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

Abstract

Kidney diseases, disorders and conditions in subjects in need of such treatments are treated using compounds of Formula I and related compositions, wherein a subject in need of such treatments is a subject carrying one or more gene mutations in ALPK1.

Description

Technical Field

[0001] The present invention relates to methods of inhibiting ALPK1 kinase activity using compounds of Formula 1, and related compositions and methods for treating 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), and transient receptor potential cation channels M6 and M (7TRPM6 and TRPM7). See Ryazanov et al., Curr Biol 9: R43 to 45 (1999) and Ryazanov et al., Proc Natl Acad Sci USA 94: 4884 to 4889 (1997).

[0003] ALPK1 is an intracytoplasmic serine-threonine protein kinase that plays an important role in activating the innate immune response to bacteria via TRAF-interacting protein and forkhead-associated domain (TIFA)-dependent proinflammatory nuclear factor-κ-B (NFkB) signaling. See Zimmermann et al. Cell Rep. 20:2384-2395 (2017); Milivojevic et al., PLoS Pathog. 13:E1006224 to E1006224 (2017); and Zhou et al., Nature 561:122 to 126 (2018). TIFA can also be activated by oxidative and inflammatory stress in vascular endothelial cells, leading to activation of the nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome; see Lin et al., Proc Natl Acad Sci USA 113:15078-15083 (2016).

[0004] Inappropriate activation of ALPK1 signaling has been implicated in diseases and conditions associated with excessive or inappropriate inflammation. For example, ALPK1 has been implicated in monosodium uric acid monohydrate (MSU)-induced inflammation and gout. Lee et al., Sci. Rep. 6:25740-25740 (2016). In oral squamous cell carcinoma, elevated ALPK1 expression is also associated with lymph node metastasis and tumor growth. Chen et al., Am J Pathol 189:190-199 (2019).

[0005] rs2074380 and rs2074381 SNPs of ALPK1 are associated with chronic kidney disease in patients with diabetes. rs2074380 and rs2074381 SNPs result in amino acid changes of G870S and N916D. Changes of G870S and N916D have been found to play a role in chronic kidney disease; see Yamada Y et al., J Med Genet. 2013; 50(6):410-8(2013). It is hypothesized that changes of G870S and N916D result in decreased ALPK1 activity during the progression of chronic kidney disease, and ALPK1 inhibitors may be used to treat patients with chronic kidney disease. Summary of the invention

[0006] The present disclosure provides methods for treating diseases, disorders or conditions characterized by excessive or inappropriate alpk1-dependent proinflammatory signaling. In particular, the present disclosure provides methods for treating kidney diseases, disorders and conditions in subjects in need of such treatment, by administering to the subject a compound of formula 1 described herein and a fruiting body of formula 1 and a pharmaceutically acceptable salt thereof. In embodiments, the relevant diseases, disorders and conditions include chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, analytical hypotension, obstructive uropathy, glomerular disease, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary and congenital renal disease, nephritis, Alport syndrome, renal inflammation, immune nephropathy, renal transplant rejection, immune complex-induced renal disease, toxic substance-induced renal disease, contrast agent-induced renal disease, etc.; minor changes in renal Glomerulonephritis (lipidic), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (diagnosed by features such as abnormally low creatinine and / or water excretion, abnormally high blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD), chronic uric acid nephropathy and syndrome of insufficient ADH secretion (SIADH).

[0007] In an embodiment, the compound of Formula I is

[0008]

[0009] Among them, A, p, R 1 , R 2 , R 3, R 4 and R 5 As defined herein.

[0010] In some embodiments, the compound of Formula I is represented by Formula IA

[0011]

[0012] Where p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 As defined herein.

[0013] In some embodiments, the compound of Formula I is represented by Formula IA-1

[0014]

[0015] Where p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 As defined herein.

[0016] In some embodiments, the compound of Formula I is represented by Formula IB

[0017]

[0018] Where p, R 2 , R 3 , R 4 , R 5 , R 13 , D, E, F and G are as defined herein.

[0019] In some embodiments, the compound of Formula I is represented by Formula IB-1

[0020]

[0021] Where p, R 2 , R 3 , R 4 , R 5 , R 15 , R 16 and R 17 As defined herein.

[0022] In some embodiments, the compound of Formula I is represented by Formula IC

[0023]

[0024] Among them, p, m, R 2 , R 3 , R 4 , R 5 , R 18 As defined herein.

[0025] In embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula I, IA, IB or IC, or subembodiments thereof as described herein, for use in methods of treating kidney diseases, disorders and conditions.

[0026] In embodiments, the disclosure provides methods for inhibiting ALPK1 kinase activity in cells or tissues of a subject in need of such therapy, the method comprising administering to the subject a compound of Formula I, IA, IB or IC, or subembodiments thereof as described herein.

[0027] In an embodiment, the present invention provides a method of inhibiting or reducing diseases, disorders and conditions of a target tissue in need of treatment of kidney disease, comprising administering to a subject a compound of Formula I, IA, IB, IC or a sub-embodiment thereof as described herein.

[0028] In an embodiment, the present disclosure provides a method for treating kidney diseases, disorders and conditions characterized by excessive or inappropriate alpk1-dependent pro-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 as described herein, or subembodiments thereof as described herein.

[0029] In an embodiment, the compound of formula I, IA, IB, IC or its subembodiments are used in combination with partial adenosine A1 receptor agonists and MR antagonists for the treatment and prevention of renal diseases, in particular acute and chronic renal insufficiency and acute and chronic renal failure, and for further renal protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 showed that stimulation of cells encoding human ALPK1 with d-glycerol-d-mannose-6-fluoro-heptose-1β-s-adp reduced IL-8 production in HEK293 cells. HEK293 cells were transfected with plasmids encoding human ALPK1, ALPK1 mutated to G870S, or ALPK1 mutated to N916D. After 16 hours, the cells were replicated on multiwell plates and 15.8 or 50 nM d-glycerol-d-mannose-6-fluoroheptose-1β-s-adp was added to the culture medium. The supernatant was collected 3 hours later and IL-8 levels were measured by ELISA.

[0031] Figure 2It is a bar graph showing the results of treatment with vehicle only group (control), vehicle and ALPK1 agonist (vehicle), d-glycero-d-glycol-6-fluoro-glucose-1β-1β-s-adp (vehicle), or ALPK1 agonist and ALPK1 inhibitor C008 (at concentrations of 2 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg, respectively) in SD rats. The mRNA expression of genes involved in innate immunity: CCL-2, CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6 increased in the vehicle and ALPK1 agonist (vehicle) groups, and the mRNA expression of these observed genes decreased after treatment with inhibitor C008. Analysis of variance after Dunnett's test ***P<0.001 compared with the vehicle group. Abbreviation: ANOVA, analysis of variance.

[0032] Figure 3A is a bar graph showing the relationship between renal cortical hydroxyproline (OH-P) levels and renal total protein levels, as measured by BCA. Figure 3B It is a bar graph showing the relationship between renal cortical hydroxyproline (OH-P) level and renal tissue mass. Compared with the sham group *P<0.05, compared with the UUO group Analysis of variance plus Dunnett's test.

[0033] Figure 4 shows representative photomicrographs (%) of Sirus Red staining and image analysis of kidney sections of UUO rats exposed to the ALPK1 inhibitor C008. (A) The figure shows representative photomicrographs of renal cortical sections of UUO rats. (B) The fibrotic area in the renal cortex is expressed as the percentage of collagen volume fraction to the total field area. Values ​​are expressed as mean ± standard error. *P<0.05 compared with the sham group, compared with the UUO group Analysis of variance plus Dunnett's test.

[0034] Figure 5 It is a bar graph showing the fold changes in mRNA expression of inflammation- and fibrosis-related genes in the kidneys of sham-operated rats and unilateral ureteral obstruction (UUO) rats treated with drug only (UUO+Vehicle) or ALPK1 inhibitor C008 (5, 10, 20 mpk). *P<0.05, **P<0.01, ***P<0.001 compared with UUO+Vehicle group, analysis of variance plus Dunnett's test.

[0035] Fig. 6A and Figure 6BThe figure shows the line graph of blood BUN (A) and creatinine (B) levels during the experimental period. The values ​​are expressed as mean ± standard error. Compared with the normal diet group (control group), *P<0.05, **P<0.01, ***P<0.001; compared with the adenine diet plus solvent group (adenine), Statistical analysis was performed using analysis of variance followed by Dunnett's test.

[0036] Figure 7 The bar graph shows the level of renal cortical hydroxyproline (OH-P) in the kidneys of mice in the vehicle group and the C008 group. After analysis of variance and Dunnett's test, compared with the normal diet group (control group), ***P<0.001; compared with the adenine diet plus solvent group (adenine),

[0037] Figure 8 shows representative photomicrographs (%) of Sirus Red staining and image analysis of kidney sections of rats on an adenine diet exposed to the ALPK1 inhibitor C008. (A) Panel shows representative photomicrographs of renal cortical sections. (B) The fibrotic area within the renal cortex is expressed as the percentage of collagen volume fraction to the total field area. Values ​​are expressed as mean ± standard error. After analysis of variance and Dunnett's test, ***P<0.001 compared with the normal diet group (control group); compared with the adenine diet plus solvent group (adenine),

[0038] Fig. 9 The bar graph shows the proteinuria score levels of different dosing groups at the end of the experiment. The scores are expressed as mean ± SEM. The proteinuria in the 10 mg / kg group was significantly reduced. Compared with the Vehicle group *P < 0.05, one-way analysis of variance followed by Dunnett's test was used. Abbreviation: ANOVA, analysis of variance.

[0039] Fig. 10A is a bar graph comparing the diameters of 20 representative glomeruli in each kidney and averaging them. Scores were assigned based on the mean. Scores are expressed as mean ± SEM. There were significant changes in glomerular scores in both the 3 mg / kg and 10 mg / kg groups. **P<0.01, ***P<0.001 compared with the Vehicle group by one-way ANOVA followed by Dunnett's test. Abbreviation: ANOVA, analysis of variance.

[0040] Fig. 10B The percentage of crescent-shaped glomeruli (proliferating epithelial cells partially surrounding the glomerulus) is shown. Scores are expressed as mean ± SEM. The 10 mg / kg group had significantly less crescent formation. **P < 0.01 compared with the Vehicle group, using one-way ANOVA followed by Dunnett's test. Abbreviation: ANOVA, analysis of variance.

[0041] Fig. 10C is a bar graph of general inflammation scores. Scores are expressed as mean ± SEM. There was significant improvement in interstitial inflammation in both the 3 mg / kg and 10 mg / kg groups. *P < 0.05 compared with the Vehicle group, one-way analysis of variance after Dunnett's test. Abbreviation: ANOVA, analysis of variance.

[0042] Fig. 10D It is a bar graph showing the score of cortical tubular protein cast, which is formed by gelatin precipitated in the tubules and forms the lumen. The score is expressed as mean ± SEM. The 10 mg / kg group significantly reduced the severity of tubular protein cast. *P < 0.05 compared with the Vehicle group, using one-way ANOVA followed by Dunnett's test. Abbreviation: ANOVA, analysis of variance.

[0043] Fig. 10E It is a bar graph showing the vasculitis score, which is an inflammation specifically related to blood vessels. The scores are expressed as mean ± SEM. There was a trend of improvement in vasculitis in the 10 mg / kg group.

[0044] Activity index scores such as Fig.10F It is used to evaluate the severity of lupus nephritis, including six indicators: endocapillary pleocytosis, neutrophil / nuclear fission, fibrinoid necrosis, hyalin deposition, cellular / fibroblastic crescents and interstitial inflammation. The scores are expressed as mean ± SEM. The 10mg / kg group significantly reduced the lupus nephritis activity index. Compared with the Vehicle group, **P<0.01, one-way analysis of variance followed by Dunnett's test was used. Abbreviation: ANOVA, analysis of variance.

[0045] Chronicity index score Figure 10G It is used to evaluate the severity of lupus nephritis and includes four indicators: total glomerular sclerosis score, fibrous crescent, tubular atrophy and interstitial fibrosis. The scores are expressed as mean ± SEM. The 10 mg / kg group showed a trend of reducing the chronicity index of lupus nephritis.

[0046] Fig.11Bar graph showing fold changes in innate immunity-related genes Ccl2, Ccl4, Ccl5, Ccr1, and IL-6 mRNA expression. Fold changes are presented as mean ± SEM. Compared with the Vehicle group, the 10 mg / kg group significantly reduced target gene overexpression **P<0.01, ***P<0.001, using one-way ANOVA followed by Dunnett's test. Abbreviation: ANOVA, analysis of variance.

[0047] Fig.12 The graph shows the inhibition of ALPK1 by C008. DETAILED DESCRIPTION

[0048] The present disclosure provides compounds as ALPK1 inhibitors, compositions comprising the same, and methods for treating kidney diseases, disorders, and conditions. In embodiments, kidney diseases, disorders, and conditions include, but are not limited to, chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal insufficiency, analytical hypotension, obstructive uropathy, glomerular disease, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, kidney disease such as primary and congenital kidney disease, nephritis, Alport syndrome, kidney inflammation, immune kidney disease, kidney transplant rejection, immune complex-induced kidney disease, toxic substance-induced kidney disease, contrast agent-induced kidney disease; subtle changes in glomerulonephritis (lipidic), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, high blood The present invention relates to nephrosclerosis and nephrotic syndrome (which can be diagnosed by features such as abnormally low creatinine and / or water excretion, abnormally high blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD) and syndrome of inadequate antidiuretic hormone secretion (SIADH). The term "ALPK1" herein refers interchangeably to isoform 1 (Q96QP1-1) or alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN).

