosis, nephritis, Alport syndrome, such as primary and congenital kidney diseases, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, nephrosis induced by toxic substances, contrast agent-induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (e.g., abnormal decrease in creatinine and / or water excretion, abnormal increase in blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, tubular dilatation, hyperlymphocytosis and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic urate nephropathy, and syndrome of inappropriate ADH secretion (SIADH).

[0008] In an embodiment, the compound of formula I is represented by formula I. [Chemical formula] Formula I (wherein A, p, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein).

[0009] In some embodiments, the compound of formula I is represented by formula IA. [Chemical formula] Formula IA (wherein p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 are as defined herein).

[0010] In some embodiments, the compound of formula I is represented by formula IA-1. [Chemical formula] Formula IA-1 (wherein p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 are as defined herein).

[0011] In some embodiments, the compound of formula I is represented by formula IB. [Chemical formula] Formula IB (wherein p, R 2 , R 3 , R 4 , R5 、R 13 、D, E, F, and G are as defined herein).

[0012] In some embodiments, the compound of Formula I is represented by Formula IB-1. [Chemical Formula] Formula IB-1 (wherein p, R 2 、R 3 、R 4 、R 5 、R 15 、R 16 、and R 17 are as defined herein).

[0013] In some embodiments, the compound of Formula I is represented by Formula IC. [Chemical Formula] Formula IC (wherein p, m, R 2 、R 3 、R 4 、R 5 、R 18 are as defined herein).

[0014] In embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, IA, IB, IC, or a sub - embodiment thereof as described herein for use in the treatment of kidney diseases, disorders, and conditions.

[0015] In embodiments, the present disclosure provides a method of inhibiting ALPK1 kinase activity in cells or tissues of a subject in need of treatment for the treatment of kidney diseases, disorders, and conditions. In embodiments, the disclosed method comprises administering to the subject a compound of Formula I, IA, IB, IC, or a sub - embodiment thereof as described herein.

[0016] In embodiments, the present disclosure provides a method for inhibiting or reducing inflammation in a target tissue of a subject in need of treatment of a kidney disease, disorder, and condition, the method comprising administering to the subject a compound of Formula I, IA, IB, IC, or a sub - embodiment thereof as described herein.

[0017] In embodiments, the present disclosure provides a method for treating kidney diseases, disorders, and conditions characterized by excessive or inappropriate ALPK1 - dependent inflammatory signaling in a subject in need of such treatment, the method comprising administering to the subject a compound of Formula I, IA, IB, IC, or a sub - embodiment thereof as described herein.

[0018] In embodiments, the compounds of Formula I, IA, IB, IC, or a sub - embodiment thereof are combined with a partial adenosine A1 receptor agonist and an MR antagonist for the treatment and prevention of kidney diseases, particularly acute and chronic renal insufficiency and acute and chronic kidney failure, and for further renal protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

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Mode for Carrying Out the Invention

[0020] The present disclosure provides compounds that are inhibitors of ALPK1, compositions containing the same, and methods of using them in the treatment of kidney diseases, disorders, and conditions. In embodiments, the kidney diseases, disorders, and conditions are chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio-renal syndrome, nephrotic syndrome, hepato-renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephrosis, nephritis, Alport syndrome, such as primary and congenital kidney diseases, inflammation of the kidney, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, nephrosis induced by toxic substances, contrast-induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (e.g., abnormal decrease in creatinine and / or water excretion, abnormal increase in blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, tubular dilation, hyperlymphocytosis and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic urate nephropathy, and syndrome of inappropriate ADH secretion (SIADH), including but not limited to these. The term "ALPK1" is used herein interchangeably to refer to isoform 1 (Q96QP1-1) or alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN).

[0021] As used herein, the term "alkyl" refers to a straight 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.

[0022] As used herein, "alkenyl" refers to a straight 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.

[0023] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkenyl can contain any number of carbons such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. An 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.

[0024] As used herein, the term "alkylene" refers to a straight-chain or branched saturated aliphatic radical having the indicated number of carbon atoms and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same or different atoms of the alkylene group. For example, a straight-chain alkylene can be a divalent radical of -(CH2)n- where n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. The alkylene group can be substituted or unsubstituted. In some embodiments, the alkylene group is substituted with 1-2 substituents. Non-limiting examples of suitable substituents include halogen and hydroxyl.

[0025] As used herein, the term "alkoxy" or "alkoxyl" refers to an alkyl group having an oxygen atom connecting to the point of attachment: alkyl-O-. With respect to the alkyl group, the alkoxyl group can have any suitable number of carbon atoms such as C1-6. Examples of alkoxyl groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy group can be substituted or unsubstituted.

[0026] As used herein, the term "alkenyloxy" or "alkenyloxyl" refers to an alkenyl group as defined above having an oxygen atom connecting the alkenyl group at the point of attachment: alkenyl-O-. The alkenyloxyl group can have any suitable number of carbon atoms, such as C1-6. The alkenyloxyl group can be further substituted with various substituents described herein. The alkenyloxyl group can be substituted or unsubstituted.

[0027] "Aminoalkyl" means a straight-chain 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 each independently hydrogen, alkyl, haloalkyl, or hydroxyalkyl as defined herein, such as aminomethyl, aminoethyl, methylaminomethyl, etc.).

[0028] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

[0029] As used herein, the term "haloalkyl" refers to an alkyl as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. For an alkyl group, the haloalkyl group can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc.

[0030] As used herein, the term "haloalkoxyl" or "haloalkoxy" refers to an alkoxyl group in which some or all of the hydrogen atoms are replaced by halogen atoms. For an alkyl group, the haloalkoxy group can have any suitable number of carbon atoms, such as C1-6. The alkoxy group can be substituted with 1, 2, 3, or more halogens.

[0031] 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.

[0032] As used herein, the term "hydroxyalkyl" refers to an alkyl radical in which at least one of the hydrogen atoms of the alkyl radical is replaced by OH. Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 4-hydroxy-butyl.

[0033] As used herein, the term "oxo" refers to an oxygen atom bonded to the point of attachment by a double bond (=O).

[0034] As used herein, the term "aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. An aryl group can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and can contain 6 - 10, 6 - 12, or 6 - 14 ring members. An aryl group can be monocyclic, fused to form a bicyclic or tricyclic group, or joined by bonds to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl having a methylene linking group. Some aryl groups have 6 - 12 ring members such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 - 10 ring members, for example, phenyl or naphthyl. Some other aryl groups have 6 ring members such as phenyl. An aryl group can be substituted or unsubstituted.

[0035] As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic aromatic ring assembly containing 5 to 12 ring atoms, wherein 1 to 5 ring atoms are heteroatoms such as N, O or S. Additional heteroatoms including, but not limited to, B, Al, Si and P may also be useful. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. The heteroaryl group can contain any number of ring atoms, for example, 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, 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 etc., can be included in the heteroaryl group. The heteroaryl group can have 5 to 9 ring members and 1 to 4 heteroatoms, or 5 to 9 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), purine etc. The heteroaryl group can also condense with an aromatic ring system such as a phenyl ring to form members including, but not limited to, benzopyrrole such as indole and isoindole, benzopyridine such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine etc. The heteroaryl group can be substituted or unsubstituted.

[0036] As used herein, "cycloalkyl" refers to a saturated cyclic assembly containing 3 to 10 ring atoms, or the indicated number of atoms. Cycloalkyl can contain any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8. The cycloalkyl ring can be saturated or unsaturated when an unsaturated cycloalkyl ring can have one or two double bonds. Examples of cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl group can be substituted or unsubstituted.

[0037] As used herein, the terms "heterocyclyl" or "heterocyclic" refer to a heterocyclic group that is saturated or partially saturated, is a monocyclic or polycyclic ring, has 3 to 16 ring atoms, most preferably 5 to 10 ring atoms, most preferably 1 or 4 ring atoms, where one or more, preferably 1 to 4, particularly 1 or 2 ring atoms are heteroatoms selected from oxygen, nitrogen and sulfur (thus, the remaining ring atoms are carbon). The term heterocyclyl excludes heteroaryl. The heterocyclic group can be bonded to the rest of the molecule via a heteroatom or a carbon atom selected from oxygen, nitrogen and sulfur. Heterocyclyl can include fused or bridged rings as well as spiro rings. Examples of heterocyclyl include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxepinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl and diazepanyl.

[0038] As used herein, "spiroheterocyclyl" refers to a specific bicyclic heterocyclic group in which two ring systems are joined via a single carbon atom. For example, the term "spiroheterocyclyl" can refer to 6- to 10-membered spiroheterocyclyl. 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.

[0039] As used herein, "bridged heterocyclyl" refers to a C3-6 cycloalkyl ring or 3- to 6-membered heterocyclyl ring as defined above, wherein two non-adjacent ring vertices (the "bridgehead atoms") of the cycloalkyl ring or heterocyclyl ring are linked to form an additional cyclic moiety (the "bridge"). The bridge contains 1 to 4 ring vertices that do not include the bridgehead atoms. Examples include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 3,9-diazabicyclo[3.3.1]nonane, 2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]hept-5-ene, 3-oxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, and 2-oxa-5-azabicyclo[2.2.1]heptane.

[0040] The term "bicyclic heterocyclyl" refers to a heterocyclic group as defined above in which two ring systems are connected via two adjacent ring vertices (e.g., a fused ring system). A typical "bicyclic heterocyclyl" ring contains 6 to 11 ring members having 1 to 4 heteroatom ring vertices selected from N, O, and S (thus the remaining ring atoms are carbon). Examples include, but are not limited to, benzodioxolyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydroisobenzofuranyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, naphthyridinyl, pyrazolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl.

[0041] As used herein, "saturated or unsaturated" refers to a cyclic system in which two atoms in the group can be bonded to each other by a single bond, a double bond, or a triple bond. A saturated moiety has only single bonds, and a moiety having multiple bonds (e.g., at least one double bond or at least one triple bond) is called unsaturated.

[0042] Optionally, any definition herein can be used in combination with any other definition for explaining a complex structural group. By convention, elements following any such definition are those that are attached to the parent moiety. For example, the complex group cycloalkoxyl means that a cycloalkyl group is attached to the parent molecule via an oxyl group.

[0043] The term "pharmaceutically acceptable salt" means salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, the base addition salts can be obtained by contacting the neutral form of such compounds 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, iron, lithium, magnesium, manganese, manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid or phosphorous acid, and 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.Salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid are also included (see, for example, Berge, S.M., 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 compound to be converted into either a base addition salt or an acid addition salt.

[0044] The neutral form of the compound can be regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.

[0045] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds, and racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed 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 during ms.

[0046] As used herein, the term "substantially free of" refers to an amount of 10% or less of another isomer, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of another form. In some embodiments, the isomers are stereoisomers.

[0047] Detailed Description of Embodiments The present disclosure provides compounds that are inhibitors of ALPK1, compositions containing the same, and methods of using them in the treatment of kidney diseases, disorders, and conditions. In embodiments, the kidney diseases, disorders, and conditions include chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio-renal syndrome, nephrotic syndrome, hepato-renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephrosis, nephritis, Alport syndrome, such as primary and congenital kidney diseases, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, nephrosis induced by toxic substances, contrast agent-induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (e.g., abnormal decrease in creatinine and / or water excretion, abnormal increase in blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubule dilation, hyperlymphocytosis and / or the need for dialysis), uremia, anemia, electrolyte disorders (including, but not limited to, hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic uric acid nephropathy, and syndrome of inappropriate ADH secretion (SIADH)). The term "ALPK1" is used herein interchangeably to refer to isoform 1 (Q96QP1-1) or alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN).

[0048] The compound is represented by Formula I. [Chemical formula] Formula I Wherein A, p, R 1 , R 2 , R 3 , R 4 and R 5is as defined herein, and A is selected from a bond, azetidinyl, -O-, -N(R 6 )-, -CH2-N(R 6 )-, -CHR 9 -N(R 6 )-, where 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 the optionally substituted R 6 moiety contains 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 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 the optionally substituted R 9 moiety is 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, -CHR 7f R 8f , -OR 7f , -OC(O)(R 7f ), -C(O)(R 7f ), -C(O)N(R 7f R8f ), -C(O)O(R 7f ), -S(O)2(R 7f ), -S(O)ON(R 7f R 8f ), and -N(R 7f R 8f ), and contains 0 to 2 substituents independently selected from each R 7f and R 8f is 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, R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 hydroxyalkyl, 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 5- to 10-membered heteroaryl containing 1 to 4 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S; and optionally substituted saturated or unsaturated 6- to 11-membered bicyclic heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, optionally substituted R 1The moiety contains 0 to 4 substituents 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, 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 ), -NR 7a (CO)R 8a , -C(O)O(R 7a ), S(O)2R 7a , -S(O)2N(R 7a R 8a ), -N(R 7a R 8a ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, monocyclic or bicyclic aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, and 6-11 membered bicyclic heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S Each X 1 is independently C1-6 alkylene, Each R 7a and R 8ais independently 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, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, wherein the aryl and the 3-7 membered heterocyclyl 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, and C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclyl, monocyclic or bicyclic aryl, 5-10 membered heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclyl, saturated or unsaturated 7-11 membered spiroheterocyclyl, and 6-11 membered bicyclic heterocyclyl 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 heterocyclyl 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 R8b ) and -N(R 7b R 8b ) are each independently selected from 0 to 3 substituents selected from the group consisting of each R 7b and R 8b 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, or R 1 and R 6 are joined to form a 3- to 6-membered heterocycloalkyl substituted with 0 to 3 substituents 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 is H, deuterium, halo, C1-C6 alkyl, C1-C6 deuterated alkyl, and C1-C6 haloalkyl, R 2 and R 3 are each independently selected from H, OH, C1-C6 alkyl, C2-C6 alkynyl, where C1-C6 alkyl and C2-C6 alkynyl are each independently substituted with 0 to 3 substituents selected from 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 ), each R 7c and R 8cis independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, 1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl and saturated or unsaturated C3-C6 cycloalkoxyl, provided that R 2 and R 3 are not both H, or R 2 and R 3 are joined to form a C3-C6 cycloalkyl ring or 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices independently selected from N, O and S, and 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 ) and may be substituted with 1-2 substituents independently selected from, each R 7d and R 8d is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, 1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl and saturated or unsaturated C3-C6 cycloalkoxyl, each R 4 is 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, CHR 7e R 8e , OR 7e , OC(O)(R 7e ), C(O)(R 7e)、C(O)N(R 7e R 8e )、C(O)O(R 7e )、S(O)2N(R 7e R 8e ) and N(R 7e R 8e ) is independently selected from, where each R 7e and R 8e 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, saturated or unsaturated C3-C6 cycloalkoxyl, the subscript p is 0, 1, 2 or 3.

[0049] In some embodiments, A in formula I is a bond.

[0050] In some embodiments, A of formula I is azetidinyl.

[0051] In some embodiments, A in formula I is -O-.

[0052] In some embodiments, A in formula I is -N(R 6 )-.

[0053] In some embodiments, A in formula I is -CH2-N(R 6 )-.

[0054] In some embodiments, A in formula I is -CHR 9 -N(R 6 )-.

[0055] In some embodiments, the compound of formula I is represented by a compound of formula IA, formula IA-1, formula IA-2 and / or its stereoisomers, stable isotopes or pharmaceutically acceptable salts. [Chemical formula] Formula IA

Chem.

Chem.

[0056] In some embodiments, R 6 in Formula I, IA, IA-1 or IA-2 is H, C1-C6 alkyl or C1-C6 hydroxyalkyl.

[0057] In some embodiments, R 9 in Formula I and 1A is CH3 or CH2OH.

[0058] In some embodiments, R 9 in Formula I and 1A is saturated C3-C6 cycloalkyl.

[0059] In some embodiments, R 1 in Formula I, IA, IA-1 or IA-2 is selected from H and optionally substituted C1-C6 alkyl, wherein the optionally substituted C1-C6 alkyl is 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(RR 7a R 8a ) and -N(R 7a R 8a ) and contains 0 to 4 substituents independently selected from each R 7a and R 8a is 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.

[0060] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 is optionally substituted saturated or unsaturated C3-C6 cycloalkyl, wherein optionally substituted C3-C6 cycloalkyl contains 0 to 4 substituents independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, and C1-C6 haloalkoxyl.

[0061] In some embodiments, R in formula I, IA, IA-1 or IA-2 1 is 6 combined with R

[0062] to form 3- to 6-membered heterocycloalkyl substituted with 0 to 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. 1 In some embodiments, R in formula I, IA, IA-1 or IA-2 7a is -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, -OC(O)(R 7a R 8a) and -N(R 7a R 8a ) is C1-C6 alkyl substituted with 0 to 4 substituents independently selected from, where each R 7a and R 8a 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.