[0049] As used herein, the term "alkyl" refers to a straight or branched saturated aliphatic radical with a number of carbon atoms shown. Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. For example, C1-6 alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, hexyl, etc. Alkyl can also refer to an alkyl group with up to 20 carbon atoms, such as but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0050] As used herein, "alkenyl" refers to a straight or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups can include 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. Alkenyl groups can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5, or more. In some embodiments, alkenyl groups have 1 double bond. Alkenyl groups can be substituted or unsubstituted.

[0051] As used herein, "alkynyl" refers to a straight or branched hydrocarbon with at least 2 carbon atoms and at least one triple bond. Alkenyl can include 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. Alkynyl groups can have any suitable number of triple bonds, including but not limited to 1, 2, 3, 4, 5 or more. In certain embodiments, alkynyl groups have 1 triple bond. Alkynyl groups can be substituted or unsubstituted.

[0052] As used herein, the term "alkylene" refers to a straight or branched saturated aliphatic radical having the number of carbon atoms shown and connecting at least two other groups, i.e. a divalent hydrocarbon radical. The two parts connected to the alkylene group can be connected to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene group can be a divalent radical of -(CH2)n-, wherein 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 certain embodiments, the alkylene group is substituted by 1 to 2 substituents. As a non-limiting example, suitable substituents include halogen and hydroxyl.

[0053] As used herein, the term "alkoxy" or "alkoxyl" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. As with alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups can be substituted or unsubstituted.

[0054] As used herein, the term "alkenyloxy" or "alkenyloxyl" refers to an alkenyl group as defined above, having an oxygen atom connecting the alkenyl group to the point of attachment: alkenyl-O-. The alkenyloxy group may have any suitable number of carbon atoms, such as C1 to 6. The alkenyloxy group may be further substituted with various substituents described herein. The alkenyloxy group may be substituted or unsubstituted.

[0055] "Aminoalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with -NR'R", wherein R' and R" are independently hydrogen, alkyl, haloalkyl or hydroxyalkyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0056] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and

[0057] As used herein, the term "haloalkyl" refers to an alkyl group as defined above, in which some or all of the hydrogen atoms are replaced by halogen atoms. As for alkyl groups, the haloalkyl group can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc.

[0058] As used herein, the term "haloalkoxyl" or "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. As for alkyl groups, the haloalkoxy group can have any suitable number of carbon atoms, such as C1-6. The alkoxy group can be substituted by 1, 2, 3 or more halogens.

[0059] As used herein, the term "deuterated alkyl" refers to an alkyl radical as defined above, wherein 1 to 6 hydrogen atoms in the alkyl radical are replaced by deuterium, for example -CH2D, -CHD2, -CD3, -CH2CD3, etc.

[0060] 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, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and 4-hydroxy-butyl.

[0061] As used herein, the term "oxo" refers to an oxygen atom connected to the point of attachment through a double bond (=0).

[0062] 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. The aryl group may include any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, and 6 to 10, 6 to 12 or 6 to 14 ring members. The aryl group may be monocyclic, may be fused to form a bicyclic or tricyclic group, or may be connected by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl with a methylene linker. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. The aryl group may be substituted or unsubstituted.

[0063] As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic aromatic ring assembly containing 5 to 12 ring atoms, of which 1 to 5 ring atoms are heteroatoms, such as N, O or S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si and P. Heteroatoms may also be oxidized, such as but not limited to -S(O)- and -S(O)2-. Heteroaryl groups may include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms may be included in the heteroaryl group, such as 1, 2, 3, 4 or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have 5 to 9 ring members and 1 to 4 heteroatoms, or 5 to 9 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms.Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), purine.Heteroaryl groups can also be fused with aromatic ring systems (such as benzene rings) to form members including but not limited to benzopyrrole (such as indole and isoindole), benzopyridine (such as quinoline and isoquinoline), benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine (such as phthalazine and cinnoline), benzothiophene and benzofuran.Other heteroaryl groups include heteroaryl rings connected by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0064] As used herein, "cycloalkyl" refers to a saturated ring combination containing 3 to 10 ring atoms or the number of atoms shown. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8. When the unsaturated cycloalkyl ring can have one or two double bonds, the cycloalkyl ring can be saturated or unsaturated. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Cycloalkyl groups can be substituted or unsubstituted.

[0065] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a saturated or partially saturated, monocyclic or polycyclic heterocyclic group; it has 3 to 16, most preferably 5 to 10 and most preferably 1 or 4 ring atoms; wherein one or more, preferably 1 to 4, especially 1 or 2 ring atoms are heteroatoms selected from oxygen, nitrogen and sulfur (the remaining ring atoms are therefore carbon). The term heterocyclyl excludes heteroaryl. The heterocyclic group may be attached to the rest of the molecule via a heteroatom or carbon atom selected from oxygen, nitrogen and sulfur. The heterocyclic group may include fused or bridged rings as well as spirocyclic rings. Examples of heterocyclic groups include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolanyl, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxazepinyl, oxazepinyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.

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

[0067] As used herein, "bridged heterocyclyl" refers to a C3-6 cycloalkyl ring or a 3- to 6-membered heterocyclyl ring as defined above, wherein two non-adjacent ring vertices "(bridgehead atoms") of the cycloalkyl ring or heterocyclyl ring are linked to form an additional cyclic portion "(bridge"). The bridge contains 1 to 4 ring vertices, excluding the bridgehead atom. Examples include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 3,9-diazabicyclo[3.3.1]nonane, 2-thia-5-azabicyclo[2.2.1]heptane, 2,2-dioxide, 2-azabicyclo[2.2.1]hept-5-ene, 3-oxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, and 2-oxa-5-azabicyclo[2.2.1]heptane.

[0068] The term "bicyclic heterocyclyl" refers to a heterocyclic group as defined above wherein two ring systems are linked via two adjacent ring vertices (e.g., a fused ring system). Typical "bicyclic heterocyclyl" rings include 6 to 11 ring members with 1 to 4 heteroatom ring vertices selected from N, O and S (the remaining ring atoms are thus carbon). Examples include, but are not limited to, benzodioxolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, naphthyridinyl, pyrazolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl.

[0069] As used herein, "saturated or unsaturated" refers to a ring system in which two atoms in the group can be bound to each other by a single bond, a double bond, or a triple bond. Saturated moieties are those having only single bonds, while moieties having multiple bonds (e.g., at least one double bond or at least one triple bond) are called unsaturated.

[0070] When necessary, any definition herein can be used in combination with any other definition to describe a composite structural group. As a rule, the trailing element of any such definition is the element attached to the parent moiety. For example, the composite group cycloalkoxy means that the cycloalkyl group is attached to the parent molecule via an oxygen group.

[0071] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, 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, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, 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, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, 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. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0072] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, the salts are otherwise equivalent to the parent form of the compound.

[0073] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are intended to be encompassed within the scope of the present invention. In certain embodiments, the compounds of the present invention are specific enantiomers, anomers or diastereomers that are substantially free of other forms.

[0074] As used herein, the term "substantially free" refers to an amount of 10% or less of another isomeric form, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less of another isomeric form. In some embodiments, the isomer is a stereoisomer.

[0075] Detailed description of the embodiments

[0076] The present invention provides methods of inhibiting ALPK1 kinase activity in a target site for treating a disease, disorder or condition, particularly a kidney disease, disorder or condition in a subject in need thereof, where excessive or inappropriate ALPK1-dependent proinflammatory signaling is present. Kidney diseases, disorders or conditions include, but are not limited to, chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease, diabetic kidney disease, hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerular disease, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, primary and congenital kidney disease, nephritis, disease, Alport syndrome, renal inflammation, immune nephropathy, renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast media-induced nephropathy; minimal changes glomerulonephritis (lipidoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, Renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (which may be characterized by, for example, abnormally decreased excretion of creatinine and / or water, abnormally elevated concentrations of urea, nitrogen, potassium and / or creatinine in the blood, changes in urine osmotic pressure or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disorders (such as hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD) and syndrome of insufficient ADH secretion (SIADH). The disclosed method comprises administering to the individual a compound represented by formula (I) or a sub-embodiment, and a pharmaceutically acceptable salt thereof. In an embodiment, the relevant disease is chronic kidney disease.

[0077] The compound is represented by formula I

[0078]

[0079] Among them, A, p, R1 , R 2 , R 3 , R 4 and R 5 As defined in this article:

[0080] A is selected from a bond, azetidinyl, -O-, -N(R 6 )-、-CH2-N(R 6 )-、-CHR 9 -N(R 6 )-,in

[0081] R 6 is selected from H, -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 alkoxy, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, and optionally substituted saturated or unsaturated C3-C6 cycloalkoxy, wherein

[0082] The optionally substituted R 6 The moiety includes 0-3 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, and C1-C6 alkoxy;

[0083] R 9 is selected from optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkoxy, wherein the optionally substituted R 9 The moiety contains 0-2 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 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7f R 8f 、-OR 7f 、-OC(O)(R 7f )、-C(O)(R 7f )、-C(O)N(R 7f R 8f )、-C(O)O(R 7f )、-S(O)2(R 7f )、-S(O)ON(R 7f R8f ) and -N(R 7f R 8f ) of a substituent, wherein

[0084] Each R 7f and R 8f Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy;

[0085] 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 haloalkoxy, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 alkoxy, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkoxy, optionally substituted monocyclic or bicyclic aryl, optionally substituted heterocyclic aryl containing 1-4 selected from N, O and S 5-10 membered heteroaryl containing 1-2 heteroatom ring vertices selected from N, O and S; saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 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 spiro heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; and saturated or unsaturated 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S;

[0086] wherein the optionally substituted R 1 The moiety contains 0-4 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 alkoxy, C1-C6 haloalkoxy, -R 7a , -X 1 -R 7a , CHR 7a R 8a 、-OR 7a 、-OX 1 -R 7a , -X 1 -OX 1 -R 7a 、-OC(O)(R 7a ),-OX 1-C(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a ),-NR 7a (CO)R 8a 、-C(O)O(R 7a )、S(O)2R 7a 、-S(O)2N(R 7a R 8a )、-N(R 7a R 8a ), a saturated or unsaturated C3-C6 cycloalkyl, a saturated or unsaturated C3-C6 cycloalkoxy, a saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, a monocyclic or bicyclic aryl, a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S, 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 a 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; wherein

[0087] Each X 1 Independently for C 1-6 Alkylene;

[0088] Each R 7a and R 8a independently selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, containing 1 -2 saturated or unsaturated 3-7 membered heterocyclic groups at the vertices of the heteroatoms selected from N, O and S, wherein the aryl and 3-7 membered heterocyclic groups are substituted with 0-3 substituents 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 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and

[0089] The C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 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 substituted with 0 to 3 moieties selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, -C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b ),-NR 7b (CO)R 8b 、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in

[0090] Each R 7b and R 8b independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl and saturated or unsaturated C3-C6 cycloalkoxy; or

[0091] R 1 and R 6 Combined to form a 3-6 membered heterocycloalkyl substituted with 0-3 moieties independently selected from the group consisting of halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy;

[0092] R 5 is selected from the group consisting of H, deuterium, halo, C1-C6 alkyl, C1-C6 deuterated alkyl and C1-C6 haloalkyl;

[0093] R 2 and R 3Each is independently selected from H, OH, C1-C6 alkyl and C2-C6 alkynyl, wherein C1-C6 alkyl and C2-C6 alkynyl are each substituted by 0-3 independently selected from halogen, -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -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 ), where

[0094] Each R 7c and R 8c Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy;

[0095] The condition is R 2 and R 3 Not all H; or

[0096] R 2 and R 3 The 3-7 membered heterocyclic group is combined to form a C3-C6 cycloalkyl ring or a 3-7 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O and S, wherein the formed ring may be optionally substituted by 1-2 independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 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 ) is substituted by a substituent, wherein

[0097] Each R 7d and R 8dIndependently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl and saturated or unsaturated C3-C6 cycloalkoxy;

[0098] Each R 4 independently selected from halo, -OH, -NH2, CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, CHR 7e R 8e , OR 7e 、OC(O)(R 7e )、C(O)(R 7e )、C(O)N(R 7e R 8e )、C(O)O(R 7e )、S(O)2N(R 7e R 8e ) and N(R 7e R 8e ),in

[0099] Each R 7e and R 8e Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, and subscript p is 0, 1, 2 or 3.

[0100] In some embodiments, A in Formula I is a bond.

[0101] In some embodiments, A in Formula I is azetidinyl.

[0102] In some embodiments, A in Formula I is -O-.

[0103] In some embodiments, A in Formula I is -N(R 6 )-.

[0104] In some embodiments, A in Formula I is -CH2-N(R 6 )-.

[0105] In some embodiments, A in Formula I is -CHR 9 -N(R 6 )-.

[0106] In some embodiments, the compound of Formula I is represented by a compound of Formula IA, Formula IA-1, Formula IA-2, and / or a stereoisomer, stable isotope, or pharmaceutically acceptable salt thereof.

[0107]

[0108] Where p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 As defined above.

[0109] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 6 It is H, C1-C6 alkyl or C1-C6 hydroxyalkyl.