[0063] In some embodiments, R 1 in formula I, IA, IA-1 or IA-2 is C1-C6 alkyl substituted with 0 to 2 substituents independently selected from -OH, C1-C6 hydroxyalkyl and -S(O)2N(R 7a R 8a ), where each R 7a and R 8a is independently selected from H and C1-C6 alkyl.

[0064] In some embodiments, R 1 in formula I, IA, IA-1 or IA-2 is optionally substituted C1-C6 hydroxyalkyl.

[0065] In some embodiments, R 1 in formula I, IA, IA-1 or IA-2 is 5- to 10-membered heteroaryl containing 1 to 4 heteroatom ring vertices selected from N, O and S, and the 5- to 10-membered bicyclic heteroaryl is halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, 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 ), and is substituted with 0 to 3 moieties selected from each R 7b and R 8b 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.

[0066] In some embodiments, R 1 in formula I, IA, IA-1 or IA-2 is pyridil substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, 3-7 membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, wherein the 3-7 membered heterocyclyl is substituted with 0 to 3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 haloalkyl.

[0067] In some embodiments, R 1 in formula I, IA, IA-1 or IA-2 is a saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, wherein the 7-8 membered bridged heterocyclyl is 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, -CHR7b 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 ) 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, where each R 7b and R 8b 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.

[0068] In some embodiments, R 1 in Formula I, IA, IA-1 or IA-2 is a saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, where the 7- to 11-membered spiroheterocyclyl is 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 ) 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, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR each R7b and R 8b each independently is 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.

[0069] In some embodiments, R in Formula I, IA, IA-1, or IA-2 1 is aryl substituted with 0-3 substituents selected from 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from halo, N, O, and S; 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; and saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, the 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl, and 7-11 membered spiroheterocyclyl are substituted with 0-3 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, 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 ), and wherein each R 7b and R 8bis 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.

[0070] In some embodiments, R in Formula I, IA, IA-1 or IA-2 1 is halo-OH, -COOH, -NH 2 2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, and aryl substituted with 0-3 moieties selected from 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, The 3-7 membered heterocyclyl is substituted with 0-3 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, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR 8b 8, -OR7b, -OC(O)(R7b), -C(O)(R7b), -C(O)N(R7bR 8b )8, -C(O)O(R7b), -S(O)2N(R7bR 8b )8, and -N(R7bR 8b )8, where each R7b and R 8b 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.

[0071] In some embodiments, R in Formula I, IA, IA-1 or IA-2 1is aryl substituted with 0 to 3 moieties selected from 3- to 7-membered heterocyclyl containing a halo and 1 to 2 heteroatom ring vertices selected from N, O, and S, The 3- to 7-membered heterocyclyl is further substituted with 0 to 3 moieties selected from -OH, -COOH, -NH2, =O, -CN and -C1-C6 alkyl.

[0072] In some embodiments, the compound of formula I is represented by a compound of formula IB and / or its stereoisomers, stable isotopes or pharmaceutically acceptable salts.

Chemical formula

[0073] In some embodiments, D, E, F, and G in formula IB are each CR10, CR14, CR12, and CR11, respectively.

[0074] In some embodiments, F and G in formula IB are each CR14 and CR11, respectively, E is N or CR14, and D is N or CR10.

[0075] In some embodiments, R10 and R11 in formula IB are each H, and R12 and R14 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 7b R 8b , -OR7b 、 -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 ) are selected from, where each R 7b and R 8b 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, and R13 is a 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, a saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, a saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and the 3- to 7-membered heterocyclyl, 7- to 8-membered bridged heterocyclyl, and 7- to 11-membered spiroheterocyclyl 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, saturated or unsaturated C3-C6 cycloalkoxyl.

[0076] In some embodiments, R12 and R14 in formula IB are H, and R10 and R11 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 7b R 8b 、 -OR7b ,-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 ), selected from, where each R 7b and R 8b 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, and R13 is a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, a saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, a saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, and the 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl, and 7-11 membered spiroheterocyclyl may be 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.

[0077] In some embodiments, R10, R11, R12, and R14 in formula IB are all H, and R13 is a 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from saturated or unsaturated C3-C6 cycloalkyl, N, O, and S, a saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, or a saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, and the 3- to 7-membered heterocyclyl, 7- to 8-membered bridged heterocyclyl, and 7- to 11-membered spiroheterocyclyl 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.

[0078] In some embodiments, R10, R11, R12, and R14 in formula IB are each H, and R13 is a 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S and 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.

[0079] In some embodiments, R10, R11, R12, and R14 in formula IB are each H, and R13 is an optionally substituted saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S and substituted with 0 to 2 substituents selected from -OH, -COOH, -NH2, =O, -CN, and -C1-C6 alkyl.

[0080] In some embodiments, the compound of formula IB is represented by a compound of formula IB-1 and / or IB-2 and / or a stereoisomer, stable isotope or pharmaceutically acceptable salt thereof. [Chemical formula] Formula IB-1 [Chemical formula] Formula IB-2 (wherein p, R2, R3, R4 and R5 are as defined above, R16 and R17 are each independently selected from halo and C1-C6 alkyl, R15 is -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 ), where each R 7b and R 8b are each 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).

[0081] In some embodiments, R15 in formula IB-1 or IB-2 is selected from 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, -CHR7bR8b, each R 7b and R 8b 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).

[0082] In some embodiments, R15 in formula IB-1 or IB-2 is C1-C6 alkyl.

[0083] In some embodiments, both R2 and R3 in formula IB-1 or IB-2 are methyl groups.

[0084] In some embodiments, R2 and R3 in formula IB-1 or IB-2 are each independently a methyl or ethynyl group.

[0085] In some embodiments, IB-1 is represented by formula IB-1-a or formula IB-2-a,

Chemical formula

Chemical formula

[0086] In some embodiments, IB-1 is represented by formula IB-1-b or formula IB-2-b,

Chemical formula

Chem.

[0087] In some embodiments, IB-1 is represented by formula (IB-1-c) or formula IB-2-c.

Chem.

Chem.

[0088] In some embodiments, R5 in formula IB-1 or IB-2 is H or methyl.

[0089] The present invention discloses a novel heterocyclic compound as an inhibitor of ALPK1. The compound is represented by formula IC.

Chem.

[0090] In some embodiments, m in formula IC is 1.

[0091] In some embodiments, R 18 in formula IC is H.

[0092] In some embodiments, for each of the formulas described herein, R 2 and R 3 are both C1-C6 alkyl groups.

[0093] In some embodiments, in each of the formulas described herein, R 2 is methyl and R 3 is CH2OMe.

[0094] In some embodiments, R 2 and R 3 are each methyl in each of the formulas described herein.

[0095] In some embodiments, R 2 is methyl and R 3 is ethynyl in each of the formulas described herein.

[0096] In some embodiments, R 2 is methyl and R 3 is C3-C6 cycloalkyl.

[0097] In some embodiments, R 2 is methyl and R 3 is phenyl.

[0098] In some embodiments, in each of the formulas described herein, the subscript p is 1 and R4 is attached to the phenyl ring as shown below:

Chemical formula

[0099] In some embodiments, in each of the formulas described herein, the subscript p is 1 and R 4 is halo attached to the phenyl ring as shown below:

Chemical formula

[0100] In some embodiments, in each of the formulas described herein, the subscript p is 1 and R 4 is chloro attached to the phenyl ring as shown below:

Chemical formula

[0101] In some embodiments, in each of the formulas described herein, the subscript p is 1 and R 4 is methoxy attached to the phenyl ring as shown below:

Chemical formula

[0102] In some embodiments, R in each of the formulas described herein5 is H.

[0103] In some embodiments, R in each of the formulas described herein 5 is deuterium.

[0104] In some embodiments, R in each of the formulas described herein 5 is C1-C6 deuterated alkyl. In some embodiments, R5 in each of the formulas described herein is selected from the group consisting of -CH2D, -CHD2, and -CD3.

[0105] In some embodiments, in each of the formulas described herein, R 2 and R 3 are attached to a chiral carbon atom. 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 an S-isomer carbon atom, 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 an R-isomer carbon atom, 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 3 is methyl and R 2 is ethynyl. In some embodiments, R 3 is methyl and R 2 is C3-C6 cycloalkyl. In some embodiments, R3 is methyl and R 2 is phenyl.

[0106] In some embodiments, the compound of Formula I is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0107] In some embodiments, the compound of formula I is [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] is selected from.

[0108] In some embodiments, the compound is selected from the examples provided herein.

[0109] Details of the preparation and analysis of the compounds of Formula I and exemplary compounds NMR: Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz) spectrometer using or not using tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported in ppm downfield from TMS, and the spectral splitting patterns are called singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unresolved or overlapping signals (m), broad signals (br). Deuterated solvents are indicated in parentheses and have chemical shifts of 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.

[0110] LC-MS: Shimadzu 20A-2010MS Detection: SPD-M20A Column: MERCK, RP-18e 25~2 mm; Wavelength: UV 220 nm, 254 nm; Column temperature: 50 °C; MS ionization: ESI Mobile phase: 1.5 mL / 4 L TFA in water (Solvent A) and 0.75 mL / 4 L TFA in acetonitrile (Solvent B), elution gradient 5% - 95% (Solvent B) used over 0.7 minutes, held at 95% for 0.4 minutes at a flow rate of 1.5 mL / min.

[0111] Flash column chromatography system System: CombiFlash Rf+ Column: Santai Technologies, Inc., SEPAFLASH (registered trademark) Samples were typically adsorbed onto isolute. HPLC separation conditions System: TRILUTION LC 4.0 Detection: Gilson 159 UV-VIS Condition 1: Column: Phenomenex Gemini-NX 80*40 mm×3 um Eluent A: water (0.05% NH3H2O + 10 mM NH4HCO3) Eluent B: CH3CN Start B: 20 - 45%, End B: 80 - 20%, Gradient time (min): 8 Condition 2: Column: Xtimate C 18 10μ250 mm*50 mm; Eluent A: water (0.04% NH3H2O + 10 mM NH4HCO3) Eluent B: CH3CN 50% - 80%; Gradient time (min): 8 SFC chiral separation conditions Mobile phase: [0.1% NH3H2O ETOH]; B%: 30% - 30%, 35% - 35% or 45 - 45% Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm); Mobile phase [0.1% NH3H2O ETOH]; B%: 30% - 30%, 40% - 40%; Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); Mobile phase [0.1% NH3H2O ETOH]; B%: 35% - 35%; Column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); Mobile phase [0.1% NH3H2O ETOH]; B%: 35% - 35%

[0112] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used for synthesizing the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art.

[0113] The following is an abbreviation table related to chemistry.

Table 1 - 1 - 1

[0114]

Table 1 - 1 - 2

[0115]

Table 1 - 1 - 3

[0116] Reaction Scheme 1:

Chem.

[0117] Properly substituted compound M1 (wherein R is a suitable 1 - 3 groups such as halo or C1 - C6 alkyl, etc., and R1 and R2 are suitable groups independently selected from H, C1 - C6 alkyl, and C2 - C6 alkynyl, which are converted to acid chlorides using SOCl2 or (COCl)2 under heating or at room temperature). The Weinreb amide was formed by the reaction of N,O - dimethylhydroxylamine hydrochloride with the acid chloride at 0 °C. The Grignard reagent in THF was added dropwise to the Weinreb amide at 0 °C to obtain a ketone, which was converted to M5 by bromination. Intermediate M6 was obtained by cyclization with thiourea under basic conditions.

[0118] Example 1: Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine (Intermediate 1) [Chemical Structure]

[0119] Step 1. Preparation of compound 2-(4-bromophenyl)-2-methylpropanoyl chloride [Chemical Structure]

[0120] Compound 2-(4-bromophenyl)-2-methylpropanoic acid (100 g, 411 mmol, 1.0 equivalent) in SOCl2 (175 mL, 6 equivalents) was heated to reflux for 2 hours. Then, the solution was cooled to room temperature and the mixture was concentrated under reduced pressure to obtain the crude acid chloride (yellow oil), which was used in the next step without further purification.

[0121] Step 2. Preparation of compound 2-(4-bromophenyl)-N-methoxy-N,2-dimethylpropanamide [Chemical Structure]

[0122] 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 obtained from the above Step 1 in DCM (200 mL) and TEA (114 mL, 2 equivalents) was added dropwise to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with H2O (200 mL). The mixture was extracted with DCM (200 mL × 3), and the combined organic layers were washed with water (200 mL × 3), brine (200 mL × 3), dried over Na2SO4, filtered, and concentrated to obtain a residue. The desired compound (108 g, pure) was obtained as a pale yellow oil, which was used in the next step without further purification.

[0123] 1H 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).

[0124] Step 3. Preparation of 3-(4-bromophenyl)-3-methylbutan-2-one

Chemical Structure

[0125] A solution of the compound obtained in Step 2 above (54 g, 189 mmol, 1 equiv) in dry THF (500 mL) was cooled to 0 °C. CH3MgBr (3 M in THF, 253 mL, 757.8 mmol, 4 equiv) was added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with EA (300 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over Na2SO4, filtered, and concentrated to give a residue. The desired compound (90.4 g, pure) was obtained as a pale yellow oil and used in the next step without further purification.

[0126] 1H 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).

[0127] Step 4. Preparation of 1-bromo-3-(4-bromophenyl)-3-methylbutan-2-one

Chemical Structure

[0128] To a solution of the compound obtained from the above step 3 (46 g, 191 mmol, 1 eq) in DCM / EtOH (250 mL / 250 mL) was added dropwise Br₂ (14.7 mL, 286 mmol, 1.5 eq). The mixture was stirred at room temperature for 3.5 h. The reaction mixture was quenched with saturated Na₂SO₃ (150 mL). The mixture was extracted with DCM (300 mL × 2), and the combined organic layers were washed with brine (300 mL × 2), dried over Na₂SO₄, filtered, and concentrated to give a residue. The desired compound (118.8 g, crude) was obtained as a white solid and used in the next step without further purification.

[0129] 1H 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).

[0130] Step 5. Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine

Chemical Structure

[0131] To a solution of the compound obtained from the above step 4 (50 g, 156 mmol, 1 eq) in MeOH (500 mL) was added dropwise thiourea (14.3 g, 188 mmol, 1.2 eq). The mixture was stirred at 50 °C for 1.5 h. The mixture was concentrated under reduced pressure. The mixture was extracted with EA (300 mL × 2), and the combined organic layers were washed with brine (300 mL × 2), dried over Na₂SO₄, filtered, and concentrated to give a residue, which was purified by silica gel chromatography with PE / EA = 10:1 to give the pure desired compound (34 g, white solid).

[0132] 1H 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.

[0133] Example 2: 4-(1-(4-Bromophenyl)cyclopentyl)thiazol-2-amine (Intermediate 2)

Chemical formula

[0134] Step 1. Preparation of ethyl 1-(4-bromophenyl)cyclopentane-1-carboxylate

Chemical formula

[0135] 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 dropwise at 0 °C, and then the reaction mixture was stirred at room temperature for 30 minutes. 1,4-Dibromobutane (8.8 g, 41.3 mmol) was slowly added dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 to 5:1). The title compound (7.8 g, yield: 63.8%) was obtained. MS (ESI) m / z (M+H)+ = 297.0

[0136] Step 2. Preparation of 1-(4-bromophenyl)cyclopentane-1-carboxylic acid

Chemical formula

[0137] A solution of ethyl 1-(4-bromophenyl)cyclopentane-1-carboxylate (7.8 g, 26.3 mmol) in THF (25 mL) was added dropwise with NaOH (3.2 g, 79 mmol) and H2O (5 mL), and the reaction mixture was stirred at 40 °C overnight. After cooling, the pH value 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 = 1:0~1:2). The desired compound (5.6 g, yield: 79.4%) was obtained. MS(ESI) m / z (M+H)+ = 269.0 The synthesis of the following steps was the same as that described for Intermediate 1.

[0138] Example 3: 4-(2-(5-Bromopyridin-2-yl)propan-2-yl)thiazol-2-amine (Intermediate 3)

Chemical formula

[0139] Step 1. Preparation of methyl 2-(5-bromopyridin-2-yl)-2-methylpropane

Chemical formula

[0140] To a solution of 3-(5-bromopyridin-2-yl)-2-oxopropanoic acid (2 g, 9.26 mmol, 1.0 equiv) in DMF (20 mL) was added dropwise NaH (1.3 g, 32.4 mmol, 3.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 20 minutes. CH3I (2 mL, 3.5 equiv) was added dropwise to the mixture at 0 °C, and the mixture was stirred for 6 hours. The reaction mixture was quenched with water (50 mL), extracted with EA (25 mL × 2), washed with brine (10 mL × 2), then dried over Na2SO4, filtered, and evaporated to dryness. The obtained residue was purified by column chromatography on silica gel to obtain the desired compound (1.95 g, yield: 93%).

[0141] Process 2. Preparation of 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid

Chem.

[0142] A mixture of 2-(5-bromopyridin-2-yl)-2-methylpropyl propanoate (1.95 g, 7.56 mmol, 1.0 eq) and KOH (1.9 mL, 2 M in H2O, 3.0 eq) was heated to 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 afford the desired compound (1.82 g, yield: 98%).

[0143] The following several steps are the same as those described for Intermediate 1.

[0144] The following examples were synthesized in the same manner as the procedure for Intermediate 1 using appropriate starting materials and thiourea:

[0145]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

[0146] Reaction Scheme 2:

Chem.

[0147] Compound M7, which is appropriately substituted with 1 to 3 suitable groups such as halo or C1-C6 alkyl, etc., was acetylated with a lithium base under conditions below -60°C. M9 was obtained by alkyl substitution such as the C1-C6 alkyl group of M8 under basic conditions at 50 - 70°C. After bromination, M10 was obtained. By cyclization of M10 with thiourea under basic conditions, thiazole intermediate M11 was obtained. A suitable protecting group was introduced to protect the amine. The reduction of the ester to alcohol was carried out at 0°C with LiBH4 to obtain M13, which was oxidized to the corresponding aldehyde using Dess-Martin periodinane (DMP) reagent. Alkynylthiazoleamine intermediate M15 was obtained by a Seyferth-Gilbert homologation reaction by treating M14 with 1-diazo-1-dimethoxyphosphoryl-propane-2-one under basic conditions at RT. The final deprotection gave intermediate M16.

[0148] Example 4: Preparation of 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-amine (Intermediate 27)

Chemical formula

[0149] Step 1. Preparation of compound methyl 2-(4-chlorophenyl)-3-oxobutanoate

Chemical formula

[0150] To a solution of 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 dropwise 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 × 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 to 5:1). The desired compound (7.47 g, yield: 60.9%) was obtained as a pale yellow oil.

[0151] MS(ESI) m / z(M + H)+ = 27.1.

[0152] Step 2. Preparation of methyl 2-(4-chlorophenyl)-2-methyl-3-oxobutanoate

Chemical formula

[0153] To a solution of the compound obtained from the above 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 a residue. The desired compound (7.79 g, yield: 98.2%) was obtained as a pale yellow oil and used in the next step without further purification.

[0154] MS(ESI) m / z(M + H)+ = 241.1.

[0155] Step 3. Preparation of methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutanoate

Chemical formula

[0156] To a solution of the compound (7.79 g, 32.4 mmol) obtained from the above step 2 in CHCl3 (80 mL) was added dropwise Br2 (4.66 g, 29.1 mmol, 1.50 mL). The mixture was stirred at 75 °C for 16 h. The reaction mixture was adjusted to pH = 6 - 7 with NaOH (1 N), then washed with H2O (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The desired compound (9.91 g, yield: 95.8%) was obtained as a light brown oil and used in the next step without further purification.

[0157] MS (ESI) m / z (M + H)+ = 319.0.

[0158] Step 4. Preparation of methyl 2-(2-aminothiazol-4-yl)-2-(4-chlorophenyl)propanoate

Chemical formula

[0159] To a solution of the compound (9.91 g, 31.0 mmol) and thiourea (2.83 g, 37.2 mmol) obtained from the above step 3 in MeOH (60 mL) was added dropwise NaHCO3 (3.13 g, 37.2 mmol, 1.45 mL). The mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated to give a 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.

[0160] MS (ESI) m / z (M + H)+ = 297.0.

[0161] Step 5. Preparation of methyl 2-(2-acetamidothiazol-4-yl)-2-(4-chlorophenyl)propanoate

Chemical formula

[0162] To a solution of the compound (3 g, 10.1 mmol) and TEA (1.53 g, 15.2 mmol, 2.11 mL) obtained from the above step 4 in DCM (60 mL), acetyl chloride (794 mg, 10.11 mmol, 721 μL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1.5 h. A second batch of acetyl chloride (794 mg, 10.1 mmol, 721 μL) and TEA (1.53 g, 15.2 mmol, 2.11 mL) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 1 h. A third batch of acetyl chloride (793.5 mg, 10.11 mmol, 721.38 μL) and TEA (1.53 g, 15.16 mmol, 2.11 mL) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with H2O (3 mL), then anhydrous Na2SO4 was added dropwise, filtered, and concentrated to give a 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.

[0163] MS (ESI) m / z (M+H)+ = 339.1.

[0164] Preparation of the compound in step 6: N-(4-(2-(4-chlorophenyl)-1-hydroxypropan-2-yl)thiazol-2-yl)acetamide

Chemical formula

[0165] To a solution of the compound obtained from the above step 5 (1.4 g, 4.13 mmol) in THF (50 mL) was added portionwise LiBH4 (450 mg, 20.66 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl (40 mL), then extracted with EA (30 mL × 3 times). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a 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.

[0166] MS(ESI) m / z (M+H)+ = 311.1.

[0167] Step 7. Preparation of compound N-(4-(2-(4-chlorophenyl)-1-oxopropan-2-yl)thiazol-2-yl)acetamide

Chemical formula

[0168] To a solution of the compound obtained from the above step 6 (970 mg, 3.12 mmol) in DCM (30 mL) was added portionwise DMP (1.72 g, 4.06 mmol) in DCM (20 mL). The mixture was stirred at 25 °C for 2 h. DMP (1.72 g, 4.06 mmol) in DCM (20 mL) was added dropwise, and the mixture was stirred at 25 °C for 1 h. DMP (1.06 g, 2.50 mmol) in DCM (20 mL) was added dropwise, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with DCM (40 mL), quenched with saturated Na2S2O3 / saturated NaHCO3 (1 / 1, 200 mL), the organic layer was separated, the aqueous layer was extracted with DCM (60 mL), and the combined organic layers were washed with saturated Na2S2O3 / saturated NaHCO3 (1 / 1, 100 mL), water (200 mL × 2), brine (200 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The desired compound (1.03 g, crude) was obtained as a yellow solid and used in the next step without further purification.

[0169] Step 8. Preparation of Compound N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)acetamide

Chem.

[0170] 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) was added dropwise K2CO3 (922 mg, 6.67 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~1:1). 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.

[0171] 1H NMR (400 MHz, CDCl3) δ 9.98 (brs, 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.

[0172] Step 9. Preparation of Compound 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-amine

Chem.

[0173] To a solution of the compound obtained from the above step 8 (180 mg, 591 μmol) in MeOH (10 mL) was added methanesulfonic acid (284 mg, 2.95 mmol, 210 μL) dropwise. The mixture was stirred at 80 °C for 16 h. The reaction mixture was adjusted to pH = 9 - 10 with solid NaHCO3 and concentrated to give a 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.

[0174] 1H NMR (400 MHz, 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)+ = 63.0.

[0175] The following examples were synthesized in the same procedure as in Example 4 (Intermediate 27) using appropriate starting materials and thiourea:

[0176]

Table 3

[0177] Example 5: 4-(2-(4-Bromophenyl)-1-methoxypropan-2-yl)thiazol-2-amine (Intermediate 33)

Chemical formula

[0178] Step 1. Preparation of compound N-(4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazol-2-yl)acetamide

Chemical formula

[0179] A solution of N-(4-(2-(4-bromophenyl)-1-hydroxypropan-2-yl)thiazol-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) was added dropwise with trimethyloxonium; tetrafluoroborate (416 mg, 2.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with DCM (10 mL), quenched with NH3.H2O (10 mL), and washed with H2O (30 mL), HCl (1 N, 20 mL), saturated NaHCO3 (20 mL), and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~1:1). The desired compound (41 mg, yield: 19.72%) was obtained as a white solid.

[0180] 1H NMR (400 MHz, CDCl3) δ 8.69 (brs, 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.

[0181] Step 2. Preparation of compound 4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazol-2-amine

Chemical Structure

[0182] The synthesis is the same as described in Intermediate 44. The desired compound (20 mg, yield: 90.3%) was obtained as a white solid.

[0183] 1H NMR (400 MHz, CDCl3) δ 7.42 - 7.36 (m, 2H), 7.18 - 7.13 (m, 2H), 6.22 (s, 1H), 4.83 (brs, 2H), 3.84 - 3.73 (m, 2H), 3.34 (s, 3H), 1.65 (s, 3H). MS (ESI) m / z (M + H)+ = 327.0.

[0184] The following intermediates were synthesized in the same manner as in the procedure of Example 5 (Intermediate 33) using appropriate starting materials and thiourea:

[0185] [Table 4]

[0186] Example 6: 1-(2-Aminothiazol-4-yl)-1-(4-bromophenyl)ethan-1-ol (Intermediate 38) [Chemical formula]

[0187] Step 1. Preparation of compound 1-(4-bromophenyl)propan-1,2-dione [Chemical formula]

[0188] To a solution of compound 1-(4-bromophenyl)propan-2-one (2.0 g, 9.4 mmol, 1.0 equivalent) in dioxane (20 mL) was added SeO2 (3.12 g, 28.1 mmol, 3.0 equivalents). 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.

[0189] Step 2. Preparation of compound 3-bromo-1-(4-bromophenyl)propan-1,2-dione [Chemical formula]

[0190] To a solution of the compound obtained from the above step 1 (960 mg, 4.23 mmol, 1.0 equiv) in CH3Cl (20 mL), Br2 (1.05 g, 6.34 mmol, 1.5 equiv) and AcOH (3 drops) were added dropwise. The mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with saturated Na2SO3 (aqueous solution) (20 mL), extracted with DCM (20 mL × 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.

[0191] Step 3. Preparation of the compound (2-aminothiazol-4-yl)(4-bromophenyl)methanone

Chemical formula

[0192] To a solution of the compound obtained from the above step 2 (800 mg, 2.62 mmol, 1.0 equiv) in MeOH (8 mL), thiourea (200 mg, 2.62 mmol, 1.0 equiv) and NaHCO3 were added dropwise. The mixture was stirred at 50 °C for 1.5 h. The mixture was concentrated under reduced pressure, extracted with EA (15 mL × 2), the combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, concentrated to give a residue, which was purified by flash silica gel chromatography (PE:EA = 3:1) to give the desired group (680 mg, yield: 90%).

[0193] Step 4. Preparation of the compound 1-(2-aminothiazol-4-yl)-1-(4-bromophenyl)ethane-1-ol

Chemical formula

[0194] A solution of the compound (2-aminothiazol-4-yl)(4-bromophenyl)methanone (200 mg, 0.71 mmol, 1.0 equiv) in dry THF (4 mL) was cooled to 0 °C, and CH3MgBr (3 M in THF, 1.6 mL, 4.9 mmol, 7.0 equiv) was added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl (200 mL), and the mixture was extracted with EA (20 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated to give a residue. The obtained residue was purified by preparative TLC to give the desired compound (40 mg, yield: 20%).

[0195] 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).

[0196] MS (ESI) m / z (M + H)+ = 221.0 Example 7. 4-(2-(4-Chlorophenyl)but-3-yn-2-yl)thiazol-5-d-2-amine

Chemical formula

[0197] Step 1. Preparation of the compound N-(5-bromo-4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)acetamide

Chemical formula

[0198] A mixture of N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-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 h. The reaction mixture was cooled to room temperature, then diluted with H2O (50 mL), extracted with EtOAc (30 mL×3), the combined organic phases were washed with brine (50 mL×3), and concentrated to give a 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.

[0199] 1 H NMR (400 MHz, 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.

[0200] Step 2. Preparation of compound 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]-5-deuterio-thiazol-2-amine

Chemical formula

[0201] A mixture of the compound obtained from the above 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 h. The reaction mixture was adjusted to pH = 8 - 9 with saturated aqueous NaHCO3, then extracted with EtOAc (30 mL×3), the combined organic phases were washed with brine (30 mL), and concentrated to give a residue. The residue was purified by silica gel chromatography (PE:EA = 1:0~3:1) to obtain a product, which was further purified by Pre-TLC (PE:EA = 3:1). The desired compound (100 mg, yield: 20.8%) was obtained as a yellow oil.

[0202] 1 1H NMR (400 MHz, 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.

[0203] Meanwhile, the by-product 5-bromo-4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-amine (300 mg, yield: 52.2%) was obtained as a yellow solid.

[0204] MS (ESI) m / z (M + H) + = 343.1.

[0205] General method I To a solution of thiazoleamine (1 equiv.) in a suitable organic solvent such as DMF, NaH (1.2 - 1.5 equiv.) was added dropwise at 0 - 10 °C, and the resulting mixture was stirred for 5 - 30 minutes. The activated amine was added dropwise to the mixture by CDI, and the mixture was stirred for 4 - 16 hours. When the reaction was completed, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the obtained residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0206] Example 8: Preparation of tert-butyl 4-(4-((3-(4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate

Chemical formula

[0207] A solution of 4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazol-2-amine (40 mg, 0.15 mmol, 1 equiv) in DMF (5 mL) was added dropwise with NaH (7 mg, 0.3 mmol, 2 equiv) at 10 °C. The resulting mixture was stirred for 5 minutes. tert-Butyl 4-(4-((1H-imidazole-1-carboxamido)methyl)phenyl)piperazine-1-carboxylate (58 mg, 0.15 mmol, 1 equiv) was added dropwise to the mixture, and the mixture was stirred overnight. The reaction was quenched with water and extracted with EA. The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and evaporated to dryness. The obtained residue was purified by preparative TLC (PE:EA = 3:1) to give 35 mg (0.06 mmol) of the title compound in 40% yield. MS(ESI) m / z (M+H) + =588.2

[0208] General method II To a solution of an amine fragment (1 equiv) and pyridine in a suitable solvent such as dry DCM, phenyl carbonochloridate (2 equiv) was slowly added dropwise at below 20 °C. The mixture was stirred at room temperature for 4 - 6 hours. When the reaction was complete, the resulting reaction mixture was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the obtained residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0209] Example 9: Preparation of tert-butyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

Chemical Structure

[0210] Phenyl carbonochloridate (336 mg, 2.2 mmol, 269.0 μL) was added dropwise to a mixture of tert-butyl 4-(5-(aminomethyl)pyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 2.1 mmol), pyridine (194 mg, 2.5 mmol, 198 μL) in CH3CN (15 mL) at -20 °C. After the addition, the mixture was warmed to 25 °C and stirred at 25 °C for 0.25 h. 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 and the solid was collected and dried under vacuum. Tert-butyl 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (420 mg, yield: 38.2%) was obtained as a white solid. MS(ESI) m / z(M+H) + =414.2.

[0211] To a mixture of tert-butyl 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (139 mg, 336 μmol) and 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine (50 mg, 168 μmol) in DCE (10 mL), DMAP (41.0 mg, 337.0 μmol, 2 eq) was added. The mixture was stirred at 85 °C for 16 h. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 13:1) and further purified by preparative TLC (SiO2, DCM:MeOH = 12:1). The desired compound (60 mg, yield: 57.7%) was obtained as a white solid.

[0212] MS(ESI) m / z(M+H) + =616.2.

[0213] General method III To a solution of a substituted thiazole-2-amine and Hunig's base or pyridine in a suitable solvent such as DCM or CH3CN or DCM / water, phenyl carbonochloridate (2 equivalents) was slowly added dropwise at 0 °C to room temperature. The mixture was stirred at room temperature for 2 - 4 hours, and the resulting reaction product was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the obtained residue was purified by chromatography to obtain a substituted thiazole-2-amine carbamate.

[0214] A mixture of a substituted thiazole-2-amine carbamate, an amine, and DMAP in a suitable solvent such as THF was heated to 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 obtained residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0215] Example 10: Preparation of 1-(4-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea

Chemical formula

[0216] To a solution of 4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-amine (100 mg, 0.34 mmol, 1 equivalent) and triethylamine in dry DCM (5 mL), phenyl carbonochloridate (106 mg, 0.68 mmol, 2 equivalents) was slowly added dropwise at 0 °C to RT, and the mixture was stirred at room temperature for 4 hours. It was quenched with brine, extracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a residue, which was purified by column chromatography on silica gel to obtain phenyl (4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)carbamate (112 mg).