[0110] In some embodiments, R in Formula I and 1A 9 It is CH3 or CH2OH.

[0111] In some embodiments, R in Formula I and 1A 9 It is a saturated C3-C6 cycloalkyl group.

[0112] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is selected from H and optionally substituted C1-C6 alkyl, wherein

[0113] The optionally substituted C1-C6 alkyl group comprises 0-4 independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7a R 8a 、-OR 7a 、-OC(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a )、-C(O)O(R 7a )、-S(O)2R 7a 、-S(O)2N(R 7a R 8a ) and -N(R 7a R 8a ) of a substituent, wherein

[0114] Each R 7a and R 8aIndependently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0115] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is an optionally substituted saturated or unsaturated C3-C6 cycloalkyl group, wherein

[0116] The optionally substituted C3-C6 cycloalkyl includes 0-4 substituents independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy.

[0117] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 With R 6 Combine to form a 3-6 membered heterocycloalkyl substituted by 0-3 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy.

[0118] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is a C1-C6 alkyl group substituted by 0-4 substituents independently selected from the following: -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -OC(O)(R 7a )、-S(O)2N(R 7a R 8a ) and -N(R 7a R 8a ),in

[0119] Each R 7a and R 8a Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0120] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is a C1-C6 alkyl group substituted by 0-2 substituents independently selected from the group consisting of -OH, C1-C6 hydroxyalkyl, and -S(O)2N(R 7aR 8a ),in

[0121] Each R 7a and R 8a Independently selected from H and C1-C6 alkyl.

[0122] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is an optionally substituted C1-C6 hydroxyalkyl group.

[0123] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 Containing 1-4 selected from

[0124] 5-10 membered heteroaryl with N, O and S as heteroatom ring vertices,

[0125] The 5-10 membered bicyclic heteroaryl is substituted by 0 to 3 moieties selected from the following: halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, a 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, a saturated or unsaturated C3-C6 cycloalkyl, a saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in

[0126] Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0127] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1is a pyridyl group substituted by 0 to 3 moieties selected from the group consisting of halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, a 3-7 membered heterocyclic group containing 1-2 heteroatoms selected from N, O and S, wherein

[0128] The 3-7 membered heterocyclic group is substituted by 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, and C1-C6 haloalkyl.

[0129] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is a saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatoms selected from N, O and S, wherein

[0130] The 7-8 membered bridged heterocyclic group is substituted by 0-3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R8b), where

[0131] Each R7b and R8b is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0132] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is a saturated or unsaturated 7-11-membered spiro heterocyclic group containing 1-2 heteroatoms selected from N, O and S, wherein

[0133] The 7-11 membered spiro heterocyclyl is substituted by 0-3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b , OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in,

[0134] Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0135] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is an aryl group substituted with 0-3 substituents selected from the following: a halo group, a 3-7 membered heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, a 7-8 membered bridged heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S; and a saturated or unsaturated 7-11 membered spiroheterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, wherein,

[0136] The 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl and 7-11 membered spiroheterocyclyl are substituted by 0 to 3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7bR 8b )、-C(O)O(R 7b )、-S(O)2R 7b 、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in,

[0137] Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0138] In some embodiments, R in Formula I, 1A, 1A-1, 1A-2 1 is an aryl group substituted by 0-3 moieties 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, C1-C6 alkoxy, and a 3-7 membered heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S,

[0139] The 3-7 membered heterocyclic group is substituted by 0-3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in,

[0140] Each R 7b and R 8bIndependently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0141] In some embodiments, R1 in Formula I, 1A, 1A-1, and 1A-2 is aryl substituted with 0-3 moieties selected from the following: halo and 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, and the 3-7 membered heterocyclyl is further substituted with 0-3 moieties selected from -OH, -COOH, -NH2, =O, -CN, and -C1-C6 alkyl.

[0142] In some embodiments, the compound of Formula I is represented by a compound of Formula IB and / or a stereoisomer, stable isotope, or pharmaceutically acceptable salt thereof

[0143]

[0144] Where p, R 2 , R 3 , R 4 and R 5 As defined above; and

[0145] D is CR 10 or N;

[0146] E is CR 14 or N;

[0147] F is CR 12 or N;

[0148] G is CR 11 or N;

[0149] The condition is that no more than three of D, E, F and G are N;

[0150] R 10 , R 11 , R 12 , R 13 and R 14 , when present, are each independently selected from H, halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -R 7a , -X 1 -R 7a , X 1 -OX 1 -R 7a 、-CHR7a R 8a 、-OR 7a 、-OX 1 -R 7a 、-OC(O)(R 7a ),-OX 1 -C(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a )、-C(O)O(R 7a )、S(O)2R 7a 、-S(O)2N(R 7a R 8a )、-N(R 7a R 8a ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, saturated or unsaturated 3-7 membered heterocyclic group 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 heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S; and saturated or unsaturated 7-11 membered spiro heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S; 6-11 membered bicyclic heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S; wherein

[0151] Each X 1 Independently for C 1-6 Alkylene;

[0152] Each R 7a and R 8a independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and

[0153] The 3-7 membered heterocyclyl, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, 7-8 membered bridged heterocyclyl, 7-11 membered spiroheterocyclyl and 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 2 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7g R 8g 、-OR7g 、-OC(O)(R 7g )、-C(O)(R 7g )、-C(O)N(R 7g R 8g ),-NR 7g (CO)R 8g 、-C(O)O(R 7g )、-S(O)2N(R 7g R 8g ) and -N(R 7g R 8g ),in

[0154] Each R 7g and R 8g Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0155] In some embodiments, D, E, F, and G in Formula IB are CR 10 , CR 14 , CR 12 , and CR 11 .

[0156] In some embodiments, F and G in Formula IB are CR 14 and CR 11 , E is N or CR 14 , and D is N or CR 10 .

[0157] In some embodiments, R in Formula IB 10 and R 11 H, R respectively 12 and R 14 Each is 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 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; R 13 It 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, and a saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl and the 7-11 membered spiroheterocyclyl are optionally substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy.

[0158] In some embodiments, R in Formula IB 12 and R 14 For H, R 10 and R 11 Each is 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 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8bR is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; 13 It 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, and a saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl and the 7-11 membered spiroheterocyclyl are optionally substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy.

[0159] In some embodiments, R 10 , R 11 , R 12 and R 14 Both are H; R 13 It is a saturated or unsaturated C3-C6 cycloalkyl group, a 3-7 membered heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, a saturated or unsaturated 7-8 membered bridged heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, and a saturated or unsaturated 7-11 membered spiroheterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, wherein the 3-7 membered heterocyclyl group, the 7-8 membered bridged heterocyclyl group and the 7-11 membered spiroheterocyclyl group are optionally substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy.

[0160] In some embodiments, R in Formula IB 10 , R 11 , R 12 and R 14 Each is H; R 13It is a 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, which is substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0161] In some embodiments, R in Formula IB 10 , R 11 , R 12 and R 14 Each is H; R 13 It is an optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, which is substituted by 0-2 substituents selected from -OH, -COOH, -NH2, =O, -CN and -C1-C6 alkyl.

[0162] In some embodiments, the compound of Formula IB is represented by a compound of Formula IB-1 or IB-2 and / or a stereoisomer, stable isotope, or pharmaceutically acceptable salt thereof,

[0163]

[0164] Where p, R 2 , R 3 , R 4 and R 5 As defined above; and

[0165] R 16 and R 17 Each is independently selected from halo and C1-C6 alkyl;

[0166] R 15 Selected from -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2R 7b and -S(O)2N(R 7b R 8b ),in

[0167] Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0168] In some embodiments, R in Formula IB-1 or IB-2 15 Selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b ,in

[0169] Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0170] In some embodiments, R in Formula IB-1 or IB-2 15 It is a C1-C6 alkyl group.

[0171] In some embodiments, R in Formula IB-1 or IB-2 2 and R 3 They are all methyl.

[0172] In some embodiments, R in Formula IB-1 or IB-2 2 and R 3 Each is independently methyl or ethynyl.

[0173] In some embodiments, IB-1 is represented by Formula IB-1-a or Formula IB-2-a

[0174]

[0175] or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, IB-1 is represented by Formula IB-1-b or Formula IB-2-b

[0177]

[0178]

[0179] or a pharmaceutically acceptable salt thereof, wherein R 4 It is a halo group.

[0180] In some embodiments, IB-1 is represented by formula (IB-1-c) or formula IB-2-c

[0181]

[0182] or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, R in Formula IB-1 or IB-2 5 It is H or methyl.

[0184] The present invention discloses novel heterocyclic compounds as ALPK1 inhibitors. These compounds are represented by formula IC

[0185]

[0186] Where R 2 , R 3 , R 4 and R 5 As defined above in Formula I; and

[0187] m is an integer between 0 and 6;

[0188] R 18 is selected from H, halo, -OH, -COOH, -NH2, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -R 7a , -X 1 -R 7a , CHR 7a R 8a 、-OR 7a 、-OX 1 -R 7a , X 1 -OX 1 -R 7a 、-OC(O)(R 7a ),-OX 1 -C(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a ),-NR 7a (CO)R 8a 、-C(O)O(R 7a )、S(O)2R 7a 、-S(O)2N(R 7aR 8a )、-N(R 7a R 8a ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, 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; wherein

[0189] Each X 1 Independently for C 1-6 Alkylene;

[0190] Each R 7a and R 8a independently selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, containing 1-2 a saturated or unsaturated 3-7 membered heterocyclic group with a heteroatom ring vertex selected from N, O and S, wherein the aryl and 3-7 membered heterocyclic groups are substituted by 0-3 substituents selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and

[0191] C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 3-7 membered heterocyclyl, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclyl, saturated or unsaturated 7-11 membered spiroheterocyclyl, 6-11 membered bicyclic heterocyclyl are each independently substituted by 0 to 3 moieties selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b ),-NR 7b (CO)R 8b 、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

[0192] In some embodiments, m in Formula IC is 1.

[0193] In some embodiments, R in Formula IC 18 For H.

[0194] In some embodiments, R in the formulas described herein is 2 and R 3 All are C1-C6 alkyl;

[0195] In some embodiments, R in the formulas described herein is 2 is methyl, R 3 It is CH2OMe.

[0196] In some embodiments, R in the formulas described herein is 2 and R 3 All are methyl.

[0197] In certain embodiments, R in the formulae described herein is 2 is methyl, R 3 It is ethynyl.

[0198] In some embodiments, R 2 is methyl, R 3 It is a C3-C6 cycloalkyl group.

[0199] In some embodiments, R 2 is methyl, R 3 It is phenyl.

[0200] In some embodiments, in the formulas described herein, subscript p is 1, and R4 Attached to the phenyl ring as follows:

[0201]

[0202] The wavy lines represent points of attachment to the rest of the formula.

[0203] In some embodiments, in the formulas described herein, subscript p is 1, and R 4 is a halide attached to a phenyl ring as shown below:

[0204]

[0205] The wavy lines represent points of attachment to the rest of the formula.

[0206] In some embodiments, in the formulas described herein, subscript p is 1, and R 4 is a chlorine attached to a phenyl ring as shown below:

[0207]

[0208] The wavy lines represent points of attachment to the rest of the formula.

[0209] In some embodiments, in the formulas described herein, subscript p is 1, and R 4 is a methoxy group attached to a phenyl ring as shown below:

[0210]

[0211] The wavy lines represent points of attachment to the rest of the formula.

[0212] In some embodiments, in the formulas described herein, R 5 For H.

[0213] In some embodiments, in the formulas described herein, R 5 For deuterium.

[0214] In some embodiments, in the formulas described herein, R 5 is a C1-C6 deuterated alkyl. In some embodiments, R 5 Selected from -CH2D, -CHD2 and -CD3.

[0215] In some embodiments, the compound attached to R in the formulae described herein is 2 and R 3 The carbon atom of is chiral. In this case, it is understood that R 2 and R 3In some embodiments, R is attached to the formulae described herein. 2 and R 3 The carbon atom of isomer is the S isomer, which refers to the absolute stereochemistry at that carbon atom. In some embodiments, the R 2 and R 3 The carbon atom at which R is present is the R isomer, referring to the absolute stereochemistry at that carbon atom. 2 is methyl, R 3 In some embodiments, R 2 is methyl, R 3 is a C3-C6 cycloalkyl group. 2 is methyl, R 3 In some embodiments, R 3 is methyl, R 2 In some embodiments, R 3 is methyl, R 2 is a C3-C6 cycloalkyl group. 3 is methyl, R 2 It is phenyl.

[0216] In some embodiments, the compound of formula I is selected from

[0217]

[0218]

[0219] In some embodiments, the compound of formula I is selected from

[0220]

[0221]

[0222] In some embodiments, the compound is selected from the examples provided herein.

[0223] Preparation of compounds of formula I and exemplary compounds

[0224] Analysis details

[0225] NMR: Measurements were made on a Bruker Ultrashield TM 400 (400 MHz) spectrometer using or not tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported in ppm downfield from TMS, and spectral splitting patterns are designated as singlets (s), doublets (d), triplets (t), quartets (q), multiplets, unresolved or overlapping signals (m), broad signals (br). Deuterated solvents are given in brackets and have the 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.