[0217] A mixture of phenyl(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)carbamate (112 mg, 0.27 mmol, 1 equiv), tert-butyl((1-(4-(aminomethyl)phenyl)piperidin-4-yl)methyl)carbamate (24 mg, 0.27 mmol, 1 equiv) and DMAP (52 mg, 0.4 mmol, 1.5 equiv) in THF (5 mL) was heated to reflux for 1 h. The mixture was cooled to room temperature and the reaction mixture was partitioned between H2O (15 mL) and EA (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford tert-butyl((1-(4-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)phenyl)piperidin-4-yl)methyl)carbamate (42 mg) as a white powder.

[0218] General Method IV A mixture of an amine and an isocyanate-alkane in THF was stirred at room temperature overnight. When the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine and then dried. After filtration and evaporation, the residue obtained was purified by trituration / preparative TLC / preparative HPLC to afford the product.

[0219] Example 11: Preparation of 1-ethyl-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea [Chemical formula]

[0220] A solution of 4-(2-(4-methoxyphenyl)propan-2-yl)thiophene-2-amine (200 mg, 0.67 mmol) in THF (5 mL) was added dropwise with isocyanatoethane (48 mg, 0.67 mmol) and TEA (136 mg, 1.34 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was concentrated at 45 °C under reduced pressure to remove THF. The resulting suspension was diluted with EtOAc, washed with brine, then dried (Na2SO4), filtered, and evaporated to dryness. The obtained residue was purified by preparative-TLC to give the desired compound (164 mg, yield: 65.4%) as a pale yellow solid. MS(ESI) m / z(M+H) + =367.1.

[0221] General method for de-BOC

[0222] 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.

[0223] Example 12: Preparation of 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6-(piperazin-1-yl)pyridin-3-yl)methyl)urea hydrochloride

Chemical Structure

[0224] HCl / MeOH (4 M, 2 mL) was added dropwise to a solution of tert-butyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)pyridin-2-yl)piperazine-1-carboxylate (70.0 mg, 113.71 μmol) in MeOH (2 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo. The desired compound (47.0 mg, yield: 74.1%, HCl) was obtained as a white solid.

[0225] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (brs, 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 (brs, 4H), 1.57 (s, 6H). MS (ESI) m / z (M + H)+ = 517.2.

[0226] The following examples were synthesized in the same manner as the procedures of Examples 8, 9, 10, 11, and 12 using appropriate intermediates and corresponding fragments.

[0227] [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

[0228] Example 13: Preparation of tert-Butyl 4-(4-((3-(4-(1-(4-Bromophenyl)ethyl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate

Chem.

[0229] A solution of tert-butyl 4-(4-((3-(4-(1-(4-bromophenyl)vinyl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate (120 mg) in MeOH (5 mL) was added dropwise with Pd / C (12 mg), and the mixture was stirred overnight at room temperature under a hydrogen pressure. After filtration and evaporation, the obtained residue was purified by silica gel column chromatography to obtain tert-butyl 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate (73 mg).

[0230] Example 14: Preparation of tert-butyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-3-fluoropyridin-2-yl)piperazine-1-carboxylate [Chemical formula]

[0231] A suspension of 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6-chloro-5-fluoropyridin-3-yl)methyl)urea (174 mg, 0.4 mmol), tert-butyl piperazine-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, and the residue was dissolved in ethyl acetate (100 mL) and washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a crude product, which was purified by flash column to give the desired product (67 mg, 25% yield).

[0232] Example 15: Preparation of 5-((3-(4-(2-(4-Methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-2-(3-methylpiperazin-1-yl)benzamide

Chemical Structure

[0233] Step 1: Preparation of 2-(4-(tert-Butoxycarbonyl)-3-methylpiperazin-1-yl)-5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)benzoic acid

Chemical Structure

[0234] A mixture of tert-butyl 4-(2-(methoxycarbonyl)-4-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-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 to reflux for 0.5 h. After cooling, the reaction mixture 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).

[0235] Step 2: Preparation of tert-butyl 4-(2-carbamoyl-4-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)phenyl)-2-methylpiperazine-1-carboxylate

Chemical Structure

[0236] A mixture of 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)benzoic acid (215 mg, 0.34 mmol, 1 equiv), EDCI (132 g, 0.69 mmol, 2 equiv), HOBt (93 mg, 0.69 mmol, 2 equiv) and DIEA (133 mg, 1.03 mmol, 3 equiv) was dissolved in THF (0.1 M) and stirred at room temperature for 15 min. Then, NH4Cl (36.9 mg, 0.69 mmol, 2 equiv) was added dropwise all at once and the reaction was stirred at room temperature. When judged to be complete by TLC analysis, the resulting suspension was diluted with EtOAc, washed with brine, then dried (Na2SO4), filtered and evaporated to dryness. The obtained residue was purified by trituration or preparative TLC to give the desired product (201 mg).

[0237] Example 16: Preparation of 1-((6-((2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea [Chemical formula]

[0238] A mixture of 1-((6-fluoropyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea (50 g, 0.13 mmol, 1.0 equiv) and 2-aminoethanol (11.9 mg, 0.19 mmol, 1.5 equiv) in EtOH was heated to 90 °C over 14 h. After the reaction was cooled to room temperature, it was concentrated to give a residue, which was purified by column chromatography on silica gel to give 1-((6-((2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea (21 mg).

[0239] Example 17: Preparation of 1-(4-(2-(4-Methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea [Chemical formula]

[0240] Step 1. Preparation of Methyl 2-(4-Methoxyphenyl)acetate [Chemical formula]

[0241] 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 h. The mixture was diluted with EA (400 mL), washed with saturated aqueous NaHCO3 solution (100 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0 - 15%). The desired product (21.6 g, yield: 99.7%) was obtained as a yellow oil.

[0242] 1 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.8 Hz, 2H) 6.87 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.58 (s, 2H)

[0243] Step 2. Preparation of Compound Methyl 2-(4-Methoxyphenyl)-3-oxobutanoate

[0244] [Chemical formula]

[0245] To a solution of the compound obtained from the above step 1 (23.8 g, 132.2 mmol) in THF (200 mL) was added dropwise LiHMDS (1 M, 159 mL) at -78 °C. The mixture was stirred at -78 °C for 20 minutes. Acetyl acetate (13.5 g, 132.2 mmol) was added dropwise to the solution. Then, the mixture was warmed to 0 °C and stirred at 0 °C for 2 hours. The mixture was quenched with saturated aqueous NH4Cl 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 in vacuo. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0 - 15%) to give the desired compound (14.23 g, yield: 48.4%) as a yellow oil.

[0246] 1 H NMR (400 MHz, CDCl3) δ 12.97 (s, 1H), 7.25 - 7.23 (m, 1.5H), 7.07 - 7.03 (m, 2H), 6.87 - 6.85 (m, 2H), 4.63 (s, 0.5H), 3.80 (s, 3H), 3.78 (s, 1.5H), 3.73 (s, 1.5H), 3.67 (s, 3H), 2.15 (s, 1.5H), 1.83 (s, 3H). MS (ESI) m / z (M + H )+ = 223.1

[0247] Step 3. Preparation of methyl 2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate

Chemical formula

[0248] To a mixture of the compound obtained from the above step 2 (14.5 g, 65.4 mmol) and K2CO3 (45.2 g, 326.9 mmol) in acetone (100 mL) was added dropwise CH3I (26.0 g, 183.3 mmol) at 15 °C. The mixture was stirred at 70 °C for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0 - 15%). The desired compound (9.76 g, yield: 63.2%) was obtained as a colorless oil.

[0249] 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 2H), 6.95 - 6.86 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 2.10 (s, 3H), 1.77 (s, 3H)

[0250] Step 4. Preparation of methyl 4 - bromo - 2 - (4 - methoxyphenyl) - 2 - methyl - 3 - oxobutanoate

Chem.

[0251] 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 dropwise at 15 °C. The mixture was stirred at 73 °C for 12 h. The mixture was washed with H2O (20 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a 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.

[0252] MS (ESI) m / z (M + H) + = 315.1

[0253] Step 5. Preparation of methyl 2 - (2 - aminothiazol - 4 - yl) - 2 - (4 - methoxyphenyl) propanoate

Chem.

[0254] A mixture of the compound obtained from the above step 4 (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 in vacuo. The residue was triturated with H2O (20 mL) at 15 °C for 10 minutes, filtered, and the cake was concentrated in vacuo to give a residue. The desired product (0.79 g, yield: 82.68%) was obtained as a yellow solid.

[0255] 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.18 (m, 2H), 6.97 - 6.92 (m, 2H), 6.88 - 6.86 (m, 2H), 5.95 (s, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 1.77 (s, 3H).

[0256] Step 6. Preparation of methyl 2-(4-methoxyphenyl)-2-(2-((phenoxycarbonyl)amino)thiazol-4-yl)propanoate

Chemical formula

[0257] To a mixture of the compound obtained from the above step 5 (300 mg, 1.03 mmol) and pyridine (97.4 mg, 1.23 mmol) in CH3CN (3 mL), phenyl carbonochloridate (169 mg, 1.08 mmol) was added dropwise at 0 °C. The mixture was stirred at 15 °C for 3 hours. The mixture was concentrated directly in vacuo. The residue was purified by silica column (ethyl acetate in petroleum ether = 0 - 30%) to give the desired compound (330 mg, yield: 77.97%) (obtained as a yellow oil).

[0258] MS (ESI) m / z (M + H) + = 413.0

[0259] Preparation of Compound tert-Butyl 4-(4-(1-(3-(4-(1-Methoxy-2-(4-methoxyphenyl)-1-oxopropan-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate

Chem.

[0260] A mixture of the compound obtained from the above Step 6 (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 at 100 °C for 1 hour under microwave irradiation. The mixture was concentrated directly in vacuo to give 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 oil.

[0261] MS(ESI) m / z (M + H) + = 646.2

[0262] Preparation of Compound tert-Butyl 4-(4-(1-(3-(4-(1-Hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate

Chem.

[0263] 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 dropwise at 15 °C. The mixture was stirred at 15 °C for 12 h. 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 in vacuo. The residue was purified by silica column (ethyl acetate in petroleum ether = 0 - 100%) to give the desired compound (307 mg, yield: 87.0%) (obtained as a yellow solid).

[0264] 1 H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz, 2H), 7.09 - 7.06 (m, 2H), 6.86 - 6.80 (m, H), 6.45 (s, 1H), 4.94 - 4.91 (m, 1H), 4.05 - 4.00 (m, 1H), 3.81 - 3.77 (m, 4H), 3.56 - 3.54 (m, 4H) 3.09 - 3.07 (m, 4H), 1.56 (d, J = 1.6 Hz, 3H), 1.49 (s, 9H), 1.46 (d, J = 6.8 Hz, 3H).

[0265] Step 9. Preparation of 1-(4-(1-Hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea hydrochloride

Chemical Structure

[0266] To a solution of the compound obtained from Step 8 above (50 mg, 83.93 μmol) in DCM (2 mL), HCl / EtOAc (4 M, 2 mL) was added dropwise at 15 °C. The mixture was stirred at 15 °C for 12 h. The mixture was concentrated in vacuo to give the desired compound (34 mg, yield: 76.1%) as a yellow solid.

[0267] 11H NMR (400 MHz, DMSO) δ 10.47 (brs, 1H), 9.11 (brs, 2H), 7.36 - 7.23 (m, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 4.77 - 4.73 (m, 1H), 3.80 - 3.76 (m, 1H), 3.70 (s, 3H) 3.34 - 3.31 (m, 4H), 3.24 - 3.16 (m, 4H), 2.07 (s, 1H), 1.55 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H). MS (ESI) m / z (M + H) + = 496.2

[0268] Step 10: Preparation of tert-Butyl 4-(4-(1-(3-(4-(2-(4-Methoxyphenyl)-1-oxopropan-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate

Chemical Structure

[0269] To a solution of oxalyl dichloride (68.2 mg, 537.14 μmol) in DCM (2 mL) was added dropwise DMSO (66 mg, 839 μmol) at -78 °C. After 10 minutes, the compound obtained from Step 9 above (100 mg, 168 μmol) in DCM (2 mL) was added dropwise and stirred at -78 °C for 1 hour. Et3N (170 mg, 1.68 mmol) was added dropwise, stirred for an additional 10 minutes, then warmed to 15 °C and stirred for an additional 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 in vacuo to obtain a 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.

[0270] Step 11: Preparation of compound tert-butyl 4-(4-(1-(3-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate

Chem.

[0271] MS(ESI) m / z (M+H) + =590.3

[0272] Step 12. Preparation of compound 1-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea

Chem.

[0273] The desired compound (39 mg, yield: 87.4%) was obtained as a yellow solid using the De-BOC method.

[0274] 11H NMR (400 MHz, DMSO-d6) δ 10.50 (brs, 1H), 9.22 (brs, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 3H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (dd, J = 8.4, 1.2 Hz, 2H), 6.81 - 6.79 (m, 1H), 4.76 - 4.73 (m, 1H), 3.71 (s, 3H), 3.39 (s, 1H), 3.35 - 3.32 (m, 4H) 3.24 - 3.16 (m, 4H), 1.82 (d, J = 2.4 Hz, 3H), 1.33 (d, J = 6.8 Hz, 3H).

[0275] MS (ESI) m / z (M+Na) + = 512.3

[0276] Example 18: Preparation of 1-(4-(2-(4-Cyclopropylphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea

Chemical formula

[0277] Step 1: Preparation of tert-Butyl 4-(4-((3-(4-(2-(4-Cyclopropylphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate

Chemical formula

[0278] To a solution of the compound obtained from the above 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 dropwise. The reaction mixture was stirred at 115 °C overnight under a N2 atmosphere. The progress of the reaction was monitored by TLC. After 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.

[0279] Step 2. Preparation of compound 1-(4-(2-(4-cyclopropylphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea

Chemical formula

[0280] The desired compound was obtained as a white solid (40 mg, HCl salt, yield: 100%) according to the procedure described in Example 9. MS(ESI) m / z(M+H) + = 476.2.

[0281] Example 19: 1-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(2-hydroxyethyl-2,2-d2)urea

Chemical formula

[0282] Step 1. Preparation of compound tert-butyl N-(2,2-dideuterio-2-hydroxy-ethyl)carbamate

Chemical formula

[0283] A solution of methyl 2-((tert-butoxycarbonyl)amino)acetate (1 g, 5.29 mmol) in THF (20 mL) was added dropwise with LiAlD4 (364.8 mg, 7.93 mmol) at 0 °C, and then the mixture was stirred at 80 °C for 3 hours. After adding dropwise EA (20 mL) and H2O (5 mL), it was extracted with EA (100 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The desired compound (610 mg, yield: 70.7%) was obtained as a yellow oil and used in the next step without further purification.

[0284] 1 H NMR (400 MHz, CDCl3) δ 5.17 (brs, 1H), 3.24 (d, J = 5.6 Hz, 2H), 3.08 (brs, 1H), 1.42 (s, 9H).

[0285] Step 2. Preparation of compound 2-amino-1,1-dideuterio-ethanol

Chemical formula

[0286] A mixture of the compound obtained from the above Step 1 (610 mg, 3.74 mmol) in HCl / MeOH (4M, 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 oil and used in the next step without further purification.

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 2.80 (q, J = 5.7 Hz, 2H).

[0288] Step 3. Preparation of compound phenyl N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-yl]carbamate

Chemical formula

[0289] A solution of 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-amine (500 mg, 1.90 mmol) and pyridine (752.60 mg, 9.51 mmol) in MeCN (20 mL) was added dropwise with phenyl carbonochloridate (327.7 mg, 2.09 mmol) at 0 °C, and then the mixture was stirred at 0 °C for 1 hour. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired compound (830 mg, crude) was obtained as a yellow oil and used in the next step without further purification.

[0290] MS(ESI) m / z (M + H) + = 383.0

[0291] Step 4. Preparation of 1-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-yl]-3-(2,2-dideuterio-2-hydroxy-ethyl)urea

Chemical Structure

[0292] A mixture of the compound obtained in Step 3 above (400 mg, 1.04 mmol), the compound obtained in Step 2 above (98.9 mg, 1.57 mmol), and DMAP (12.8 mg, 104.48 μmol) in DCE (20 mL) was stirred at 80 °C for 5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18 150*40 mm*5 μm; mobile phase: [water (HCl)-ACN]; B%: 28% - 58%, 10 minutes). The desired compound (90 mg, yield: 24.5%) was obtained as a white solid.

[0293] MS(ESI) m / z (M + H) + = 352.1.

[0294] SFC: Column: ChiralPak IG-3 100×4.6mm I.D., 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5% to 40% of B in 5.5 minutes and hold at 40% for 3 minutes, then hold at 5% of B for 1.5 minutes, Flow rate: 2.5 mL / min, Column temperature: 40°C (P1: Rf = 4.159 minutes, P2: Rf = 4.831 minutes).