[0226] LC-MS: Shimadzu 20A-2010MS

[0227] Detection: SPD-M20A

[0228] Column: Merck, RP-18e

[0229] 25-2mm;

[0230] Wavelength: UV 220nm, 254nm;

[0231] Column temperature: 50°C; MS ionization: ESI

[0232] Mobile phase: aqueous solution containing 1.5 ML / 4 L TFA (solvent A) and acetonitrile solution containing 0.75 ML / 4 L TFA (solvent B), using an elution gradient of 5% to 95% (solvent B) over 0.7 minutes and maintaining at 95% for 0.4 minutes, with a flow rate of 1.5 ml / min;

[0233] Flash column chromatography system

[0234] System: CombiFlash Rf+

[0235] Column: Santai Technologies, Inc.

[0236] Samples are usually adsorbed on isolute

[0237] HPLC separation conditions

[0238] System: TRILUTION LC 4.0

[0239] Detection: Gilson 159UV-VIS

[0240] Condition 1: Column: Phenomenex Gemini-NX 80*40mm*3um

[0241] Eluent A: Water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)

[0242] Eluent B: CH3CN

[0243] Start B: 20 ​​to 45%, End B: 80 to 20%, Gradient time (min): 8

[0244] Condition 2: Column: Xtimate C18 10μ250mm*50mm;

[0245] Eluent A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3).

[0246] Eluent B: CH3CN 50% to 80%; Gradient time (min): 8

[0247] SFC chiral separation conditions

[0248] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 30% to 30%, 35% to 35% or 45 to 45%

[0249] Column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5um);

[0250] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 30% to 30%, 40% to 40%;

[0251] Column: CHIRALPAK AD (250mm*30mm, 10um);

[0252] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 35% to 35%;

[0253] Column: CHIRALPAK AS (250mm*30mm, 10um);

[0254] Mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 35% to 35%

[0255] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used in the synthesis of the compounds of the present invention are commercially available or can be prepared by organic synthesis methods known to those of ordinary skill in the art.

[0256] Following is a table of abbreviations used in chemistry:

[0257]

[0258]

[0259] Reaction scheme 1:

[0260]

[0261] The appropriately 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, such as independently selected from H, C1-C6 alkyl and C2-C6 alkynyl, is converted to an acid chloride with SOCl2 or (COCl)2 under heating or room temperature. Weinreb amide is formed by reaction of N,O-dimethylhydroxylamine hydrochloride with an acid chloride at 0°C. THF containing a Grignard reagent is added to the Weinreb amide at 0°C to give a ketone, which is converted to M5 by bromination. Cyclization with thiourea under basic conditions gives intermediate M6.

[0262] Example 1: Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine (Intermediate 1)

[0263]

[0264] Step 1. Preparation of compound 2-(4-bromophenyl)-2-methylpropanoyl chloride

[0265]

[0266] Compound 2-(4-bromophenyl)-2-methylpropionic acid (100 g, 411 mmol, 1.0 eq) in SOCl (175 mL, 6 eq) was heated to reflux for 2 h. The solution was then cooled to room temperature and the mixture was concentrated under reduced pressure to give dry acyl chloride (yellow oil), which was used in the next step without further purification.

[0267] Step 2. Preparation of compound 2-(4-bromophenyl)-N-methoxy-N,2-dimethylpropionamide

[0268]

[0269] The solution of compound N, O-dimethylhydroxylamine HCl salt (48.2g, 49mmol, 1.2 equivalents) in DCM (300mL) is cooled to 0 ° C. Then the crude acyl chloride (1.0 equivalent) obtained from the above step 1 in DCM (200mL) and TEA (114mL, 2 equivalents) is added to the mixture, and the mixture is stirred at room temperature overnight. The reaction mixture is quenched with H2O (200ml). The mixture is extracted with DCM (200mL x 3), the combined organic layer is washed with water (200mL x 3), brine (200mL x 3), dried over Na2SO4, filtered and concentrated to obtain residue. The desired compound (108g, pure) is obtained as a light yellow oil, which is used for the next step without further purification.

[0270] 1 H NMR (400MHz, CDCl3) δ7.42(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),3.08(s,3H),2.71(s,3H),1.49(s,6H).

[0271] Step 3. Preparation of compound 3-(4-bromophenyl)-3-methylbutan-2-one

[0272]

[0273] The compound (54g, 189mmol, 1 equivalent) obtained from step 2 above in dry THF (500mL) is cooled to 0 ° C. CH3MgBr (3M in THF, 253mL, 757.8mmol, 4 equivalents) is added dropwise. The mixture is stirred at room temperature overnight. The reaction mixture is quenched with saturated NH4Cl (200mL) and extracted with EA (300mL x 2). The combined organic layer is washed with brine (300mL x 2), dried over Na2SO4, filtered and concentrated to obtain a residue. The desired compound (90.4g, pure) is obtained as a light yellow oil, which is used in the next step without further purification.

[0274] 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 1.90 (s, 3H), 1.44 (s, 6H).

[0275] Step 4. Preparation of compound 1-bromo-3-(4-bromophenyl)-3-methylbutan-2-one

[0276]

[0277] To the compound (46g, 191mmol, 1 equivalent) obtained from step 3 above, Br (14.7mL, 286mmol, 1.5 equivalent) was added dropwise in a solution of DCM / EtOH (250mL / 250mL) and the mixture was stirred at room temperature for 3.5 hours, and the reaction mixture was quenched with saturated NaSO (150mL). The mixture was extracted with DCM (300mL x 2) and the combined organic layer was washed with brine (300mL x 2), dried over NaSO, filtered and concentrated to obtain residue. The desired compound (118.8g, crude product) was obtained as a white solid and was used in the next step without further purification.

[0278] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 3.82 (s, 2H), 1.52 (s, 6H).

[0279] Step 5. Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine

[0280]

[0281] To the solution of the compound (50 g, 156 mmol, 1 eq.) obtained from step 4 above in MeOH (500 mL), thiourea (14.3 g, 188 mmol, 1.2 eq.) was added. The mixture was stirred at 50 ° C for 1.5 hours. The mixture was concentrated under reduced pressure. The mixture was extracted with EA (300 mL x 2), the combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered and concentrated to obtain a residue, which was purified by silica gel chromatography (PE / EA=10:1) to obtain the pure desired compound (34 g, white solid).

[0282] 1 H NMR(400MHz,DMSO-d6)δ7.39(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),6.78(s,2H),6.22(s,1H),1.50(s,6H).MS(ESI)m / z(M+H) + =297.0.

[0283] Embodiment 2:

[0284] 4-(1-(4-bromophenyl)cyclopentyl)thiazol-2-amine (Intermediate 2)

[0285]

[0286] Step 1. Preparation of compound 1-(4-bromophenyl)cyclopentane-1-carboxylic acid ethyl ester

[0287]

[0288] To a solution of compound 2-(4-bromophenyl)ethyl acetate (10 g, 41.3 mmol) in DMF (50 mL) was slowly added NaH (8.3 g, 207 mmol) at 0 ° C, and the reaction was then stirred at room temperature for 30 min. 1,4-dibromobutane (8.8 g, 41.3 mmol) was slowly added 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.

[0289] MS (ESI) m / z (M+H) + =297.0

[0290] Step 2. Preparation of compound 1-(4-bromophenyl)cyclopentane-1-carboxylic acid

[0291]

[0292] To a solution of compound 1-(4-bromophenyl)cyclopentane-1-carboxylic acid ethyl ester (7.8 g, 26.3 mmol) in THF (25 mL) was added NaOH (3.2 g, 79 mmol) and H2O (5 mL) and the reaction 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 to 1: 2). The desired compound (5.6 g, yield: 79.4%) was obtained.

[0293] MS (ESI) m / z (M+H) + =269.0.

[0294] The synthesis of the following steps was similar as described in Intermediate 1.

[0295] Embodiment 3:

[0296] 4-(2-(5-bromopyridin-2-yl)propan-2-yl)thiazol-2-amine (Intermediate 3)

[0297]

[0298] Step 1. Preparation of compound 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid methyl ester

[0299]

[0300] To a solution of 3-(5-bromopyridin-2-yl)-2-oxopropanoic acid (2 g, 9.26 mmol, 1.0 eq.) in DMF (20 mL) was added NaH (1.3 g, 32.4 mmol, 3.5 eq.) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. Iodomethane (2 mL, 3.5 eq.) was added to the mixture at 0 °C and stirred for 6 hours. The reaction mixture was quenched with water (50 mL), extracted with EA (25 mL x 2) and washed with brine (10 mL x 2), then dried over Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by silica gel column chromatography to obtain the desired compound (1.95 g, yield: 93%).

[0301] Step 2. Preparation of compound 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid

[0302]

[0303] A mixture of 2-(5-bromopyridin-2-yl)-2-methylpropanoate (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 h. The reaction was cooled to room temperature and quenched with 0.1 M HCl, extracted with EA, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the desired compound (1.82 g, yield: 98%).

[0304] The next few steps were similar as described for Intermediate 1.

[0305] The following examples were synthesized using a method similar to Intermediate 1 and using appropriate starting materials and thiourea

[0306] Table 1

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313] Reaction Scheme 2:

[0314]

[0315] The appropriately substituted compound M7 (wherein R is a suitable 1-3 groups, such as a halo or C1-C6 alkyl group, etc.) is acetylated with a lithium base at below -60°C. M9 is obtained by alkyl substitution of M8 (such as C1-C6 alkyl) at 50-70°C under alkaline conditions. After bromination, M10 is obtained. M10 is cyclized with thiourea under alkaline conditions to obtain the thiazole intermediate M11. Appropriate protecting groups are introduced to protect the amine. Reduction of the ester to the alcohol by LiBH4 at 0°C produces M13, which is oxidized to the corresponding aldehyde using a Dess-Martin periodinane (DMP) reagent. M14 is treated with 1-diazo-1-dimethoxyphosphoryl-propan-2-one to obtain the alkynyl thiazole amine intermediate M15 by Seyferth-Gilbert homologation at room temperature under alkaline conditions. Finally, deprotection gives the intermediate M16.

[0316] Embodiment 4:

[0317] Preparation of 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-amine (Intermediate 27)

[0318]

[0319] Step 1. Preparation of compound 2-(4-chlorophenyl)-3-oxobutanoic acid methyl ester

[0320]

[0321] LiHMDS (1M, 65.0mL) was added dropwise to a solution of compound 2-(4-chlorophenyl) methyl acetate (10g, 54.2mmol, 8.77mL) in THF (80mL) at -78°C. The mixture was stirred at -78°C for 20min. Then acetoacetate (5.53g, 54.17mmol, 5.07mL) was added at -78°C. The mixture was heated to 0°C and stirred at 0°C for 2h. The mixture was quenched with saturated NH4Cl (200mL) and extracted with EA (100mL x 3). The combined organic layers were washed with brine (200mL), 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 (7.47g, yield: 60.9%) was obtained as a light yellow oil.

[0322] MS (ESI) m / z (M+H) + =227.1.

[0323] Step 2. Preparation of compound 2-(4-chlorophenyl)-2-methyl-3-oxobutanoic acid methyl ester

[0324]

[0325] To a solution of the compound obtained from step 1 above (7.47 g, 33.0 mmol) and K2CO3 (22.8 g, 165 mmol) in acetone (60 mL) was added iodomethane (13.10 g, 92.28 mmol, 5.74 mL). The mixture was stirred at 70 ° C for 16 hours. The mixture was filtered and the filtrate was concentrated to give a residue. The desired compound (7.79 g, yield: 98.2%) was obtained as a light yellow oil, which was used in the next step without further purification.

[0326] MS (ESI) m / z (M+H) + =241.1.

[0327] Step 3. Preparation of compound 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutanoic acid methyl ester

[0328]

[0329] To a solution of the compound (7.79 g, 32.4 mmol) obtained from step 2 above in CHCl (80 mL) was added Br (4.66 g, 29.1 mmol, 1.50 mL). The mixture was stirred at 75 ° C for 16 hours. The reaction mixture was adjusted to pH = 6-7 with NaOH (1N), and then washed with H2O (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue. The desired compound 10 (9.91 g, yield: 95.8%) was obtained as a light brown oil and used in the next step without further purification.

[0330] MS (ESI) m / z (M+H) + =319.0.

[0331] Step 4. Preparation of methyl 2-(2-aminothiazol-4-yl)-2-(4-chlorophenyl)propanoate

[0332]

[0333] To the solution of the compound (9.91 g, 31.0 mmol) obtained from step 3 above and thiourea (2.83 g, 37.2 mmol) in MeOH (60 mL) was added NaHCO (3.13 g, 37.2 mmol, 1.45 mL). The mixture was stirred at 50 ° C for 1 hour. The reaction mixture was concentrated to obtain a residue. The precipitate was ground in H2O (100 mL) and collected by filtration. The desired compound (8.49 g, yield: 92.3%) was obtained as a brown solid.

[0334] MS (ESI) m / z (M+H) + =297.0.

[0335] Step 5. Preparation of methyl 2-(2-acetylaminothiazol-4-yl)-2-(4-chlorophenyl)propanoate

[0336]

[0337] To a solution of the compound obtained from step 4 above (3 g, 10.1 mmol) and TEA (1.53 g, 15.2 mmol, 2.11 mL) in DCM (60 mL) was added acetyl chloride (794 mg, 10.11 mmol, 721 uL) 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 uL) and TEA (1.53 g, 15.2 mmol, 2.11 mL) were added at 0°C, and the mixture was stirred at 25°C for 1 h. A third batch of acetyl chloride (793.5 mg, 10.11 mmol, 721.38 uL) and TEA (1.53 g, 15.16 mmol, 2.11 mL) were added at 0°C, and the mixture was stirred at 25°C for 1.5 h. The reaction mixture was quenched with H2O (3 mL) and then anhydrous Na2SO4 was added, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE:EA=1:0 to 2:1). The desired compound (1.4 g, yield: 32.6%) was obtained as a light yellow solid.

[0338] MS (ESI) m / z (M+H) + =339.1.

[0339] Step 6. Preparation of compound N-(4-(2-(4-chlorophenyl)-1-hydroxypropan-2-yl)thiazol-2-yl)acetamide

[0340]

[0341] To the solution of the compound (1.4 g, 4.13 mmol) obtained from step 5 above in THF (50 mL) was partially added LiBH4 (450 mg, 20.66 mmol). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched with saturated NH4Cl (40 mL) and then extracted with EA (30 mL x 3), the combined organic layer was washed with brine (60 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 2: 3). The desired compound (970 mg, yield: 73.4%) was obtained as a light yellow solid.

[0342] MS (ESI) m / z (M+H) + =311.1.

[0343] Step 7. Preparation of compound N-(4-(2-(4-chlorophenyl)-1-oxopropan-2-yl)thiazol-2-yl)acetamide

[0344]

[0345] To a solution of the compound (970 mg, 3.12 mmol) obtained from step 6 above in DCM (30 mL) was partially added 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 and the mixture was stirred at 25 ° C for 1 h. DMP (1.06 g, 2.50 mmol) in DCM (20 mL) was added and the mixture was stirred at 25 ° C for 2 h. The reaction mixture was diluted with DCM (40 mL) and quenched with saturated Na2S2O3 / saturated NaHCO3 (1 / 1, 200 mL). The organic layer was separated and the aqueous layer was extracted with DCM (60 mL), the combined organic layers were washed with saturated Na2S2O3 / saturated NaHCO3 (1 / 1, 100 mL), water (200 mL x 2), brine (200 mL x 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 was used in the next step without further purification.

[0346] Step 8. Preparation of compound N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)acetamide

[0347]

[0348] To the compound obtained from step 7 above (1.03g, 3.34mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (961mg, 5.00mmol) in MeOH (40mL) solution, K2CO3 (922mg, 6.67mmol) was added. The mixture was stirred at 25°C for 12h. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE:EA=1:0 to 1:1). The residue was purified by preparative HPLC (column: Venusil ASB Phenyl 150x30mm x5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 9min). The desired compound (219mg, yield: 21.54%) was obtained as a white solid.

[0349] 1 H NMR (400MHz, CDCl3) δ9.98 (br s,1H),7.45(d,J=8.5Hz,2H),7.30(d,J=8.5Hz,2H),6.88(s,1H),2.63(s,1H),2.25(s,3H),1.99(s,3H).MS(ESI)m / z(M+H) + =305.1.

[0350] Step 9. Preparation of compound 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-amine

[0351]

[0352] To the solution of the compound (180 mg, 591 umol) obtained from step 8 above in MeOH (10 mL), methanesulfonic acid (284 mg, 2.95 mmol, 210 μL) was added and 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 to 2: 1) to obtain the desired compound (137 mg, yield: 88.3%) as a light yellow solid.

[0353] 1 H NMR (400MHz, CDCl3) δ7.39-7.32(m,2H),7.20-7.16(m,2H),6.35(s,1H),4.90(br s,2H),2.46(s,1H),1.82(s,3H).MS(ESI)m / z(M+H) + =263.0.

[0354] The following example was synthesized similarly to the procedure of Example 4 (Intermediate 27) using appropriate starting materials and thiourea:

[0355] Table 2

[0356]

[0357]

[0358]

[0359] Example 5: 4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazol-2-amine (Intermediate 33)

[0360]

[0361] Step 1. Preparation of compound N-(4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazol-2-yl)acetamide

[0362]

[0363] To a solution of N-(4-(2-(4-bromophenyl)-1-hydroxypropan-2-yl)thiazol-2-yl)acetamide (200 mg, 563 μmol, synthesized in a similar manner 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 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), 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 to 1:1). The desired compound was obtained as a white solid (41 mg, yield: 19.72%)

[0364] 1 H NMR (400MHz, CDCl3) δ8.69 (br s,1H),7.39(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),6.69(s,1H),3.80(s,2H),3.34(s,3H),2.20(s,3H),1.68(s,3H).MS(ESI)m / z(M+H) + =371.0.

[0365] Step 2. Preparation of compound 4-(2-(4-bromophenyl)-1-methoxypropan-2-yl)thiazol-2-amine

[0366]

[0367] The synthesis was analogous to that described in Intermediate 44. The desired compound was obtained as a white solid (20 mg, yield: 90.3%).

[0368] 1 H NMR (400MHz, CDCl3) δ7.42-7.36(m,2H),7.18-7.13(m,2H),6.22(s,1H),4.83(br s,2H),3.84-3.73(m,2H),3.34(s,3H),1.65(s,3H).MS(ESI)m / z(M+H) + =327.0.

[0369] The following intermediate was synthesized using a procedure similar to Example 5 (Intermediate 33) using appropriate starting materials and thiourea:

[0370] Table 3

[0371]

[0372]

[0373] Embodiment 6:

[0374] 1-(2-Aminothiazol-4-yl)-1-(4-bromophenyl)ethan-1-ol (Intermediate 38)

[0375]

[0376] Step 1. Preparation of compound 1-(4-bromophenyl)propane-1,2-dione

[0377]

[0378] To a solution of compound 1-(4-bromophenyl)propan-2-one (2.0 g, 9.4 mmol, 1.0 equiv) in dioxane (20 mL) was added SeO2 (3.12 g, 28.1 mmol, 3.0 equiv). The mixture was stirred at 110 ° C for 4 h. After cooling, the reaction mixture was concentrated to give 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.

[0379] Step 2. Preparation of compound 3-bromo-1-(4-bromophenyl)propane-1,2-dione

[0380]

[0381] To the compound (960mg, 4.23mmol, 1.0 equivalent) obtained from step 1 above in CH3Cl (20mL) solution, Br2 (1.05g, 6.34mmol, 1.5 equivalent) and AcOH (3 drops) were added. The mixture was stirred at 60 ° C for 16h. The reaction mixture was quenched with saturated Na2SO3 (aqueous solution) (20mL), extracted with DCM (20mL x 2) and washed with brine (15mL), 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 (800mg, yield: 74%) was obtained as a yellow oil.

[0382] Step 3. Preparation of the compound (2-aminothiazol-4-yl)(4-bromophenyl)methanone

[0383]

[0384] To the compound obtained from step 2 above (800 mg, 2.62 mmol, 1.0 eq.) in MeOH (8 mL) was added thiourea (200 mg, 2.62 mmol, 1.0 eq.) and NaHCO . The mixture was stirred at 50° C. for 1.5 hours. The mixture was concentrated under reduced pressure, extracted with EA (15 mL x 2), the combined organic layers were washed with brine (10 mL x 2), dried over Na 2 SO 4 , filtered and concentrated to give a residue, which was purified by flash silica gel chromatography (PE: EA=3: 1) to give the desired compound (680 mg, yield: 90%).

[0385] Step 4 Preparation of Compound 1-(2-aminothiazol-4-yl)-1-(4-bromophenyl)ethan-1-ol

[0386]

[0387] A solution of compound (2-aminothiazole-4-yl) (4-bromophenyl)methanone (200 mg, 0.71 mmol, 1.0 equiv) in dry THF (4 mL) was cooled to 0 ° C, and CH MgBr (3M 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 NH Cl (200 mL), the mixture was extracted with EA (20 mL x 2), the combined organic layers were washed with brine (10 mL x 2), dried over Na SO , filtered and concentrated to obtain a residue. The obtained residue was purified by preparative TLC to obtain the desired compound (40 mg, yield: 20%).

[0388] 1 H NMR (400MHz, DMSO) δ7.45–7.38(m,2H),7.22(t,J=7.5Hz,2H),7.12(t,J=7.3Hz,1H),6.77(s,2H),6.30(s,1H),5.37(s,1H),1.67(s,3H).

[0389] MS (ESI) m / z (M+H) + =221.0

[0390] Example 7: 4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazole-5-d-2-amine

[0391]

[0392] Step 1. Preparation of compound N-(5-bromo-4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)acetamide

[0393]

[0394] A mixture of a solution 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 hours. The reactant was cooled to room temperature, then diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3), and the combined organic phases were washed with brine (50 mL x 3) and concentrated to give a residue. The resulting residue was purified by flash silica gel chromatography (PE:EA=1:0 to 3:1). The desired compound (800 mg, yield: 52.6%) was obtained as a yellow solid.

[0395] 1H NMR(400MHz, CDCl3)δ8.89(br.s,1H),7.33-7.41(m,2H),7.24-7.32(m,2H),2.61(s,1H),2.29(s,3H),2.00(s,3H).MS(ESI)m / z(M+H) + =384.8.

[0396] Step 2. Preparation of compound 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]-5-deuterated thiazol-2-amine

[0397]

[0398] The mixture of the compound (600 mg, 1.56 mmol) obtained from step 1 above and MsOH (751.43 mg, 7.82 mmol) in CD3OD (8 mL) was stirred at 80 ° C for 16 h. The reaction pH was adjusted to 8-9 with saturated NaHCO3 aqueous solution, then extracted with ethyl acetate (30 mL×3), and the combined organic phase was washed with brine (30 mL) and concentrated to obtain a residue. The residue was purified by silica gel chromatography (PE: EA = 1: 0 to 3: 1) to obtain the product, which was purified again by Pre-TLC (PE: EA = 3: 1). The target compound (100 mg, yield: 20.8%) was obtained as a yellow oil.

[0399] 1 H NMR(400MHz, CDCl3)δ8.89(br.s,1H),7.33-7.41(m,2H),7.24-7.32(m,2H),2.61(s,1H),2.29(s,3H),2.00(s,3H).MS(ESI)m / z(M+H) + =263.8.

[0400] At the same time, 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.

[0401] MS (ESI) m / z (M+H) + =343.1.

[0402] General Method I

[0403] To a solution of thiazole amine (1 equivalent) in an appropriate organic solvent (such as DMF) is added NaH (1.2-1.5 equivalents) at 0°C-10°C and the resulting mixture is stirred for 5-30 min. Amine activated by CDI is added to the mixture and stirred for 4-16 hours. Once the reaction is complete, the resulting suspension is diluted with an organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue is purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0404] Example 8: 4-(4-(3-(4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)benzene Preparation of tert-butyl piperazine-1-carboxylate

[0405]

[0406] To a solution of 4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazol-2-amine (40 mg, 0.15 mmol, 1 eq.) in DMF (5 mL) was added NaH (7 mg, 0.3 mmol, 2 eq.) at 10 °C. The resulting mixture was stirred for 5 min. To the mixture was added tert-butyl 4-(4-((1H-imidazole-1-carboxamido)methyl)phenyl)piperazine-1-carboxylate (58 mg, 0.15 mmol, 1 eq.) and stirred overnight. The reaction was quenched with water, extracted with EA and the combined organic layers were washed with brine, then dried (Na2SO4), filtered and evaporated to dryness. The resulting residue was purified by preparative TLC (PE:EA=3:1) to give the title compound 35 mg (0.06 mmol) with a yield of 40% MS (ESI) m / z (M+H) + =588.2

[0407] General Method II

[0408] To a solution of the amine fragment (1 equivalent) and pyridine in an appropriate solvent (such as dry DCM) is slowly added phenyl chloroformate (2 equivalents) below 20°C. The mixture is stirred at room temperature for 4-6h. Once the reaction is complete, the resulting reaction is diluted with an organic solvent and washed with salt water and then dried. After filtration and evaporation, the resulting residue is purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0409] Example 9: 4-(5-(3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)pyrimidine-2-yl Preparation of tert-butyl piperazine-1-carboxylate

[0410]

[0411] Phenyl chloroformate (336 mg, 2.2 mmol, 269.0 μL) was added 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 addition, the mixture was allowed to heat to 25 °C and stirred at 25 °C for 0.25 h. The solvent was removed under vacuum. The residue was ground with ice water (15 mL). A white solid precipitated from the mixture. The mixture was filtered and the solid was collected and dried under vacuum. 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.

[0412] 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)thiazole-2-amine (50 mg, 168 μmol) in DCE (10 mL) was added DMAP (41.0 mg, 337.0 μmol, 2 equiv). The mixture was stirred at 85 ° C for 16 h. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO , DCM:MeOH=13:1) and further purified by preparative TLC (SiO , DCM:MeOH=12:1). The desired compound (60 mg, yield: 57.7%) was obtained as a white solid.

[0413] MS (ESI) m / z (M+H) + =616.2.

[0414] General Method III

[0415] To a solution of substituted thiazole-2-amine and hunin or pyridine in a suitable solvent such as DCM or CH3CN or DCM / water, phenyl chloroformate (2 equivalents) is slowly added at 0°C to room temperature. The mixture is stirred at room temperature for 2-4h and the resulting reaction is diluted with an organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue is purified by chromatography to give the substituted thiazole-2-amine carbamic acid.