[0295] Step 5. Preparation of compound 1-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-yl]-3-(2,2-dideuterio-2-hydroxy-ethyl)urea

Chemical formula

[0296] The compound obtained in the above step 4 ((90 mg, 255.79 μmol) was separated by SFC (Column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); Mobile phase: [0.1% NH3H2O ETOH]; B%: 40% - 40%, minutes). Chiral isomer 1 (26.85 mg, Yield: 29.8%) was obtained as a white solid.

[0297] 1 H NMR (400 MHz, 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.

[0298] Chiral isomer 2 (27.90 mg, Yield: 31.0%) was obtained as a white solid.

[0299] 1 H NMR (400 MHz, 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.

[0300] General method A

[0301] Carboxylic acid (1 equivalent), with or without HOBt (2 equivalents) and DIEA (3 equivalents) / pyridine / DMAP, and EDCI (2 - 2.5 equivalents) were dissolved in THF / DMF and stirred at room temperature for 15 - 30 minutes. Then, amine (1 equivalent) was added dropwise all at once, and the reaction mixture was stirred at room temperature to 70 °C for 2 - 16 hours. When the reaction was complete, the resulting suspension was diluted with an organic solvent, washed with brine, and then dried. After filtration and evaporation, the obtained residue was purified by trituration / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0302] Example 20: Preparation of compound 4 - ((2 - hydroxyethyl)amino)-N-(4-(2-(4 - methoxyphenyl)propan - 2 - yl)thiazol - 2 - yl)benzamide.

Chemical formula

[0303] To a solution of 4 - ((2 - hydroxyethyl)amino)benzoic acid (200 mg, 1.10 mmol) and 4 - [1 - (4 - methoxyphenyl)-1 - methyl - ethyl]thiazol - 2 - amine (261.98 mg, 919.85 μmol, HCl) in Py (8 mL), EDCI (440.84 mg, 2.30 mmol) was added dropwise. 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 minutes). The desired compound (52 mg, yield: 13.57%) was obtained as a pale yellow solid.

[0304] 11H NMR (400 MHz, DMSO-d6) δ 12.06 (brs, 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.

[0305] General method B

[0306] The acid chloride was obtained by using SOCl2 in a suitable solvent such as DCM. To the acyl chloride solution, TEA or pyridine (3 equivalents) and amine (1 equivalent) in DCM were slowly added dropwise at 0 °C under N2, and the mixture was further stirred at room temperature for 0.5 - 2 hours. When the reaction was completed, it was quenched with H2O, extracted with EA, washed with brine, then dried (Na2SO4), filtered, and evaporated to dryness. The obtained residue was purified by trituration / fractional TLC / chromatography / fractional HPLC to obtain the product.

[0307] Example 21

Chemical formula

[0308] To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2,6-difluoro-benzoic acid (150 mg, 438.16 μmol) in DCM (6 mL) was added dropwise SOCl2 (31.8 μL, 438.16 μmol). The mixture was stirred at 25 °C for 1 h. Py (176.74 μL, 2.19 mmol) was added dropwise, the reaction was stirred at 25 °C for 5 min, then 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-amine (115.07 mg, 437.94 μmol) was added dropwise and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:0~1:1:1). The desired compound (152 mg, yield: 54.4%) was obtained as a colorless oil.

[0309] MS(ESI) m / z (M+H) + = 587.1.

[0310] Example 22 Preparation of compound methyl N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-carboxamide [Chemical formula]

[0311] A solution of 3-[tert-butyl(diphenyl)silyl]oxycyclobutanecarboxylic acid (1.36 g, 3.84 mmol) in DCM (10 mL) was added dropwise with PyBOP (2.00 g, 3.84 mmol) at 25 °C. After stirring for 10 minutes, methyl 2-(2-aminothiazol-4-yl)-2-(4-bromophenyl)propanoate (523.61 mg, 1.53 mmol) and DIPEA (594.97 mg, 4.60 mmol) were added dropwise 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 in vacuo. 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 oil. MS(ESI) m / z (M+H) + =643.1

[0312]

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

[0313]

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

[0314]

Table 8-1

Table 8-2

Table 8-3

Table 8-4

Table 8-5

Table 8-6

[0315] Example 23: 6-((2-(Dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)nicotinamide

Chem.

[0316] Step 1. Preparation of compound 6-chloro-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)nicotinamide

Chem.

[0317] A mixture of compound 4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-amine (100 mg, 0.35 mmol, HCl salt), compound 6-chloronicotinic acid (83.0 mg, 0.53 mmol) and EDCI (135 mg, 0.70 mmol) in pyridine (3 mL) was stirred at 80 °C for 2 h. 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.

[0318] MS(ESI) m / z (M+H) + = 388.0

[0319] Step 2. Preparation of 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)nicotinamide

Chem.

[0320] A mixture of the compound obtained from the above 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 h. 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.

[0321] 1 H NMR (400 MHz, 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).

[0322] MS (ESI) m / z (M + H) + = 440.2

[0323] Example 24: Preparation of 6-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-N-(4-(2-(p-tolyl)propan-2-yl)thiazol-2-yl)nicotinamide

Chem.

[0324] A solution of 6-(piperazin-1-ylmethyl)-N-(4-(2-(p-tolyl)propan-2-yl)thiazol-2-yl)nicotinamide (0.03 g, 69 μmol, 1 equiv) in CH3CN (10 mL) was added with 2-bromoethanol (9.47 mg, 76 μmol, 5 μL, 1.1 equiv) and K2CO3 (19 mg, 137.8 μmol, 2 equiv). Subsequently, the reaction mixture was stirred at 80 °C for 16 h. The reaction 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.

[0325] 1 H NMR (400 MHz, 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.

[0326] Example 25: (1r,3r)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl)cyclobutane-1-carboxamide

Chem.

[0327] Step 1. Preparation of compound methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylate

Chem.

[0328] To a solution of methyl 3-(hydroxymethyl)cyclobutanecarboxylate (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 dropwise at 25 °C. The solution was stirred at 25 °C for 12 h. The mixture was diluted with DCM (30 mL), washed with H2O (3 × 10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a 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.

[0329] MS(ESI) m / z (M + H) + = 383.1

[0330] Step 2. Preparation of 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylic acid

Chemical Structure

[0331] To a mixture of the compound obtained from the above Step 1 (412 mg, 1.08 mmol) in THF (1.5 mL) / MeOH (0.5 mL) / H2O (0.5 mL), LiOH·H2O (90.6 mg, 2.16 mmol) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was diluted with H2O (15 mL), adjusted to pH = 6 - 7, and extracted with EA (15 mL × 3 times). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a 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.

[0332] MS(ESI) m / z (M + Na) + = 391.1

[0333] Preparation of Compound Methyl 2-(4-Bromophenyl)-2-(2-((1R,3R)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamido)thiazol-4-yl)propanoate [Chemical Formula]

[0334] A solution of the compound obtained from the above 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-Aminothiazol-4-yl)-2-(4-bromophenyl)propanoate (152 mg, 446 μmol) and PyBOP (580 mg, 1.11 mmol) were added dropwise 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 in vacuo to obtain a 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 oil. Another desired compound B (186 mg, crude) was obtained as a yellow oil. The crude product was used directly in the next step without further purification. The chirality of the product was confirmed in the final step.

[0335] Preparation of Compound (1R,3R)-N-(4-(2-(4-Bromophenyl)-1-hydroxypropan-2-yl)thiazol-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide [Chemical Formula]

[0336] 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 dropwise at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL), diluted with H2O (20 mL), and extracted with EA (20 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a 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.

[0337] MS(ESI) m / z (M + H) + = 663.1

[0338] Step 5. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)-1-oxopropan-2-yl)thiazol-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide

Chemical Structure

[0339] To a mixture of Dess-Martin (73 mg, 171.2 μmol, 53 μL) in DCM (2 mL), a solution of the compound obtained from Step 4 above (77 mg, 132 μmol) in DCM (2 mL) was added dropwise at 20 °C. The mixture was stirred at 20 °C for 3 h. The mixture was quenched with saturated NaHCO3 (10 mL) / saturated Na2S2O4 (10 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a 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.

[0340] Preparation of Compound (1R,3R)-N-(4-(2-(4-Bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide

Chemical formula

[0341] A solution of the compound obtained from the above Step 5 (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 in vacuo to give a residue. The residue was purified by silica column (ethyl acetate in petroleum ether = 0 - 15%). The desired compound (37 mg, yield: 48.3%) was obtained as a yellow oil.

[0342] MS (ESI) m / z (M + H) + = 657.1

[0343] Preparation of Compound (1R,3R)-N-(4-(2-(4-Bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl)cyclobutanecarboxamide

Chemical formula

[0344] To a solution of the compound obtained in the above Step 6 (37 mg, 56.3 μmol) in THF (2 mL), TBAF (1 M, 0.1 mL) was added dropwise 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 × 3), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a 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.

[0345] 1 1H NMR (400 MHz, CDCl3) δ 13.28 (brs, 1H), 7.56 - 7.48 (m, 4H), 6.91 (s, 1H), 3.65 (d, J = 4.4 Hz, 2H), 3.34 - 3.30 (m, 1H), 2.77 (s, 1H), 2.63 - 2.61 (m, 1H), 2.52 - 2.43 (m, 2H), 2.34 - 2.32 (m, 2H), 2.15 (s, 3H). MS (ESI) m / z (M + H)+ = 419.0.

[0346] Other isomers were synthesized using the same procedure as above.

[0347] Example 26: 4 - ((4 - (2 - Hydroxyethyl)piperazin - 1 - yl)methyl)-N-(4-(2-(4 - methoxyphenyl)propan - 2 - yl)thiazol - 2 - yl)benzamide

Chemical Structure

[0348] To a solution of compound 4 - formyl - N-(4-(2-(4 - methoxyphenyl)propan - 2 - yl)thiazol - 2 - yl)benzamide (120 mg, 0.32 mmol) and 2 - (piperazin - 1 - yl)ethan - 1 - ol (42 mg, 0.32 mmol) in DCM (5 mL) were added NaBH3CN (59 mg, 0.95 mmol) and HOAc (2 drops). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to obtain a 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.

[0349] MS (ESI) m / z (M + H) + = 495.2

[0350] Usage ALPK1 is a cytoplasmic serine threonine protein kinase that plays an important role in the activation of the innate immune response. ALPK1 binds to the bacterial pathogen associated molecular pattern metabolite (PAMP), ADP-D-glycero-β-D-manno-heptose (ADP-heptose). The ALPK1-ADP-heptose binding occurs via direct interaction in the ALPK1 N-terminal domain. This interaction stimulates the kinase activity of ALPK1 as well as the phosphorylation and activation of its forkhead related domain (TRAF interacting protein with TIFA). Next, TIFA activation induces pro-inflammatory NFkB signaling including the expression and / or secretion of pro-inflammatory cytokines and chemokines. Thus, the compounds disclosed herein are generally useful as inhibitors of ALPK1 kinase activity and downstream activation of NFkB pro-inflammatory signaling.

[0351] The present disclosure provides the use of a compound of Formula I, or a sub - embodiment thereof as described herein, for inhibiting ALPK1 kinase activity and reducing inflammation in a target tissue. The methods also include the use of a compound of Formula I, or a sub - embodiment thereof as described herein, for treating a disease, disorder, or condition characterized by excessive or inappropriate ALPK1 - dependent inflammatory signaling. In an embodiment, the disease is a kidney disease, disorder, or condition. In embodiments, the kidney diseases, disorders, and conditions include chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non - diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio - renal syndrome, nephrotic syndrome, hepato - renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulo - interstitial disease, nephrosis, nephritis, Alport syndrome, such as those including kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex - induced kidney disease, nephrosis induced by toxic substances, contrast - induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (e.g., can be diagnostically characterized by abnormal decrease in creatinine and / or water excretion, abnormal increase in blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubule dilation, hyperlymphocytosis and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., including, but not limited to, hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic urate nephropathy, and syndrome of inappropriate ADH secretion (SIADH)).

[0352] In embodiments, the present disclosure provides a method of inhibiting ALPK1 kinase activity in mammalian cells or target tissues by contacting the cells or target tissues with a compound of Formula I, or a sub - embodiment described herein. In embodiments, the method comprises administering to a subject a pharmaceutical composition comprising a compound of Formula I, or a sub - embodiment described herein, in an amount effective to inhibit ALPK1 kinase activity in the target cells or tissues of the subject. In embodiments, the method comprises reducing inflammation in the target tissues of a subject in need of such treatment by administering to the subject a compound of Formula I, or a sub - embodiment described herein, or a pharmaceutical composition comprising the same.

[0353] In embodiments, the present disclosure provides a method of treating a subject having a disease or disorder characterized by excessive or inappropriate activation of ALPK1 kinase activity. In embodiments, the method comprises administering to the subject a compound of Formula I, or a sub - embodiment described herein. In embodiments, the disease is a kidney disease, disorder, or condition. In embodiments, the kidney diseases, disorders, and conditions include chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non - diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio - renal syndrome, nephrotic syndrome, hepato - renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulo - interstitial disease, nephrosis, nephritis, Alport syndrome, such as primary and congenital kidney diseases, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex - induced kidney disease, nephrosis induced by toxic substances, contrast - induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis, and nephrotic syndrome (e.g., characterized diagnostically by abnormal reduction in creatinine and / or water excretion, abnormal elevation in blood concentrations of urea, nitrogen, potassium, and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions of glomeruli and arterioles, tubular dilation, hyperlymphocytosis, and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic uric acid nephropathy, and syndrome of inappropriate antidiuretic hormone secretion (SIADH), including but not limited to these).

[0354] In embodiments, the present disclosure further provides a method for identifying a compound of Formula I or a disease, disorder, or condition for treatment according to a sub - embodiment described herein, the method comprising assaying a biological sample from a subject diagnosed with the disease, disorder, or condition for overexpression of ALPK1 mRNA or protein in a cell or tissue involved in the disease, disorder, or condition as compared to one or more activating mutations in ALPK1 and a reference cell or tissue not involved in the disease, disorder, or condition.

[0355] In the context of the methods described herein, the term "treatment" can refer to the improvement or stabilization of one or more symptoms associated with the disease, disorder or condition being treated. The term "treatment" also includes the management of a disease, disorder or condition and refers to a beneficial effect obtained by the subject that does not result in a cure of the underlying disease, disorder, or condition.

[0356] In embodiments where a therapeutically effective amount of a compound described herein is administered to a subject, the therapeutically effective amount is an amount sufficient to achieve a desired therapeutic result, such as improvement or stabilization of one or more symptoms of the disease, disorder or condition being treated.

[0357] In embodiments, the therapeutically effective amount is an amount necessary to achieve at least an equivalent therapeutic effect as compared to standard therapy. Examples of standard therapy include FDA - approved drugs indicated for treating the same disease, disorder, or condition.

[0358] In any context 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.

[0359] In embodiments, the human subject is selected from an adult human, a pediatric human, or an elderly human as these terms are understood by medical practitioners, such as as defined by the U.S. Food and Drug Administration (FDA).

[0360] The present disclosure includes methods of treating kidney diseases, disorders, and conditions, the methods including administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of Formula I, or a sub - embodiment described herein.

[0361] In embodiments, the methods described herein may include monotherapy with a compound of Formula (I), or a sub - embodiment described herein, or a combination therapy, for example, combining a therapeutic regimen comprising a compound of Formula (I), or a sub - embodiment described herein, with one or more additional therapies or active agents. In embodiments, the administration of a compound of Formula (I), or a sub - embodiment described herein, or a therapeutic regimen comprising the same results in the reduction or elimination of at least one symptom (e.g., a kidney disease, disorder, and condition) of a disease or disorder characterized by excessive or inappropriate activation of ALPK1 kinase activity during treatment, or an improvement in at least one marker of disease progression or disease severity. In embodiments, the method reduces autoantibody production and resulting autoimmune sequelae and pathology as measured by an appropriate disease - related scale.

[0362] In embodiments, provided herein is a method of treating a kidney disease in a subject in need thereof, which includes administering a compound of Formula (I), or a sub - embodiment described herein, or a therapeutic regimen comprising a compound of Formula (I), or a sub - embodiment described herein, and at least one additional treatment or therapeutic agent. The methods of the present disclosure reduce or eliminate at least one symptom of a kidney disease, disorder, and condition.

[0363] In embodiments directed to methods of treating kidney diseases, disorders, and conditions, administration of a compound of formula (I), or a sub - embodiment compound described herein, or a treatment regimen comprising a compound of formula (I), or a sub - embodiment compound described herein, and at least one additional treatment or therapeutic agent results in a reduction or elimination of at least one marker of disease progression or disease severity. Such markers can include, but are not limited to, plasma BUN, plasma urea, plasma creatinine, protein area, C - reactive protein (CRP), IL - 6, IL - 17A / F, TNFa, and CCL - 2. Kidney diseases, disorders, and conditions

[0364] Kidney disease, or nephropathy, is specifically called nephrosis and is an injury or disease of the kidneys. Nephritis is an inflammatory kidney disease and there are several types depending on the location of the inflammation. Inflammation can be diagnosed by a blood test. Nephrosis is a non - inflammatory kidney disease. Nephritis and nephrosis can each cause nephritic syndrome and nephrotic syndrome, respectively. Kidney disease usually causes some loss of kidney function and can lead to renal failure, which is a complete loss of kidney function. Renal failure is known as the end - stage of kidney disease and dialysis or kidney transplantation are the only treatment options.

[0365] Chronic kidney disease is defined as a long - term kidney abnormality (functional and / or structural nature) that lasts for three months or more. Acute kidney disease is currently called acute kidney injury and is characterized by a rapid decline in kidney function over a period of seven days.

[0366] Exemplary kidney diseases, disorders, and conditions treated by the compounds disclosed herein include kidney diseases, disorders, and conditions such as chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio-renal syndrome, nephrotic syndrome, hepato-renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephrosis, nephritis, Alport syndrome, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, nephrosis induced by toxic substances, contrast agent-induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis, and nephrotic syndrome (e.g., characterized diagnostically by abnormal reduction in creatinine and / or water excretion, abnormal elevation in blood concentrations of urea, nitrogen, potassium, and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperlymphocytosis, and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic urate nephropathy, and syndrome of inappropriate ADH secretion (SIADH), including but not limited to these).

[0367] Cytokines are protein mediators that play important roles in inflammation. Cytokines are a very diverse group of molecules that include over 100 secreted factors that can be subdivided into several classes, such as interleukins (IL), tumor necrosis factor (TNF), interferons (IFN), transforming growth factor (TGF), colony-stimulating factors (CSF), and various chemokines. Cytokines are produced by T cells, monocytes, macrophages, platelets, and endothelial cells (EC), SMC, and adipocytes in response to inflammation and other stimuli. Increased production of pro-inflammatory cytokines is associated with disease progression and promotes kidney disease.

[0368] There is some clinical evidence that anti-inflammatory treatment using anti-TNF-α therapy in rheumatoid arthritis patients and anti-IL-1β therapy in patients with a history of myocardial infarction reduces the incidence of cardiovascular events. The present invention is based in part on the inventors' discovery that small molecule inhibitors of ALPK1, as described herein, mediate the inflammatory response in model systems associated with kidney disease, as further described in the Examples section below. Combination therapy

[0369] The present disclosure also provides methods comprising combination therapy. As used herein, "combination therapy" or "co-therapy" refers to a treatment regimen intended to provide a beneficial effect from the co-action of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional active agent, which is also referred to herein as an "active pharmaceutical ingredient" ("API"), comprising the administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one additional therapeutic or active agent. According to the embodiments described below, "additional API" is understood to refer to at least one additional therapeutic agent administered in a combination therapy regimen with a compound of formula (I), or a pharmaceutically acceptable salt thereof. The additional API may be administered in the same or a different dosage form as the compound of formula (I), or a pharmaceutically acceptable salt thereof. The additional API may be administered by the same or a different route of administration as the compound of formula (I), or a pharmaceutically acceptable salt thereof. Further, it is understood that two or more of the additional APIs described below may be utilized in a combination therapy regimen. The terms "combination therapy" or "combination therapy regimen" are not intended to encompass the administration of two or more therapeutic compounds as part of separate monotherapy regimens that incidentally and arbitrarily result in beneficial effects that were not intended or predicted.

[0370] Preferably, administering a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more additional APIs as discussed herein results in a synergistic response in the subject being treated. In this context, the term "synergistic" refers to the combination being more effective than the additive effect of either single treatment alone.

[0371] The synergistic effect of the combination therapies according to the present disclosure can enable administration of at least one agent in the combination therapy at a lower dose and / or less frequent dosing compared to its dose and / or frequency exclusive of the combination therapy. Further beneficial effects of the combination therapy can manifest in the avoidance or reduction of adverse or undesirable side effects associated with the use of either treatment alone in the combination therapy (also referred to as monotherapy).

[0372] In the context of combination therapy, administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be carried out simultaneously with, or sequentially to, the administration of one or more additional active agents or APIs. In another embodiment, administration of the different components of the combination therapy may be carried out at different frequencies.

[0373] In an embodiment, the additional API may be formulated for co - administration with a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single - dose formulation. The additional API can also be administered separately from the dosage form comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof. When the additional active agent is administered separately from the compound of formula (I) or a pharmaceutically acceptable salt thereof, it can be administered by the same or different routes of administration and / or at the same or different times.

[0374] In embodiments directed to methods of combination therapy for treating kidney diseases, disorders, and conditions, the method can include administering a compound of formula (I), or a sub - embodiment thereof as described herein, and at least one additional therapeutic agent selected from an SGLT2 inhibitor, a phosphate binder, an erythropoiesis - stimulating agent drug, a vitamin D analog drug, a vaptan - based agent, an adrenocorticosteroid - based agent, an aldosterone antagonist, an iron supplement, an opioid receptor agonist, a cholesterol - lowering drug, an antithrombotic drug, and an antihypertensive drug.

[0375] In embodiments, the present disclosure provides a method for treating kidney diseases, disorders, and conditions characterized by excessive or abnormal ALPK1 - dependent inflammatory signaling in a subject in need of such treatment, the method including administering to the subject a compound of formula I, IA, IB, IC or a sub - embodiment thereof as described herein.

[0376] In embodiments, the compound of formula I, IA, IB, IC or a sub - embodiment thereof is combined with a partial adenosine A1 receptor agonist and a mineralocorticoid receptor (MR) antagonist for the treatment and prevention of kidney diseases, particularly acute and chronic renal insufficiency and acute and chronic kidney failure, and for further renal protection. Exemplary MR antagonists include, but are not limited to, spironolactone, eplerenone, aldactone, carospir, and finerenone. Exemplary partial adenosine A1 receptor agonists include, but are not limited to, neladenosine, neladenosine viaraminate, and capadenosine.

[0377] In embodiments, the compound of formula I, IA, IB, IC, or a sub - embodiment thereof is combined with one or more diuretics. Exemplary diuretics include, but are not limited to, thiazides, thiazide - like diuretics, carbonic anhydrase inhibitors, and potassium - sparing diuretics.

[0378] In embodiments, the compounds of Formula I, IA, IB, IC or their sub - embodiments are combined with an SGLT2 inhibitor. Exemplary SGL2 inhibitors include, but are not limited to, dapagliflozin, empagliflozin, canagliflozin, ipragliflozin and tofogliflozin.

[0379] In embodiments, the compounds of Formula I, IA, IB, IC or their sub - embodiments are combined with an antithrombotic agent. Exemplary antithrombotic agents include, but are not limited to, platelet aggregation inhibitors, anticoagulants, profibrinolytic substances, lipid metabolism modifiers, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG - CoA reductase and squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma, PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, high - molecular - weight bile acid sequestrants, bile acid reabsorption inhibitors and lipoprotein(a) antagonists.

[0380] In embodiments, the compounds of Formula I, IA, IB, IC or their sub - embodiments are combined with a blood pressure - lowering agent. Exemplary blood pressure - lowering agents include, but are not limited to, angiotensin II receptor antagonists, ACE inhibitors, calcium antagonists, endothelin antagonists, renin inhibitors, alpha - receptor blockers, beta - receptor blockers, mineralocorticoid - co - receptor antagonists and diuretics. Pharmaceutical composition

[0381] In an embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I described herein or a sub - embodiment thereof and one or more carriers or excipients, preferably a pharmaceutically acceptable carrier or excipient. As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, carriers and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio. 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 sterile liquids, water, buffered saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), oils, detergents, suspending agents, carbohydrates (e.g., glucose, lactose, sucrose or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, and suitable mixtures of any of the foregoing, but are not limited thereto. The particular excipient utilized in the composition depends on various factors including the chemical stability and solubility of the compound being formulated and the intended route of administration.

[0382] The pharmaceutical composition can be provided in bulk or in unit dosage form. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the pharmaceutical composition in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit doses for the subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The unit dosage form can be an ampoule, vial, suppository, dragee, tablet, capsule, IV bag, or a single pump on an aerosol inhaler.

[0383] For therapeutic use, the dosage can vary depending on the chemical and physical properties of the active compound and the clinical characteristics of the subject, including, for example, age, weight and co-existing conditions. Generally, the dosage should be a therapeutically effective amount. An effective amount of the pharmaceutical composition is an amount that provides an objectively identifiable improvement as indicated by a clinician or other qualified observer. For example, alleviating the symptoms of a disorder, disease or condition.

[0384] The pharmaceutical compositions described herein can be in any suitable form (e.g., liquid, aerosol, solution, inhalant, mist, spray; or solid, powder, ointment, paste, cream, lotion, gel, patch, etc.) for administration by any desired route (e.g., pulmonary, inhalation, intranasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, transdermal, transmucosal, rectal, etc.). In embodiments, the pharmaceutical composition is in an orally acceptable dosage form, including, but not limited to, capsules, tablets, buccal forms, troches, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions or solutions. Capsules can contain excipients such as diluents including 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, gums, etc. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added dropwise.

[0385] In an embodiment, the pharmaceutical composition is in the form of a tablet. The tablet can contain the unit dose of the compound described herein together with an inert diluent or carrier, such as a sugar or sugar alcohol, for example lactose, sucrose, sorbitol or mannitol. The tablet can further contain a non-sugar-derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivative such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch such as corn starch. The tablet can further contain a binder and granulating agent such as polyvinylpyrrolidone, a disintegrant (e.g., a swelling cross-linked polymer such as cross-linked carboxymethylcellulose), a lubricant (e.g., stearate), a preservative (e.g., parabens), an antioxidant (e.g., butylated hydroxytoluene), a buffer (e.g., phosphate buffer or citrate buffer), and a releasing agent such as a citrate / bicarbonate mixture. The tablet can be a coated tablet. The coating can be a protective film coating (e.g., wax or varnish) or a coating designed to control the release of the active compound, such as extended release (release of the active substance after a predetermined extended time after ingestion) or release at a specific location in the gastrointestinal tract. The latter can be achieved, for example, using an enteric film coating such as those sold under the trade name Eudragit®.

[0386] Tablet formulations can 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 magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starch and powdered sugar, but not limited thereto). Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, magnesium aluminum silicate and triethanolamine.

[0387] In an embodiment, the pharmaceutical composition is in the form of hard or soft gelatin capsules. According to this formulation, the compound of the present invention can be in solid, semi-solid or liquid form.

[0388] In an embodiment, 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-synovial, intrasternal, intramedullary, intralesional and intracranial injection or infusion techniques.

[0389] In an embodiment, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for administration by direct injection or by dropping into a sterile injectable liquid for intravenous injection, and includes 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 co-solvent or a 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 alkyl phenols, polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, sorbitan fatty acid esters, ionic surfactants, fat-soluble vitamins and their salts, water-soluble vitamins and their amphiphilic derivatives, amino acids and their salts, and organic acids and their esters and anhydrides. The dispersion can also be prepared, for example, in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.

[0390] The present disclosure also provides a package and a kit including a pharmaceutical composition for use in the methods described herein. The kit can include one or more containers selected from the group consisting of bottles, vials, ampoules, blister packs, and syringes. The kit can further include instructions for use, one or more syringes, one or more applicators, or one or more of the sterile solutions suitable for reconstituting the compounds or compositions described herein.

[0391] All percentages and ratios used herein are by weight unless otherwise specified.

[0392] The present invention is further illustrated and exemplified by the following non-limiting examples. Examples

[0393] In an embodiment, the compound of Formula I, or a sub - embodiment described herein, is an inhibitor of ALPK1 as 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 inflammatory cytokines and chemokines such as IL - 8 (also called CXCL - 8).

[0394] The following examples also provide additional evidence for the use of ALPK1 as a therapeutic target for kidney diseases, small molecule ALPK1 inhibitors as described herein, and kidney diseases, disorders, and conditions including, but not limited to, chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio-renal syndrome, nephrotic syndrome, hepato-renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary and congenital kidney diseases, nephrosis, nephritis, Alport syndrome, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, toxin-induced nephrosis, contrast-induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis, and nephrotic syndrome (e.g., abnormal decrease in creatinine and / or water excretion, abnormal increase in blood concentrations of urea, nitrogen, potassium, and / or creatinine, changes in urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperlymphocytosis, and / or need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic urate nephropathy, and syndrome of inappropriate ADH secretion (SIADH)). The following examples include studies demonstrating that the ALPK1 inhibitor C008 can inhibit ALPK1 kinase activity in an in vitro kinase assay and that it can inhibit NF-κB reporter activity in HEK293 cells stimulated with the ALPK1 agonist D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP. The following examples also include ALPK1 transgenic HEK293 cells showing that ALPK1 having the SNP of rs2074380 or rs2074381 can reduce the kinase activity of ALPK1 when activated by the ALPK1 agonist D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP.The following examples also include studies on in vivo rat models of UUO-induced chronic kidney disease in which the ALPK1 inhibitor C008 showed an antifibrotic effect. The following examples also include studies on in vivo rat models of adenine diet-induced chronic kidney disease in which the ALPK1 inhibitor C008 showed a glomerular function-protecting and anti-Toxoplasma effect.

[0395] ALPK1 in vitro kinase assay

[0396] ALPK1 kinase activity was measured in an in vitro assay using ADP-heptose as an activator of ALPK1 ligand and kinase activity and TIFA protein as an ALPK1 phosphorylation substrate. Since phosphorylated TIFA protein oligomerizes, protein interaction between HA-tagged TIFA proteins was measured as an indicator of TIFA phosphorylation using Homogeneous Time-Resolved Fluorescence (HTRF).

[0397] Briefly, the dose-response test was performed 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 disodium β-glycerophosphate, 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.

[0398] For HTRF, the sample was incubated with a Tb cryptate-labeled anti-HA antibody for capturing the HA-tagged protein 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 (thereby using the signal at 620 nm as an internal standard).

[0399] In this assay, all compounds showed a dose-dependent decrease in TIFA phosphorylation. The 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 ~50 nanomolar (nM) in this assay. The IC50 values of the test compounds are in the range of 1 - 1000 nM and are shown in Tables 4 - 7. NFκB gene reporter alkaline phosphatase assay

[0400] An alkaline phosphatase reporter assay system was used to measure the inhibition of activation of the ALPK1-dependent NFκB reporter gene. Briefly, HEK293 cells (referred to herein as "G9 cells") stably expressing the NF-κB reporter were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Hyclone™) containing antibiotics (pen / strep, G418) in 384-well assay plates. For the assay, cells were seeded at a density of 10,000 cells / well in 96-well plates in Freestyle™ 293 Expression Medium (ThermoFisher) and allowed to adhere overnight. Cells were pretreated with serially diluted compounds for 30 minutes and then stimulated with D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP. This compound is an analog of ADP-heptose and shows improved stability in vitro along with a similar ability to activate ALPK1 kinase activity. Activation of the NFκB gene was detected using the chromogenic substrate p-nitrophenyl phosphate (pNPP) according to the manufacturer's protocol (pNPP Phosphatase Assay, Beyotime Biotechnology). In this assay, all compounds showed a dose-dependent decrease in NFκB promoter-driven gene expression. The IC50 values are in the range of 1 - 10 micromolar (μM) and are shown in Tables 4 - 7. SNP of ALPK1 is associated with chronic kidney disease

[0401] The rs2074380 and rs2074381 SNPs of ALPK1 are significantly associated with chronic kidney disease in diabetic patients (Yamada Y, Nishida T, Ichihara S, Kato K, Fujimaki T, Oguri M, Horibe H, Yoshida T, Watanabe S, Sato K, Aoyagi Y, Fukuda M, Sawabe M. Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese by genome-wide association study. J Med Genet. 2013 Jun;50(6):410-8. doi: 10.1136 / jmedgenet-2013-101518. Epub 2013 Mar 28. PMID: 23539754.) The rs2074380 and rs2074381 SNPs cause amino acid changes at G870S and N916D. Both SNPs were found to prevent chronic kidney disease. To examine whether the mutated amino acids affect the activity of ALPK1, wild-type ALPK1 and its mutants ALPK1-G870S and ALPK1-N916D were overexpressed in the kidney cell line HEK293 cells treated with 100 nM D-glycero-D-manno-6-fluoroheptose-1β-S-ADP, a derivative of ADP-heptose, to stimulate the activation of ALPK1. ELISA analysis of IL8 in the supernatant showed that both ALPK1-G870S and ALPK1-N916D caused a decrease in IL8 compared with wild-type ALPK1. These results indicated that the mutations G870S and N916D decreased the ALPK1 activity that activates downstream IL8 expression. (Figure 1) Therefore, a hypothesis was proposed that these changes lead to a decrease in the activity of the ALPK1 protein in chronic kidney disease and that inhibition of ALPK1 activity might be preventive in chronic kidney disease. This hypothesis was verified by administering the ALPK1 inhibitor C008 to rats with a chronic kidney disease model. Inhibition of ALPK1 in the kidney

[0402] It was investigated whether an ALPK1 inhibitor could suppress the activation of ALPK1-dependent genes in rats. The compound C008 was orally administered to the animals, and ALPK1-dependent gene expression was induced by intraperitoneal administration of an ALPK1 agonist, D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP. Kidneys were harvested and gene expression was analyzed as described in detail below.