[0416] By substituted thiazole-2-amine carbamate, amine and DMAP in suitable solvent, as the mixture in THF is heated to reflux and continues 1-2h.After cooling, the gained reaction is concentrated and with suitable organic solvent, like EA, dilute and use salt water washing and then dry.After filtration and evaporation, the gained resistates is passed through grinding / preparative TLC / chromatography / preparative HPLC purifying to obtain product.

[0417] Example 10: 1-(4-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzyl)-3-(4-(2- Preparation of (4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea

[0418]

[0419] To a solution of 4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-amine (100 mg, 0.34 mmol, 1 eq) and triethylamine in dry DCM (5 mL) was slowly added phenyl chloroformate (106 mg, 0.68 mmol, 2 eq) at 0°C-room temperature and the mixture was stirred at room temperature for 4 h. Quenched with saline, extracted with EA, the combined organic layers were washed with saline, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel column chromatography to give phenyl (4-(2-(4-bromophenyl)propan-2-yl)thiazole-2-yl)carbamate (112 mg).

[0420] A mixture of phenyl (4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)carbamate (112 mg, 0.27 mmol, 1 eq), tert-butyl ((1-(4-(aminomethyl)phenyl)piperidin-4-yl)methyl)carbamate (24 mg, 0.27 mmol, 1 eq) and DMAP (52 mg, 0.4 mmol, 1.5 eq) in THF (5 mL) was heated to reflux for 1 h. After cooling to rt, the reaction mixture was partitioned between H2O (15 mL) and EA (10 mL x 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 give 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.

[0421] General Method IV

[0422] The mixture of amine and isocyanato-alkane in THF is stirred at room temperature overnight. Once the reaction is complete, the obtained suspension is diluted with an organic solvent and washed with salt water and then dried. After filtration and evaporation, the obtained residue is purified by grinding / preparative TLC / preparative HPLC to obtain the product.

[0423] Example 11: Preparation of 1-ethyl-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea

[0424]

[0425] To a solution of 4-(2-(4-methoxyphenyl)propan-2-yl)thiophene-2-amine (200 mg, 0.67 mmol) in THF (5 mL) was added isocyanatoethane (48 mg, 0.67 mmol) and TEA (136 mg, 1.34 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure at 45 ° C to remove THF. The resulting suspension was diluted with EtOAc and washed with brine, then dried (Na2SO4), filtered and evaporated to dryness. The resulting residue was purified by preparative TLC to give the desired compound (164 mg, yield: 65.4%) as a light yellow solid. MS (ESI) m / z (M+H) + =367.1.

[0426] De-BOC General Method

[0427] 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.

[0428] Embodiment 12: Preparation of compound 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6-(piperazin-1-yl)pyridin-3-yl)methyl)urea hydrochloride

[0429]

[0430] 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) was added HCl / MeOH (4 M, 2 mL) and 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.

[0431] 1H NMR(400MHz,DMSO-d6)δ10.90(br s,1H),9.66(br s,2H),8.05-7.92(m,2H),7.48-7.28(m,4H),7.21-7.10(m,2H),6.75(s,1H),4.30-4.20(m,2H),4.04-3.92(m,4H),3.24(br s,4H),1.57(s,6H).MS(ESI)m / z(M+H) + =517.2.

[0432] The following examples were synthesized using methods similar to those of Examples 8, 9, 10, 11 and 12 using appropriate intermediates and corresponding fragments:

[0433] Table 4

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684] Example 13: 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazol-2-yl)ureido)methyl)phenyl)piperazine- Preparation of tert-butyl 1-formate

[0685]

[0686] To 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 Pd / C (12 mg), and the mixture was stirred at room temperature under hydrogen pressure overnight. After filtration and evaporation, the obtained residue was purified by column chromatography on silica gel to give tert-butyl 4-(4-((3-(4-(1-(4-bromophenyl)ethyl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1-carboxylate (73 mg).

[0687] Example 14: 4-(5-(3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl-3-fluoropyrrolidone Preparation of tert-butyl (2-pyridin-2-yl)piperazine-1-carboxylate

[0688]

[0689] 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), Pd(dba) (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 N2 atmosphere. The reaction mixture was cooled to room temperature and the solid was filtered off, the residue was dissolved in ethyl acetate (100 mL) and washed with brine. The organic phase was dried over MgSO4, filtered, concentrated in vacuo to give the crude product, which was purified by flash column to give the desired product (67 mg, 25% yield).

[0690] Example 15: 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-2-(3- Preparation of 1-methylpiperazine-1-yl)benzamide

[0691]

[0692] 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

[0693]

[0694] 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 eq) and KOH (23.5 mg, 0.42 mmol, 1 eq) was heated to reflux for 0.5 h. After cooling, the reaction was quenched with saturated NH4Cl(aq), extracted with EA, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by preparative TLC to give the desired compound (215 mg).

[0695] 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

[0696]

[0697] 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 eq), EDCI (132 mg, 0.69 mmol, 2 eq), HOBt (93 mg, 0.69 mmol, 2 eq) and DIEA (133 mg, 1.03 mmol, 3 eq) was dissolved in THF (0.1 M) and stirred at room temperature for 15 min. NH4Cl (36.9 mg, 0.69 mmol, 2 eq) was then added in one portion and the reaction was stirred at room temperature. Once determined to be complete by TLC analysis, the resulting suspension was diluted with EtOAc and washed with brine and then dried (Na2SO4), filtered and evaporated to dryness. The resulting residue was purified by trituration or preparative TLC to give the desired product (201 mg).

[0698] Example 16: 1-((6-((2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl) Preparation of propan-2-yl)thiazole-2-yl)urea

[0699]

[0700] 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 eq) and 2-aminoethanol (11.9 mg, 0.19 mmol, 1.5 eq) in EtOH was heated to 90 °C for 14 h. After the reaction, it was cooled to room temperature and concentrated to give a residue, which was purified by silica gel column chromatography to give 1-((6-((2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea (21 mg).

[0701] Example 17: 1-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(1-(4-(piperazine- Preparation of 1-methyl)phenyl)ethyl)urea

[0702]

[0703] Step 1. Preparation of methyl 2-(4-methoxyphenyl)acetate

[0704]

[0705] To a mixture of 2-(4-methoxyphenyl)acetic acid (20.0 g, 120.4 mmol) in MeOH (100 mL) was added H2SO4 (1.2 g, 12.0 mmol, 642 μL) at 15 °C. The mixture was stirred at 85 °C for 12 h. The mixture was diluted with EA (400 mL), washed with saturated NaHCO3 aqueous solution (100 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 = 0-15%). The desired product (21.6 g, yield: 99.7%) was obtained as a yellow oil.

[0706] 1 H NMR(400MHz, CDCl3)δ7.21(d,J=8.8Hz,2H)6.87(d,J=8.8Hz,2H),3.80(s,3H),3.69(s,3H),3.58(s,2H)

[0707] Step 2. Preparation of compound 2-(4-methoxyphenyl)-3-oxobutanoic acid methyl ester

[0709]

[0710] At -78 ° C, LiHMDS (1M, 159 mL) was added to a solution of the compound (23.8 g, 132.2 mmol) obtained from step 1 above in THF (200 mL). The mixture was stirred at -78 ° C for 20 min. Acetoacetate (13.5 g, 132.2 mmol) was added to the solution. The mixture was then heated to 0 ° C and stirred for 2 h at 0 ° C. The mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was 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 obtain the desired compound (14.23 g, yield: 48.4%) as a yellow oil.

[0711] 1 H NMR (400MHz, CDCl3) δ12.97(s,1H),7.25-7.23(m,1.5H),7.07-7.03(m,2H),6.87 -6.85(m,2H),4.63(s,0.5H),3.80(s,3H),3.78(s,1.5H),3.73(s,1.5H),3.67(s,3H),2.15(s,1.5H),1.83(s,3H).MS(ESI)m / z(M+H) + =223.1

[0712] Step 3. Preparation of compound 2-(4-methoxyphenyl)-2-methyl-3-oxobutanoic acid methyl ester

[0713]

[0714] To a mixture of the compound (14.5 g, 65.4 mmol) obtained from step 2 above and K2CO3 (45.2 g, 326.9 mmol) in acetone (100 mL) was added CH3I (26.0 g, 183.3 mmol) at 15 ° C. The mixture was stirred at 70 ° C for 12 h. The mixture was filtered and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by a silica column (ethyl acetate in petroleum ether = 0-15%). The desired compound (9.76 g, yield: 63.2%) was obtained as a colorless oil.

[0715] 1 H NMR (400MHz, CDCl3) δ7.25-7.19(m,2H),6.95-6.86(m,2H),3.82(s,3H),3.79(s,3H),2.10(s,3H),1.77(s,3H)

[0716] Step 4. Preparation of compound 4-bromo-2-(4-methoxyphenyl)-2-methyl-3-oxobutanoic acid methyl ester

[0717]

[0718] To a solution of the compound obtained from step 3 above (1 g, 4.2 mmol) in CHCl (20 mL) was added Br (676 mg, 4.2 mmol) at 15 °C. The mixture was stirred at 73 °C for 12 h. The mixture was washed with H2O (20 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The target compound (1.03 g, crude) was obtained as a colorless oil. The crude product was used directly in the next step without further purification.

[0719] MS (ESI) m / z (M+H) + =315.1

[0720] Step 5. Preparation of methyl 2-(2-aminothiazol-4-yl)-2-(4-methoxyphenyl)propanoate

[0721]

[0722] A mixture of the compound (1.03 g, 3.3 mmol), thiourea (299 mg, 3.9 mmol) and NaHCO (329 mg, 3.9 mmol) obtained from step 4 above in MeOH (15 mL) was stirred at 50 ° C for 1 h. The mixture was directly concentrated in vacuo. The residue was ground with H2O (20 mL) at 15 ° C for 10 min, filtered and the filter cake was concentrated in vacuo to give a residue. The desired product (0.79 g, yield: 82.68%) was obtained as a yellow oil.

[0723] 1 H NMR (400MHz, CDCl3) δ7.20-7.18(m,2H),6.97-6.92(m,2H),6.88–6.86(m,2H),5.95(s,1H),3.73(s,3H),3.61(s,3H),1.77(s,3H).

[0724] Step 6. Preparation of methyl 2-(4-methoxyphenyl)-2-(2-((phenoxycarbonyl)amino)thiazol-4-yl)propanoate

[0725]

[0726] To the mixture of the compound (300 mg, 1.03 mmoL) obtained from step 5 above and pyridine (97.4 mg, 1.23 mmol) in CH3CN (3 mL) was added phenyl chloroformate (169 mg, 1.08 mmol) at 0°C. The mixture was stirred for 3 h at 15°C. The mixture was directly concentrated in vacuo. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-30%) to obtain the desired compound (330 mg, yield: 77.97%), and the obtained compound was a yellow oil.

[0727] MS (ESI) m / z (M+H) + =413.0

[0728] Step 7. Preparation of 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

[0729]

[0730] The compound obtained from step 6 above (330 mg, 800 μmol) and tert-butyl 4-[4-(1-aminoethyl)phenyl]piperazine-1-carboxylate (269 mg, 880 μmol) in THF (2 mL) were stirred under microwave at 100 ° C for 1 h. The mixture was directly concentrated 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.

[0731] MS (ESI) m / z (M+H) + =646.2.

[0732] Step 8. Preparation of tert-butyl 4-(4-(1-(3-(4-(1-hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate

[0733]

[0734] To the solution of the compound (370 mg, 593 μmol) obtained from step 7 above in THF (10 mL) was added LiBH4 (26 mg, 1.2 mmol) at 15 ° C. The mixture was stirred for 12 h at 15 ° C. The mixture was diluted with saturated NH4Cl (15 mL) and extracted with EA (3x15 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 obtain the desired compound (307 mg, yield: 87.0%), and the obtained compound was a yellow solid.

[0735] 1 H NMR (400MHz, CDCl3) δ7.17 (d, J = 8.4Hz, 2H), 7.09-7.06 (m, 2H), 6.86-6.80 (m, 4H), 6.45 (s, 1H), 4.94-4.91 (m, 1H), 4.05-4.0 0(m,1H),3.81-3.77(m,4H),3.56-3.54(m,4H)3.09-3.07(m,4H),1.56(d,J=1.6Hz,3H),1.49(s,9H),1.46(d,J=6.8Hz,3H).

[0736] Step 9. Preparation of the compound 1-(4-(1-hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea hydrochloride

[0737]

[0738] To a solution of the compound obtained from step 8 above (50 mg, 83.93 μmol) in DCM (2 mL) was added HCl / EtOAc (4 M, 2 mL) 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.

[0739] 1H NMR(400MHz,DMSO)δ10.47(br s,1H),9.11(br s,2H),7.36-7.23(m,1H),7.19(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),6.75(d,J=8.0Hz,2H),6.69(s,1H),4.77-4.73( 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=6.8Hz,3H).MS(ESI)m / z(M+H) + =496.2

[0740] 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

[0741]

[0742] DMSO (66 mg, 839 μmol) was added to a solution of oxalyl chloride (68.2 mg, 537.14 μmol) in DCM (2 mL) at -78 ° C. After 10 min, the compound (100 mg, 168 μmol) obtained from step 9 above in DCM (2 mL) was added and stirred for 1 h at -78 ° C. Et3N (170 mg, 1.68 mmol) was added and stirred for another 10 min, then warmed to 15 ° C, and stirred for another 1 h. The mixture was diluted with H2O (20 mL) and extracted with DCM (3x20 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 product) was obtained as a yellow oil. The crude product was directly used in the next step without further purification.

[0743] Step 11. Preparation of tert-butyl 4-(4-(1-(3-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-1-carboxylate

[0744]

[0745] A mixture of the compound obtained from step 10 above (100 mg, 168 μmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (49 mg, 252.6 μmol) and KCO (47 mg, 337 μmol) in MeOH (5 mL) was stirred at 15° C. for 1 h. The reaction was directly concentrated in vacuo. The residue was purified by preparative HPLC (column: Venusil ASB Phenyl 150*30mm*5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 65%-95%, 10 min) to obtain the desired compound (50 mg, yield: 50.34%), which was a yellow oil.

[0746] MS (ESI) m / z (M+H) + =590.3

[0747] Step 12. Preparation of the compound 1-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(1-(4-(piperazin-1-yl)phenyl)ethyl)urea

[0748]

[0749] The desired compound (39 mg, yield: 87.4%) was obtained as a yellow solid using the De-BOC method.

[0750] 1 H NMR(400MHz,DMSO-d6)δ10.50(br s,1H),9.22(br s,2H),7.31(d,J=8.8Hz,2H),7.19(d,J=8.4Hz,3H),6.95(d,J=8.4Hz,2H),6.85(dd,J=8.4,1.2Hz,2H),6.81-6.79(m,1H),4. 76-4.73(m,1H),3.71(s,3H),3.39(s,1H),3.35-3.32(m,4H)3.24-3.16(m,4H),1.82(d,J=2.4Hz,3H),1.33(d,J=6.8Hz,3H).

[0751] MS (ESI) m / z (M+NA) + =512.3

[0752] Example 18: 1-(4-(2-(4-cyclopropylphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl Preparation of urea

[0753]

[0754] 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

[0755]

[0756] To the compound (81 mg, 0.13 mmol) obtained from step 1 above in 1,4-dioxane (4 mL) and H2O (1 mL) was added cyclopropylboronic acid (14 mg, 0.16 mmol), Pd (dppf) Cl2 (10 mg, 0.013 mmol), KOAc (25 mg, 0.26 mmol). The reaction mixture was stirred overnight at 115 ° C under N2 atmosphere. The reaction progress was monitored by TLC. After the reaction was completed, 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.

[0757] Step 2. Preparation of compound 1-(4-(2-(4-cyclopropylphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea

[0758]

[0759] The desired compound (40 mg, HCl salt, yield: 100%) was obtained as a white solid using the procedure described in Example 9. MS (ESI) m / z (M+H)+ = 476.2.

[0760] Example 19: 1-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(2-hydroxyethyl-2,2- d2) Urea

[0761]

[0762] Step 1. Preparation of compound N-(2,2-dideuterio-2-hydroxyethyl)carbamate tert-butyl ester

[0763]

[0764] To a solution of methyl 2-((tert-butoxycarbonyl)amino)acetate (1 g, 5.29 mmol) in THF (20 mL) was added LiAlD4 (364.8 mg, 7.93 mmol) at 0 ° C, and the mixture was stirred at 80 ° C for 3 hours. EA (20 mL) and H2O (5 mL) were added dropwise, followed by extraction with EA (100 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The desired compound (610 mg, yield: 70.7%) was obtained as a yellow oil, which was used in the next step without further purification.

[0765] 1 H NMR (400MHz, CDCl3) δ5.17 (br s, 1H), 3.24 (d, J = 5.6Hz, 2H), 3.08 (br s, 1H), 1.42 (s, 9H).

[0766] Step 2. Preparation of compound 2-amino-1,1-dideutero-ethanol

[0767]

[0768] A mixture of the compound obtained from step 1 above (610 mg, 3.74 mmol) in HCl / MeOH (4 M, 5 mL) was stirred at 25° C. for 3 hours. The reaction mixture was concentrated. The desired compound (520 mg, crude, HCl) was obtained as a yellow oil, which was used in the next step without further purification.

[0769] 1 H NMR (400MHz, DMSO-d6) δ2.80 (q, J=5.7Hz, 2H).

[0770] Step 3. Preparation of phenyl N-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-yl]carbamate

[0771]

[0772] To a solution of 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazole-2-amine (500 mg, 1.90 mmol) and pyridine (752.60 mg, 9.51 mmol) in MeCN (20 mL) at 0 ° C., phenyl chloroformate (327.7 mg, 2.09 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The desired compound (830 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification.

[0773] MS (ESI) m / z (M+H) + =383.0

[0774] Step 4. Preparation of the compound 1-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-yl]-3-(2,2-dideutero-2-hydroxy-ethyl)urea

[0775]

[0776] The compound obtained from step 3 above (400 mg, 1.04 mmol) was stirred in a mixture of the compound obtained in step 2 (98.9 mg, 1.57 mmol) and DMAP (12.8 mg, 104.48 umol) in DCE (20 mL) at 80°C for 5 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Xtimate C18 150*40mm*5um; mobile phase: [water (HCl)-ACN]; B: 28%-58%, 10min) to obtain the desired compound (90 mg, yield: 24.5%), which was a white solid.

[0777] MS (ESI) m / z (M+H) + =352.1.

[0778] SFC: Column: ChiralPak IG-3 100×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: B from 5% to 40% in 5.5min, and maintain at 40% for 3min, then 5% B for 1.5min Flow rate: 2.5mL / min Column temperature: 40℃, (P1: Rf=4.159min, P2: Rf=4.831min).

[0779] Step 5. Preparation of the compound 1-[4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazol-2-yl]-3-(2,2-dideutero-2-hydroxy-ethyl)urea

[0780]

[0781] The compound obtained in the above step 4 (90 mg, 255.79 umol) was separated by SFC (column: DAICELCHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 40%-40%, min). The chiral isomer 1 (26.85 mg, yield: 29.8%) was obtained as a white solid.

[0782] 1 H NMR (400MHz, CDCl3) δ7.34-7.28(m,2H),7.22-7.19(m,2H),6.69(s,1H),3.23(d,J=5.5Hz,2H),2.48(s,1H),1.84(s,3H).MS(ESI)m / z(M+H) + =351.9.SFCRf=4.151min.

[0783] The desired chiral isomer 2 (27.90 mg, yield: 31.0%) was obtained as a white solid.

[0784] 1 H NMR (400MHz, CDCl3) δ7.43-7.35(m,2H),7.31-7.27(m,2H),6.76(s,1H),3.31(d,J=5.5Hz,2H),2.55(s,1H),1.92(s,3H).MS(ESI)m / z(M+H) + =351.9.SFC:Rf=4.815min.

[0785] General Method A

[0786] Carboxylic acid (1 eq.), EDCI (2-2.5 eq.) with or without HOBt (2 eq.) and DIEA (3 eq.) / pyridine / DMAP were dissolved in THF / DMF and stirred at room temperature for 15-30 min. Amine (1 eq.) was then added once and the reaction was stirred at room temperature to 70 ° C for 2-16 hours. Once the reaction was complete, the resulting suspension was diluted with an organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0787] Example 20: Compound 4-((2-hydroxyethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazole- Preparation of 2-aminobenzoic acid (2-yl)benzamide

[0788]

[0789] 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 umol, HCl) in Py (8 mL) was added EDCI (440.84 mg, 2.30 mmol). The mixture was stirred at 70 ° C for 16 hours. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: Agela ASB 150x25mm x 5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 48%-78%, 10 min) to obtain the desired compound (52 mg, yield: 13.57%) as a light yellow solid.

[0790] 1 H NMR(400MHz,DMSO-d6)δ12.06(br s,1H),7.87(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),6.86(s,1H),6.82(d,J=8.8Hz,2H),6.62(d,J=8 .8Hz,2H),3.70(s,3H),3.54(t,J=5.9Hz,2H),3.16(t,J=5.9Hz,2H),1.62(s,6H).MS(ESI)m / z(M+H) + =412.5.

[0791] General Method B

[0792] Acid chlorides are obtained by using SOCl in an appropriate solvent (like DCM). TEA or pyridine (3 eq.) and amine (1 eq.) in DCM are slowly added to the acid chloride solution under N at 0°C and further stirred at room temperature for 0.5-2h. Once the reaction is complete, it is quenched with H2O, extracted with EA and washed with brine and then dried (Na2SO4), filtered and evaporated to dryness. The resulting residue is purified by grinding / preparative TLC / chromatography / preparative HPLC to obtain the product.

[0793] Embodiment 21:

[0794]

[0795] To a solution of 4-(4-tert-butoxycarbonylpiperazine-1-yl)-2,6-difluoro-benzoic acid (150 mg, 438.16 umol) in DCM (6 mL) was added SOCl2 (31.8 uL, 438.16 umol). The mixture was stirred at 25 ° C for 1 hour. Py (176.74 uL, 2.19 mmol) was added and the reaction was stirred at 25 ° C for 5 min, then 4-[1-(4-chlorophenyl)-1-methyl-prop-2-ynyl]thiazole-2-amine (115.07 mg, 437.94 umol) was added and the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE: EA = 1: 0 to 1: 1). The desired compound (152 mg, yield: 54.4%) was obtained as a colorless oil.

[0796] MS (ESI) m / z (M+H) + =587.1.

[0797] Example 22: Preparation of the compound methyl N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-carboxamide

[0798]

[0799] To a solution of 3-[tert-butyl(diphenyl)silyl]oxycyclobutanecarboxylic acid (1.36 g, 3.84 mmol) in DCM (10 mL) was added PyBOP (2.00 g, 3.84 mmol) at 25° C. After stirring for 10 min, 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 at 25° C. and the mixture was stirred for 12 h at 25° C. The mixture was diluted with DCM (30 mL), washed with H2O (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The obtained 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

[0800] Table 5 The following examples were synthesized using the appropriate intermediates and corresponding fragments in a similar manner to the procedures of Examples 16, 17 and 18.

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927] Table 6 Experimental procedures similar to Examples 16, 17 and 18 were used to synthesize the following examples using appropriate intermediates and corresponding fragments.

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978] Table 7 Experimental procedures similar to Examples 17 and 18 were used to synthesize the following examples using appropriate intermediates and corresponding fragments.

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990] Example 23: 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl) Thiazol-2-yl) nicotinamide

[0991]

[0992] Step 1. Preparation of compound 6-chloro-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)nicotinamide

[0993]

[0994] A mixture of compound 4-(2-(4-methoxyphenyl)propan-2-yl)thiazole-2-amine (100 mg, 0.35 mmol, HCl salt), compound 6-chloronicotinic acid (83.0 mg, 0.53 mmol) and EDCI (135 mg, 0.70 mmol) in pyridine (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (PE: EA = 2: 1). The desired compound (63 mg, 46.26% yield) was obtained as a yellow oil.

[0995] MS (ESI) m / z (M+H) + =388.0

[0996] Step 2. Preparation of compound 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)nicotinamide

[0997]

[0998] A mixture of the compound obtained from step 1 above (63 mg, 0.16 mmol), N,N-dimethylethane-1,2-diamine (43.0 mg, 0.49 mmol) and DIEA (84.0 mg, 0.65 mmol) in DMF (5 mL) was stirred at 65 ° C for 16 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (water (0.05% HCl)-ACN]). The desired compound (25.01 mg, 35.0% yield) was obtained as a yellow solid.

[0999] 1 H NMR(400MHz,MeOD)δ8.43-8.32(m,1H),8.18-8.11(m,1H),7.35(s,1H),7.23 -7.14(m,3H),6.83(d,J=8.8Hz,2H),6.79(s,1H),3.76(m,4H),1.70(s,6H).

[1000] MS (ESI) m / z (M+H) + =440.2

[1001] Example 24: Compound 6-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-N-(4-(2-(p-tolyl)propane- Preparation of 2-thiazol-2-yl)nicotinamide

[1002]

[1003] To a solution of compound 6-(piperazin-1-ylmethyl)-N-(4-(2-(p-tolyl)propan-2-yl)thiazol-2-yl)nicotinamide (0.03 g, 69 μmol, 1 eq.) in CH3CN (10 mL) was added 2-bromoethanol (9.47 mg, 76 μmol, 5 μL, 1.1 eq.) and K2CO3 (19 mg, 137.8 μmol, 2 eq.). The reaction mixture was then stirred at 80°C for 16 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (water (0.225% FA)-ACN]; B%: 15%-45%, 7.5 min). The compound was obtained as a white solid (2.3 mg, yield: 6.9%).

[1004] 1H NMR (400MHz, CDCl3) δ9.09-9.05(m,1H),8.33-8.28(m,1H),7.75(br d,J=8.8Hz,3H),7.45-7.41(m,1H),7.13-7.08(m,3H),7.06-7.02(m,1H),6.61-6.57(m,1H),3.83-3.77(m,3H ),3.64-3.55(m,1H),2.45-2.38(m,8H),2.26-2.18(m,1H),1.63-1.58(m,3H),1.19(s,6H).MS(ESI)m / z(M+H) + =480.3.

[1005] Example 25: (1r, 3r)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl) Cyclobutane-1-carboxamide

[1006]

[1007] Step 1. Preparation of methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylate

[1008]

[1009] To a solution of methyl 3-(hydroxymethyl)cyclobutanecarboxylate (200 mg, 1.39 mmol) and imidazole (189 mg, 2.77 mmol) in DCM (5 mL) was added TBDPSCl (458 mg, 1.66 mmol, 427 μL) at 25 ° C. The solution was stirred at 25 ° C for 12 h. The mixture was diluted with DCM (30 mL), washed with H2O (3x10 mL), 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 (420 mg, yield: 79.1%) was obtained as a yellow oil.