[0403] Thirty-six male Sprague-Dawley (SD) rats were randomly divided into six groups. The first control group ("normal") was orally administered the vehicle (0.5% MC) and 21 hours later was administered PBS by intraperitoneal injection (ip). The second control group ("vehicle") was orally administered the vehicle (0.5% MC) and 21 hours later was ip administered D-glycero-D-manno-6-fluoro-heptose-1β-S-ADP (50 μpk), an ALPK1 agonist. The treatment groups were orally administered an ALPK1 inhibitor (2, 5, 10, 20 mpk) and 21 hours later were ip administered an ALPK1 agonist. Three hours after administration of the ALPK1 agonist, kidneys were harvested from each group. RNA was isolated and samples were analyzed by RT-PCR for the expression of MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β and IL-6 mRNA. Briefly, total RNA was extracted according to the protocol of the Rneasy Mini Kit (QIAGEN, Germany). Messenger RNA was reverse transcribed into cDNA using HiScript Q RT SuperMix for qPCR Kit (Vazyme, Nanjing, China). Quantitative PCR was performed on a QuantStudio 5 Applied Biosystems (Thermo scientific, USA) using the AceQ qPCR SYBR Green Master Mix Kit (Vazyme, Nanjing, China). Relative mRNA levels were calculated using the 2-ΔΔCT method and HPRT was used as a reference for gene expression normalization. Data were presented as the fold change in gene expression relative to each expression in the control group. As shown in Figure 2, the C008-treated group showed a significant decrease in the mRNA expression of CCL-2, CCL-7, CXCL-1, CXCL-10, IL-1β and IL-6 compared to the vehicle group. Inhibition of ALPK1 in the unilateral ureteral obstruction (UUO) model

[0404] Renal fibrosis is a common pathway for most forms of progressive kidney disease. The unilateral ureteral obstruction (UUO) model is widely used in the study of renal fibrosis. Furthermore, experimental UUO in rodents is thought to accelerate the mimicry of human chronic obstructive nephropathy. (Martinez-Klimova E, Aparicio-Trejo OE, Tapia E, Pedraza-Chaverri J. Unilateral ureteral obstruction as a model for investigating antifibrotic therapies. Biomolecules. 2019 Apr 8;9(4):141. doi: 10.3390 / biom9040141. PMID: 30965656; PMCID: PMC6523883.) Here, the effects of the ALPK1 inhibitor C008 (2, 7, 20 mg / kg) were verified in a rat UUO model. Briefly, the left ureter of rats was ligated, and oral treatment was initiated daily for 7 days immediately after surgery. Renal fibrosis was measured by hydroxyproline content measurement and Sirius red staining. Due to the high amount of renal inflammation, the hydroxyproline (OH-P) content indexed to total protein was used to interpret UUO-induced fibrosis and the effectiveness of the compound (Figure 3A). To be complete, the OH-P content indexed to tissue mass was also analyzed (Figure 3B). UUO increased renal cortical OH-P compared to sham-operated controls. ALK5i and C008 (7 mpk and 20 mpk) attenuated the increase in renal cortical OH-P by UUO. Sirius red staining composite data represent the average of three anatomically different depths (10 images / depth / rat / group = ~60 - 65% of the renal cortex area). Renal cortical fibrosis, represented by the collagen volume fraction (CVF, by quantification of Sirius red-stained tissue sections), increased in UUO-obstructed kidneys treated with vehicle compared to sham-operated controls. ALK5i and C008 (7 mpk & 20 mpk) attenuated the increase in renal cortical CVF by UUO (Figures 4A, 4B). These results suggest that C008 can dose-dependently suppress UUO-induced renal fibrosis. Also, when the gene expression of the kidney was examined in another study with different doses of C008 (5, 10, 20 mg / kg), it was found that C008 inhibits genes involved in fibrosis and inflammation (Figure 5). Inhibition of ALPK1 in the adenine diet induces chronic kidney disease

[0405] The 0.25% adenine diet induces pathophysiological changes that mimic the structural and functional changes of human chronic kidney disease (CKD), characterized by renal dysfunction, inflammation, fibrosis, and increased oxidative markers, tubulointerstitial fibrosis, tubular epithelial apoptosis, and increased podocyte injury. (Diwan V, Brown L, Gobe GC. Adenine-induced chronic kidney disease in rats. Nephrology (Carlton). 2018 Jan;23(1):5-11. doi: 10.1111 / nep.13180. PMID: 29030945.) The effects of the ALPK1 inhibitor C008 (7, 20 mg / kg) were verified in an adenine diet-induced rat CKD model. Combination administration was initiated for 6 weeks starting on the 14th day after the start of the adenine diet. During the study, plasma was collected and the levels of blood urea nitrogen (BUN) (Figure 6A) and creatinine (Figure 6B) were measured weekly. Adenine intake increased plasma BUN and creatinine on days 7 - 56 compared to the control. ALK5i attenuated the adenine-induced increase in plasma BUN and creatinine on days 35 - 56. C008 attenuated the adenine-induced increase in plasma BUN on days 42 (20mpk), 49 (7&20mpk), 56 (20mpk) and plasma creatinine on days 35 (20mpk), 49&56 (7&20mpk). At the end of the study, the kidneys of the rats were collected and renal fibrosis was quantified by measuring the hydroxyproline content. The results showed that adenine intake increased the OH-P content in the renal cortex indexed to tissue volume compared to the control. ALK5i attenuated the adenine-induced increase in the OH-P content in the renal cortex indexed to tissue volume. C008 (7mpk) attenuated the adenine-induced increase in OH-P in the renal cortex indexed to tissue volume. (Figure 7) Sirius red staining composite data represents the average of three anatomically different depths (10 images / depth / rat / group = ~60 - 65% of the renal cortex area). Adenine intake increased renal cortex fibrosis expressed as the collagen volume fraction (CVF, by quantification of PSR-stained tissue sections) compared to non-diseased controls. ALK5i attenuated the adenine-induced increase in renal cortex CVF. C008 (7 and 20 mpk) attenuated the increase in renal cortex CVF by adenine (Figures 8A, 8B).These results indicate that C008 can significantly inhibit adenine diet-induced renal dysfunction and renal fibrosis. Inhibition of ALPK1 in the MRL / MpJ-Faslpr / J mouse lupus nephritis model

[0406] The MRL / MpJ-Faslpr / J mouse model is similar to human systemic lupus erythematosus. Also, this mouse model develops renal impairment and is useful for examining the efficacy of therapeutic agents for lupus nephritis. To evaluate the efficacy of the ALPK1 inhibitor C008 against the treatment of lupus nephritis, from 12 weeks of age, 12 vehicle-treated non-diseased control mice ("MRL / MpJ") and 12 vehicle-treated diseased control mice ("MRL / MpJ-Faslpr / J, vehicle") were orally administered daily with the vehicle (0.1% MC), and 36 MRL / MpJ-Faslpr / J mice (12 mice / group) were orally administered C008 at 3 mg / kg or 10 mg / kg / day. In another group, 50 mg / kg of cyclophosphamide was injected intraperitoneally once a week. After 8 weeks of treatment, the animals were sacrificed and urine was collected for proteinuria evaluation using urine protein test strips (Figure 9). The right kidney was collected and stained with hematoxylin and eosin (H&E) for pathological evaluation (Figure 10A-G). Furthermore, the mRNA expression levels of Ccl2, Ccl4, Ccl5, Ccr1, and IL-6 in the left kidney were quantified using qPCR (Figure 11).

[0407] In summary, compared with the vehicle disease group, 10 mg / kg of C008 showed a significant decrease in the proteinuria score. In renal pathology, mice treated with 10 mg / kg C008 showed significantly lower pathological scores in glomerular diameter, crescents, interstitial inflammation, protein casts, and the lupus nephritis activity index. Regarding gene expression, in the C008-administered group, the mRNA expression of Ccl2, Ccl4, Ccl5, Ccr1, and IL-6 was significantly decreased compared with the vehicle group. These results indicate that C008 can improve renal function and attenuate disease-induced morphological changes in the lupus nephritis disease model. HotSpot kinase profiling

[0408] This assay is32 It is based on the transfer of P-labeled phosphate from ATP to a kinase substrate. The ALPK1 kinase activity can be measured by detecting the remaining radioactive phosphorylated substrate TIFA. Briefly, the substrate TIFA was prepared in freshly prepared reaction buffer (buffer conditions: 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO). The necessary cofactors were delivered to the above substrate solution. Kinase ALPK1 was delivered to the substrate solution and gently mixed. C008 in DMSO was added to the kinase reaction mixture using acoustic technology (Echo550). 33P-ATP (specific activity 0.01 μCi / μl final) was delivered to the reaction mixture to initiate the reaction. The kinase reaction was incubated at room temperature for 60 minutes. The reaction was spotted on P81 ion exchange paper (Whatman #3698-915). The filter was extensively washed with 0.75% phosphoric acid, and the radioactive phosphorylated substrate remaining on the filter paper was measured. Data analysis: The kinase activity data was expressed as the residual rate of kinase activity in the test samples compared to the vehicle (dimethyl sulfoxide) reaction. The IC50 value and curve fitting were obtained using Prism4 software (GraphPad).

[0409] Equivalents

[0410] One of ordinary skill in the art will recognize or be able to ascertain, using only routine experimentation, many equivalents to the specific embodiments of the invention as described herein. Such equivalents are intended to be encompassed by the following claims.

[0411] All references cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0412] The scope of the present invention is not limited by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become 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. A method for treating kidney diseases, disorders, and conditions in a subject in need of treatment, comprising: administering to the subject a compound of Formula I 【Chemical 1】 Formula I or a pharmaceutically acceptable salt thereof, wherein in the formula, A is selected from bonding, azetidinyl, -O-, -N(R ６ ), -CH ２ -N(R ６ ), -CHR ９ -N(R ６ ), where 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, wherein R which may be replaced ６ The moieties are selected independently from 0 to 3 substituents including -D, halo, -OH, -COOH, -NH ２ , =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 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 which may be replaced ９ The moiety is halo, -OH, -COOH, -NH ２ , =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, -CHR ７ｆ R ８ｆ , -OR ７ｆ , -OC(O)(R ７ｆ ), -C(O)(R ７ｆ ), -C(O)N(R ７ｆ R ８ｆ ), -C(O)O(R ７ｆ ), -S(O) ２ (R ７ｆ ), -S(O)ON(R ７ｆ R ８ｆ ), and -N(R ７ｆ R ８ｆ ), and contains 0 to 2 substituents independently selected from, where Each R ７ｆ and R ８ｆ 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, R １ is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 hydroxyalkyl, 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, 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S; optionally substituted saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; optionally substituted saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; and optionally substituted saturated or unsaturated 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, R which may be replaced １ The moiety is halo, -OH, -COOH, -NH ２ =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 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 -NR ７ａ (CO)R ８ａ -C(O)O(R ７ａ )-S(O) ２ R ７ａ -S(O) ２ N(R ７ａ R ８ａ -N(R ７ａ R ８ａ ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, monocyclic or bicyclic aryl, 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, and 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, and contains 0-4 substituents independently selected from Each X １ is independently C1-6 alkylene, Each R ７ａ and R ８ａ are independently 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, a saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, and the aryl and the 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH ２ , -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 The C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3- to 7-membered heterocyclyl, the monocyclic or bicyclic aryl, the 5- to 10-membered heteroaryl, the saturated or unsaturated 7- to 8-membered bridged heterocyclyl, the saturated or unsaturated 7- to 11-membered spiroheterocyclyl, and the 6- to 11-membered bicyclic heterocyclyl are each independently halo, -OH, -COOH, -NH ２ , =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, a saturated or unsaturated 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, -CHR ７ｂ R ８ｂ , -OR ７ｂ , -OC(O)(R ７ｂ ), -C(O)(R ７ｂ ), -C(O)N(R ７ｂ R ８ｂ ), -NR ７ｂ (CO)R ８ｂ , -C(O)O(R ７ｂ ), -S(O) ２ N(R ７ｂ R ８ｂ ), and -N(R ７ｂ R ８ｂ ), and are substituted with 0 to 3 moieties selected from Each R ７ｂ and R ８ｂ are each 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 are combined to form a 3- to 6-membered heterocycloalkyl substituted with 0 to 3 moieties independently selected from the group consisting of halo, -OH, -COOH, -NH ２ , =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl R ５ is selected from H, deuterium, halo, C1-C6 alkyl, C1-C6 deuterated alkyl, and C1-C6 haloalkyl, R ２ and R ３ are each independently selected from H, OH, C1-C6 alkyl, C2-C6 alkynyl, where C1-C6 alkyl, C2-C6 alkynyl, each, 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) ２ N(R ７ｃ R ８ｃ ), and N(R ７ｃ R ８ｃ ) and are independently selected from 0 to 3 moieties selected therefrom, Each R ７ｃ and R ８ｃ 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, However, R ２ and R ３ are both not H, or R ２ and R ３ combine to form a C3-C6 cycloalkyl ring or 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices independently selected from N, O and S, and 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) ２ N(R ７ｄ R ８ｄ ), and N(R ７ｄ R ８ｄ ), and may be substituted with 1-2 substituents independently selected from Each R ７ｄ and R ８ｄ 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, Each R ４ is halo, -OH, -NH ２ , 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 ７ｅ R 8ｅ , OR ７ｅ , OC(O)(R ７ｅ ), C(O)(R ７ｅ ), C(O)N(R ７ｅ R 8ｅ ), C(O)O(R ７ｅ ), S(O)2N(R ７ｅ R 8ｅ ) and N(R ７ｅ R 8ｅ ) and is independently selected from, where Each R ７ｅ and R 8ｅ 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, a compound of Formula I, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein A is a bond.

3. The method of claim 1, wherein A is azetidinyl.

4. The method of claim 1, wherein A is -O-.

5. where A is -N(R 6 ), the method according to claim 1.

6. A is -CH ２ -N(R 6 )-, the method according to claim 1.

7. A is -CHR 9 -N(R 6 )-, the method according to claim 1.

8. The method of claim 1, comprising a compound of Formula IA 【Chemical 2】 Formula IA or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, comprising a compound of Formula IA-1 【Chemical Formula 3】 Formula IA-1 or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, comprising a compound of Formula IA-2 【Chemical 4】 Formula IA-2 or a pharmaceutically acceptable salt thereof.

11. R 6 The method according to any one of claims 1 to 10, wherein R is selected from H, C1-C6 alkyl, C1-C6 hydroxyalkyl, and C1-C6 hydroxydeuterated alkyl.

12. R 9 is CH ３ and CH ２ OH, the method according to any one of claims 1 to 8.

13. R ９ The method according to any one of claims 1 to 8, wherein R is a saturated C3-C6 cycloalkyl.

14. R １ is selected from H and optionally substituted C1-C6 alkyl, The C1-C6 alkyl which may be substituted is halo, -OH, -COOH, -NH ２ , =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) ２ R ７ａ , -S(O) ２ N(R ７ａ R ８ａ ) and -N(R ７ａ R ８ａ ), and contains 0 to 4 substituents independently selected from the group consisting of, each R ７ａ and R ８ａ is 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, the method according to any one of claims 1 to 13.

15. R １ is a saturated or unsaturated C3-C6 cycloalkyl which may be substituted, and the optionally substituted C3-C6 cycloalkyl is halo, -OH, -COOH, -NH ２ , =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, and a method according to any one of claims 1 to 13, comprising 0 to 4 substituents independently selected from C1-C6 haloalkoxyl.

16. R １ is combined with R ６ to form a 3- to 6-membered heterocycloalkyl substituted with 0 to 3 moieties independently selected from the group consisting of halo, -OH, -COOH, NH ２ , =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl, the method according to any one of claims 1 to 13.

17. R １ is C1-C6 alkyl substituted with 0 to 4 substituents independently selected from -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, -OC(O)(R ７ａ ), -S(O) ２ N(R ７ａ R ８ａ ), and -N(R ７ａ R ８ａ ); Each R ７ａ and R ８ａ 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, the method according to any one of claims 1 to 13.

18. R １ is C1-C6 alkyl substituted with 0 to 2 substituents independently selected from -OH, C1-C6 hydroxyalkyl, and -S(O) ２ N(R ７ａ R ８ａ ), and Each R ７ａ and R ８ａ is independently selected from H and C1-C6 alkyl, the method according to any one of claims 1 to 13.

19. R １ The method according to any one of claims 1 to 13, wherein R is a C1-C6 hydroxyalkyl which may be substituted.

20. R １ is a 5- to 10-membered heteroaryl containing 1 to 4 heteroatomic ring vertices selected from N, O, and S, The 5- to 10-membered bicyclic heteroaryl is halo, -OH, -COOH, -NH ２ , -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, N, O, and S, a 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected therefrom, 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) ２ N(R ７ｂ R ８ｂ ), and -N(R ７ｂ R ８ｂ ), and is substituted with 0 to 3 moieties selected therefrom, where each R ７ｂ and R ８ｂ 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, the method according to any one of claims 1 to 13.

21. R １ is pyridyle substituted with 0 to 3 moieties selected from a halo, -OH, -COOH, -NH ２ , -CN, C1-C6 alkyl, C1-C6 alkenyl, and 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S The 3- to 7-membered heterocyclyl is substituted with 0 to 3 substituents selected from halo, -OH, -COOH, -NH ２ , -CN, C1-C6 alkyl, C1-C6 alkenyl, and C1-C6 haloalkyl. The method according to any one of claims 1 to 13.

22. R １ is a saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, The 7- to 8-membered bridged heterocyclyl is halo, -OH, -COOH, -NH ２ , =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) ２ N(R ７ｂ R ８ｂ ) and -N(R ７ｂ R ８ｂ ) and is substituted with 0 to 3 moieties selected from, where Each R ７ｂ and R ８ｂ 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, the method according to any one of claims 1 to 13.

23. R １ is a saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, The 7- to 11-membered spiroheterocyclyl is halo, -OH, -COOH, -NH ２ , =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 ) and is substituted with 0 to 3 moieties selected from, where Each R ７ｂ and R ８ｂ 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, the method according to any one of claims 1 to 13.

24. R １ is aryl substituted with 0 to 3 substituents selected from 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from halo, N, O, and S; 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S; and saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, The 3- to 7-membered heterocyclyl, the 7- to 8-membered bridged heterocyclyl, and the 7- to 11-membered spiroheterocyclyl are each substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH ２ , =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) ２ R ７ｂ , -S(O) ２ N(R ７ｂ R ８ｂ ), and -N(R ７ｂ R ８ｂ ), provided that Each R ７ｂ and R ８ｂ 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, the method according to any one of claims 1 to 13.

25. R １ is aryl substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH ２ , =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, and 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S The 3- to 7-membered heterocyclyl is halo, -OH, -COOH, -NH ２ , =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) ２ N(R ７ｂ R ８ｂ ) and -N(R ７ｂ R ８ｂ ) and is substituted with 0 to 3 moieties selected from the group consisting of, where Each R ７ｂ and R ８ｂ 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, the method according to any one of claims 1 to 13.

26. R １ is aryl substituted with 0 to 3 moieties selected from 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from halo and N, O, and S, The 3- to 7-membered heterocyclyl is further substituted with 0 to 3 moieties selected from -OH, -COOH, -NH ２ , =O, -CN, and -C1-C6 alkyl. The method according to any one of claims 1 to 13.

27. The method of claim 1, comprising a compound of Formula IB 【Chemical Formula 5】 Formula IB or a pharmaceutically acceptable salt thereof, wherein D is CR10 or N, E is CR14 or N, F is CR12 or N, G is CR11 or N, provided that no more than three of D, E, F, and G are N. R １０ 、R １１ 、R １２ 、R １３ and R １４ are, when present, each independently H, halo, -OH, -COOH, -NH ２ 2, =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 -O-X １ -R ７ａ , -CHR ７ａ R ８ａ , -OR ７ａ , -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 ), -C(O)O(R ７ａ ), S(O) ２ R ７ａ , -S(O) ２ N(R ７ａ R ８ａ ), -N(R ７ａ R ８ａ ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S; saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; and saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, where Each X １ is independently C1-6 alkylene, Each R ７ａ and R ８ａ 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, The 3- to 7-membered heterocyclyl, the monocyclic or bicyclic aryl, the 9- to 10-membered bicyclic heteroaryl, the 7- to 8-membered bridged heterocyclyl, the 7- to 11-membered spiroheterocyclyl, and the 6- to 11-membered bicyclic heterocyclyl 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) ２ N(R ７ｇ R ８ｇ ) and -N(R ７ｇ R ８ｇ ) and are each independently substituted with 0 to 2 moieties selected from the group consisting of, where Each R ７ｇ and R ８ｇ is each 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, the method according to claim 1.

28. D, E, F, and G are each CR １０ , CR １４ , CR １２ , and CR １１ as described in claim 27, the method according to claim 27.

29. F and G are each CR １４ and CR １１ where E is N or CR １４ where D is N or CR １０ The method according to claim 27, wherein.

30. R １０ and R １１ are each H, R １２ and R １４ are each independently halo, -OH, -COOH, -NH ２ , =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 ) are selected from, where Each R ７ｂ and R ８ｂ 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, R １３ is selected from 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, and saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, wherein, The 3- to 7-membered heterocyclyl, the 7- to 8-membered bridged heterocyclyl, and the 7- to 11-membered spiroheterocyclyl are each independently selected from halo, -OH, -COOH, -NH ２ , =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, and may be substituted with 0 to 2 moieties independently selected therefrom. The method according to any one of claims 27 to 29.

31. R １２ and R １４ is H, R １０ and R １１ are each independently halo, -OH, -COOH, -NH ２ , =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) ２ N(R ７ｂ R ８ｂ ), and -N(R ７ｂ R ８ｂ ), and are selected from, where Each R ７ｂ and R ８ｂ 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, R １３ is selected from 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, and saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, wherein, The method according to any one of claims 27 to 29, wherein the 3- to 7-membered heterocyclyl, the 7- to 8-membered bridged heterocyclyl, and the 7- to 11-membered spiroheterocyclyl are optionally 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.

32. R １０ 、 R １１ 、 R １２ and R １４ are, if present, each H, R １３ is selected from saturated or unsaturated C3-C6 cycloalkyl, 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7- to 11-membered spiroheterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, where The 3- to 7-membered heterocyclyl, 7- to 8-membered bridged heterocyclyl, and 7- to 11-membered spiroheterocyclyl are each independently selected from halo, -OH, -COOH, -NH ２ , =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, and may be substituted with 0 to 2 moieties independently selected therefrom, the method according to any one of claims 27 to 29.

33. R １０ 、R １１ 、R １２ and R １４ are, when present, each H, R １３ is a 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S, which is substituted with 0 to 2 moieties independently selected from halo, -OH, -COOH, -NH ２ , =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, the method according to any one of claims 27 to 29.

34. R １０ 、R １１ 、R １２ and R １４ are, if present, each H, R １３ is a substituted or unsubstituted saturated or unsaturated 7- to 8-membered bridged heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O, and S substituted with 0 to 2 substituents selected from -OH, -COOH, -NH ２ , =O, -CN, and -C1-C6 alkyl, the method according to any one of claims 27 to 29.

35. The method of claim 1, comprising a compound of Formula IB-1 or IB-2 [Chemical Formula 6] Formula IB-1 【Chemical Formula 7】 Formula IB-2 or a pharmaceutically acceptable salt thereof, wherein R １５ is selected from -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) ２ R ７ｂ and -S(O)2N(R ７ｂ R ８ｂ ), where Each R ７ｂ and R ８ｂ is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, 1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl and saturated or unsaturated C3-C6 cycloalkoxyl, the method according to claim 27.

36. R １６ and R １７ The method according to claim 35, wherein each of them is independently selected from halo and C1-C6 alkyl.

37. R １５ is 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 is selected from, where Each R ７ｂ and R ８ｂ 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, the method according to claim 35 or 36.

38. R １５ The compound according to claim 35 or 36, wherein R is selected from C1-C6 alkyl.

39. A compound of formula IB-1-a or formula IB-2-a, 【Chemical 8】 Formula IB-1-a 【Chemical Formula 9】 Formula IB-2-a or a pharmaceutically acceptable salt thereof, the method according to any one of claims 35 to 38.

40. A compound of formula IB-1-b or formula IB-2-b, 【Chemical Formula 10】 (IB-1-b) 【Chemical Formula 11】 (IB-2-b) or a pharmaceutically acceptable salt thereof, wherein R ４ is halo, the method according to any one of claims 35 to 38.

41. A compound of formula IB-1-c or formula IB-2-c, 【Chemical 12】 (IB-1-c) 【Chemical 13】 (IB-2-c) or a pharmaceutically acceptable salt thereof, the method according to any one of claims 35 to 38.

42. A compound of formula IC, 【Chemical Formula 14】 Formula IC or a pharmaceutically acceptable salt thereof, m is an integer from 0 to 6, R １８ is H, halo, -OH, -COOH, -NH ２ , -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)(R7a), -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 ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, and 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, and is selected from Each X １ is independently C1-6 alkylene, Each R ７ａ and R ８ａ is independently 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, a saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom vertices selected from N, O and S, and the aryl and the 3-7 membered heterocyclyl 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, The C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3- to 7-membered heterocyclyl, the monocyclic or bicyclic aryl, the 9- to 10-membered bicyclic heteroaryl, the saturated or unsaturated 7- to 8-membered bridged heterocyclyl, the saturated or unsaturated 7- to 11-membered spiroheterocyclyl, and the 6- to 11-membered bicyclic heterocyclyl are each independently halo, -OH, -COOH, -NH ２ =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, a saturated or unsaturated 3- to 7-membered heterocyclyl containing 1 to 2 heteroatom ring vertices selected from N, O and S, -CHR ７ｂ R ８ｂ -OR ７ｂ -OC(O)(R ７ｂ ), -C(O)(R ７ｂ ), -C(O)N(R ７ｂ R ８ｂ ), -NR ７ｂ (CO)R ８ｂ -C(O)O(R ７ｂ ), -S(O) ２ N(R ７ｂ R ８ｂ ) and -N(R ７ｂ R8b) and are each 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, and are substituted with 0 to 3 moieties selected therefrom, wherein each R ７ｂ and R8b is, independently, 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, according to the method of claim 1.

43. The method according to claim 42, wherein m is 1.

44. R １８ The method according to claim 42 or 43, wherein R is H.

45. R ２ and R ３ The method according to any one of claims 1 to 44, wherein both are C1-C6 alkyl.

46. R ２ and R ３ The method according to any one of claims 1 to 44, wherein both are methyl.

47. R ２ is methyl, and R ３ is ethynyl, the method according to any one of claims 1 to 44.

48. R ２ is methyl and R ３ is CH ２ OMe, the method according to any one of claims 1 to 44.

49. The subscript p is 1, and R ４ is bonded to the phenyl ring as shown below, the method according to any one of claims 1 to 38 or 42 to 48: 【Chemical Formula 15】 (wherein the wavy line represents the point of attachment to the rest of the formula).

50. The subscript p is 1, and R ４ is halo bonded to the phenyl ring as shown below, the method according to any one of claims 1 to 38 or 42 to 48: 【Chemical 16】 (wherein the wavy line represents the point of attachment to the rest of the formula).

51. The subscript p is 1, and R ４ is chloro bonded to the phenyl ring as shown below, the method according to any one of claims 1 to 38 or 42 to 48: 【Chemical 17】 (wherein the wavy line represents the point of attachment to the rest of the formula).

52. The subscript p is 1, and R ４ is methoxy bonded to the phenyl ring as shown below, the method according to any one of claims 1 to 38 or 42 to 48: 【Chemical Formula 18】 (wherein the wavy line represents the point of attachment to the rest of the formula).

53. R ５ The method according to any one of claims 1 to 52, wherein R is H or methyl.

54. R ５ The method according to any one of claims 1 to 52, wherein R is H.

55. R ５ The method according to any one of claims 1 to 52, wherein R is deuterium.

56. R ５ The method according to any one of claims 1 to 52, wherein R is a C1-C6 deuterated alkyl.

57. R ５ is selected from the group consisting of -CH ２ D, -CHD ２ and -CD ３ The method according to any one of claims 1 to 52.

58. R ２ and R ３ The method according to any one of claims 1 to 57, wherein the carbon atom bonded to is the S isomer.

59. R ２ and R ３ The method according to any one of claims 1 to 57, wherein the carbon atom bonded to

60. The compound of formula I is 【Chemical 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 【Chemical 29】 【Chemical 30】 【Chemical Formula 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical Formula 36】 【Chemical 37】 【Chemical Formula 38】 selected from, the method according to claim 1.

61. The compound of formula I is 【Chemical 39】 【Chemical Formula 40】 【Chemical Formula 41】 【Chemical 42】 【Chemical Formula 43】 【Chemical 44】 【Chemical 45】 【Chemical 46】 【Chemical 47】 【Chemical Formula 48】 【Chemical 49】 【Chemical Formula 50】 【Chemical Formula 51】 【Chemical 52】 【Chemical Formula 53】 【Chemical 54】 【Chemical 55】 【Chemical Formula 56】 selected from, the method according to claim 1.

62. The method according to claim 1, selected from the tables or examples disclosed herein.

63. The subject in need of treatment is a subject having one or more genetic mutations of ALPK1, the method according to any one of claims 1 to 62.

64. The subject in need of treatment is a subject diagnosed with a kidney disease, disorder, or condition, the method according to any one of claims 1 to 63.

65. The method according to any one of claims 1 to 64, wherein the kidney disease, disorder, or condition is characterized by excessive or abnormal ALPK1-dependent inflammatory signaling.

66. The method according to claim 65, wherein the kidney disease, disorder, or condition is chronic kidney disease (CKD), inflammatory kidney disease, non-inflammatory kidney disease, or renal insufficiency.

67. The kidney diseases, disorders, and conditions are one or more of lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive kidney disease, cardio-renal syndrome, nephrotic syndrome, hepato-renal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephrosis, nephritis, Alport syndrome, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, nephrosis induced by toxic substances, contrast agent-induced nephropathy, minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cyst, hypertensive nephrosclerosis and nephrotic syndrome, uremia, anemia, electrolyte disorder, hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic urate nephropathy, and syndrome of inappropriate ADH secretion (SIADH), the method according to claim 66, characterized in that.

68. The method according to any one of claims 1 to 67, characterized in that it comprises administering the compound in combination with one or more drugs to a subject.

69. The method according to claim 68, characterized in that the one or more drugs are selected from the group consisting of partial adenosine A1 receptor agonists, mineralocorticoid receptor (MR) antagonists, diuretics, SGLT2 inhibitors, antithrombotic agents, antihypertensive agents, and any combination thereof.

70. The method according to claim 69, characterized in that the MR antagonist comprises spironolactone, eplerenone, aldactone, carospir, and finerenone.

71. The method according to claim 69, characterized in that the partial adenosine A1 receptor agonist comprises neladenosine, neladenosine via alanine, and capadenosine.

72. The method according to claim 69, characterized in that the diuretic comprises thiazide, thiazide-like diuretics, carbonic anhydrase inhibitors, and potassium-sparing diuretics.

73. The method according to claim 69, characterized in that the SGL2 inhibitor comprises dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, and tofogliflozin.

74. The method according to claim 69, wherein the antithrombotic agent comprises a platelet aggregation inhibitor, an anticoagulant, a profibrinolytic substance, a fat metabolism modifier, a thyroid receptor agonist, a cholesterol synthesis inhibitor, an ACAT inhibitor, a CETP inhibitor, an MTP inhibitor, a PPARα, a PPARγ, a PPARΔ agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a high molecular weight bile acid adsorbent, a bile acid reabsorption inhibitor, and a lipoprotein(a) antagonist.

75. The method according to claim 69, wherein the hypotensive agent comprises an ACE inhibitor, an angiotensin II receptor blocker, a calcium channel blocker, a diuretic, a β blocker, an endothelin antagonist, a renin inhibitor, an α receptor blocker, and a mineralocorticoid co-receptor antagonist.

76. The method according to any one of claims 68 to 75, wherein the compound and the one or more drugs are administered separately.

77. The method according to any one of claims 68 to 75, wherein the compound and the one or more drugs are administered together.

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