[1010] MS (ESI) m / z (M+H) + =383.1

[1011] Step 2. Preparation of compound 3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxylic acid

[1012]

[1013] To the mixture of the compound (412 mg, 1.08 mmol) obtained from step 1 above in THF (1.5 mL) / MeOH (0.5 mL) / HO (0.5 mL) was added LiOH.HO (90.6 mg, 2.16 mmol) at 0 ° C. The mixture was stirred for 3 h at 25 ° C. The mixture was diluted with HO (15 mL), pH = 6-7 was adjusted, and EA (15 mL x 3) was extracted. The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to obtain 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.

[1014] MS (ESI) m / z (M+Na) + =391.1

[1015] Step 3. Preparation of methyl 2-(4-bromophenyl)-2-(2-((1R,3R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamido)thiazol-4-yl)propanoate

[1016]

[1017] The compound (410mg, 1.11mmol) obtained from step 2 above and DIPEA (173mg, 1.34mmol, 233μL) solution in DCM (5mL) was stirred at 20°C for 10min. 2-(2-aminothiazole-4-yl)-2-(4-bromophenyl)propionic acid methyl ester (152mg, 446μmol) and PyBOP (580mg, 1.11mmol) were added at 20°C. The mixture was stirred at 20°C for 12h. The mixture was diluted with DCM (30mL), washed with H2O (10mL), brine (10mL), 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 A (194mg, crude product) was obtained as a yellow oil. Another desired compound B (186mg, crude product) was obtained as a yellow oil. The crude product was used directly in the next step without further purification.Confirmation of the chirality of the product in the final step.

[1018] Step 4. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)-1-hydroxypropan-2-yl)thiazol-2-yl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide

[1019]

[1020] To the solution of the compound (194 mg, 280.4 μmol) obtained from step 3 above in THF (5 mL) was added LiBH4 (31 mg, 1.40 mmol) at 20 ° C. The mixture was stirred at 20 ° C for 12 h. The mixture was quenched with saturated NH4Cl aqueous solution (10 mL), diluted with H2O (20 mL) and extracted with EA (20 mL x 3). The organic layer was washed with 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 = 0-30%). The desired compound (77 mg, yield: 41.4%) was obtained as a yellow oil.

[1021] MS (ESI) m / z (M+H) + =663.1

[1022] 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

[1023]

[1024] To the mixture of Dess-Martin (73mg, 171.2μmol, 53μL) in DCM (2mL) at 20°C, add the compound (77mg, 132μmol) obtained from step 4 above in DCM (2mL) solution. The mixture is stirred at 20°C for 3h. The mixture is quenched with saturated NaHCO (10mL) / saturated Na2S2O4 (10mL), extracted with DCM (15mL x 3). The combined organic layer is washed with brine (10mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain a residue. The desired compound (77mg, crude product) is obtained as a yellow solid. The crude product is directly used in the next step without further purification.

[1025] Step 6. Compound (1R,3R)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-

[1026] Preparation of (((tert-butyldiphenylsilyl)oxy)methyl)cyclobutanecarboxamide

[1027]

[1028] To the compound obtained from step 5 above (77 mg, 116 μmol), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (34 mg, 174.5 μmol) and K2CO3 (32 mg, 232.7 μmol) in MeOH (2 mL) was stirred at 20 ° C for 12 h. 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.

[1029] MS (ESI) m / z (M+H) + =657.1

[1030] Step 7. Preparation of compound (1R,3R)-N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl)cyclobutanecarboxamide

[1031]

[1032] To a solution of the compound (37 mg, 56.3 μmol) obtained from step 6 above in THF (2 mL) was added TBAF (1 M, 0.1 mL) at 20 ° C. The mixture was stirred at 20 ° C for 12 h. 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.

[1033] 1 H NMR (400MHz, CDCl3) δ13.28 (br s, 1H), 7.56-7.48 (m, 4H), 6.91 (s, 1H), 3.65 (d, J = 4.4Hz, 2H), 3.34 -3.30(m,1H),2.77(s,1H),2.63-2.61(m,1H),2.52-2.43(m,2H),2.34-2.32(m,2H),2.15(s,3H).MS(ESI)m / z(M+H) + =419.0.

[1034] Another isomer was synthesized using a similar procedure as above.

[1035] Example 26: 4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-N-(4-(2-(4-methoxyphenyl)propane-2- base)

[1036] Thiazol-2-yl)benzamide

[1037]

[1038] 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) was added NaBH3CN (59 mg, 0.95 mmol) and HOAc (2 drops). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (DCM:MeOH=1:0 to 10:1). The desired compound (80 mg, yield: 51.4%) was obtained as a white solid.

[1039] MS (ESI) m / z (M+H) + =495.2

[1040] How to use

[1041] ALPK1 is an intracytoplasmic serine-threonine protein kinase that plays an important role in activating the innate immune response. ALPK1 binds to molecular pattern metabolites (PAMPs) associated with bacterial pathogens, ADP-D-glyceryl-β-D-mannoheptose (ADP-heptose). ALPK1-ADP-heptose binding occurs through direct interactions at the ALPK1 N-terminal domain. This interaction stimulates the kinase activity of ALPK1 and its phosphorylation and activation of TRAF interacting proteins and forkhead-associated domains (TIFA). TIFA activation in turn triggers pro-inflammatory NFkB signaling, including expression and / or secretion of pro-inflammatory cytokines and chemokines. Therefore, the compounds disclosed herein are generally useful as inhibitors of downstream activation of ALPK1 kinase activity and NFkB pro-inflammatory signaling.

[1042] The present disclosure provides the use of a compound of Formula 1 as described herein or its sub-implementation body for inhibiting ALPK1 kinase activity and reducing inflammation in target tissues. The method also includes using a compound of Formula 1 as described herein or its sub-implementation body for treating a disease, disorder or condition characterized by excessive or inappropriate alpk1-dependent proinflammatory signaling. In an embodiment, the disease is a kidney disease, disorder or condition. In an embodiment, kidney disease, disorder and condition include but are not limited to: chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic kidney disease (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, hypotension in dialysis, obstructive uropathy, glomerular disease, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, renal disease such as primary and congenital nephropathy, nephritis, Alport syndrome, renal inflammation, immune nephropathy, renal transplant rejection, immune complex-induced nephropathy, toxic substances-induced nephropathy, and contrast agent-induced nephropathy; Minimal change glomerulonephritis (lipidoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (whose diagnostic features may be, for example, abnormally decreased creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolality or urine volume, microalbuminuria, increased macroalbuminuria, glomerular and arteriole damage, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD), chronic uric acid nephropathy and the syndrome of insufficient secretion of diuretic hormone (SIADH).

[1043] In an embodiment, the present disclosure provides a method of inhibiting ALPK1 kinase activity in a mammalian cell or target tissue by contacting the cell or target tissue with a compound of Formula I or a sub-embodiment described herein. In an embodiment, 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 a target cell or tissue of the subject. In an embodiment, the method comprises reducing inflammation in a target tissue 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 compound.

[1044] In an embodiment, the present disclosure provides a method for treating a subject with a disease or condition characterized by excessive or inappropriate activation of ALPK1 kinase activity. In an embodiment, the method comprises administering to the subject a compound of Formula I or a sub-embodiment described herein. In an embodiment, the disease is a kidney disease, disorder or condition. In an embodiment, kidney diseases, disorders or conditions include, but are not limited to, chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic nephropathy (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, hypotension in dialysis, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, renal diseases such as primary and congenital kidney disease, nephritis, Alport syndrome, renal inflammation, immune kidney disease, renal transplant rejection, immune complex-induced kidney disease, toxic substance-induced kidney disease, contrast agent-induced kidney disease; minor disease Degenerative glomerulonephritis (lipidic), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (whose diagnostic features may be, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolality or urine volume, microalbuminuria, increased macroalbuminuria, glomerular and arteriole damage, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disturbances (e.g., hyperkalemia, hyponatremia, disorders of bone and carbohydrate metabolism, polycystic kidney disease (PCKD), chronic uric acid nephropathy and the syndrome of inadequate antidiuretic hormone secretion (SIADH).

[1045] In an embodiment, the present disclosure further provides a method of identifying a disease, disorder or condition for treatment with a compound of Formula I or a sub-embodiment described herein, the method comprising assaying a biological sample from a subject diagnosed with the disease, disorder or condition for one or more activating mutations in ALPK1 and overexpression of ALPK1 mRNA or protein in cells or tissues involved in the disease, disorder or condition in the biological sample as compared to a reference cell or tissue not involved in the disease, disorder or condition.

[1046] In the context of the methods described herein, the term "treating" may refer to the improvement or stabilization of one or more symptoms associated with the disease, disorder or condition being treated. The term "treating" may also include the management of the disease, disorder or condition, which refers to the beneficial effects that a subject obtains from the treatment, but such treatment does not cure the underlying disease, disorder or condition.

[1047] 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 the desired therapeutic result, such as improvement or stabilization of one or more symptoms of the disease, disorder or condition being treated.

[1048] In embodiments, a therapeutically effective amount is an amount required to achieve a therapeutic effect at least equivalent to that of a standard therapy. An example of a standard therapy is a drug approved by the FDA for the treatment of the same disease, disorder or condition.

[1049] In the context of any of the methods described herein, the subject is preferably a human, but may be a non-human mammal, preferably a non-human primate. In other embodiments, the non-human mammal may be, for example, a dog, 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.

[1050] In embodiments, the human subject is selected from an adult, a child, or a geriatric patient, as such terms are understood by medical practitioners, such as those defined by the U.S. Food and Drug Administration.

[1051] The present disclosure provides methods of treating kidney diseases, disorders and conditions comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of Formula I or a sub-example described herein.

[1052] In an embodiment, the method described herein may include a monotherapy using a compound of formula (I) or a sub-embodiment described herein, or a combination therapy, such as a treatment regimen comprising a compound of formula (I) or a sub-embodiment described herein, used in combination with one or more other therapies or active agents. In an embodiment, administration of a compound of formula (I) or a sub-embodiment described herein, or a treatment regimen comprising the compound, results in a reduction or elimination of at least one symptom of the disease or condition being treated, the disease or condition being characterized by excessive or inappropriate activation of ALPK1 kinase activity (e.g., kidney disease, disorders, and conditions), or improvement of at least one marker of disease progression or disease severity. In an embodiment, the method reduces the production of autoantibodies and the resulting autoimmune sequelae and pathology by an appropriate disease-related scale.

[1053] In embodiments, provided herein are methods for treating kidney. The methods include administering a compound of formula (I) or a sub-embodiment described herein, or a treatment regimen including a compound of formula (I) or a sub-embodiment described herein, and at least one additional therapy or therapeutic agent. The disclosed methods reduce or eliminate at least one symptom of kidney disease, disorder, and condition.

[1054] In embodiments directed to methods of treating kidney diseases, disorders and conditions, administration of a compound of formula (I) or a sub-embodiment described herein, or a treatment regimen comprising a compound of formula (I) or a sub-embodiment described herein and at least one additional therapy or therapeutic agent, results in a reduction or elimination of at least one marker of disease progression or disease severity. Such markers may include, but are not limited to, plasma BUN, plasma UREA, plasma creatinine, proteinuria, C-reactive protein (CRP), IL-6, IL-17A / F, TNFa, and CCL-2.

[1055] Kidney diseases, disorders and conditions

[1056] Kidney disease, or nephropathy, technically known as nephropathy, refers to damage or disease of the kidneys. Nephritis is an inflammatory kidney disease that is divided into several types depending on the site of inflammation. Inflammation can be diagnosed through blood tests. Nephropathy is a non-inflammatory kidney disease. Nephritis and nephropathy can cause nephritic syndrome and nephrotic syndrome, respectively. Kidney disease usually results in some loss of kidney function and may lead to renal failure, which is a complete loss of kidney function. Kidney failure is known as the end stage of kidney disease, and dialysis or a kidney transplant are the only treatment options.

[1057] Chronic kidney disease is defined as kidney abnormalities (functional and / or structural) that persist for more than three months. Acute kidney disease, now called acute kidney injury, is characterized by a sudden decline in kidney function within seven days.

[1058] Exemplary renal diseases, disorders, and conditions treated by the compounds disclosed herein include, but are not limited to, chronic kidney disease (CKD), lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic nephropathy (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, renal diseases such as primary and congenital renal disease, nephritis, Alport syndrome, renal inflammation, immune renal disease, renal transplant rejection, immune complex-induced renal disease, toxic substance-induced renal disease, contrast-induced Kidney disease; minimal change glomerulonephritis (lipidic), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis and nephrotic syndrome (whose diagnostic features may be, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar damage, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD), chronic uric acid nephropathy and syndrome of inadequate antidiuretic hormone secretion (SIADH).

[1059] Cytokines are protein mediators that play a key role in inflammation. Cytokines are a very diverse group of molecules that include more than 100 secreted factors that can be subdivided into several categories: interleukins (IL), tumor necrosis factor (TNF), interferons (IFN), transforming growth factor (TGF), colony stimulating factor (CSF) and various chemokines. Cytokines are produced by T cells, monocytes, macrophages and platelets, as well as endothelial cells (EC), SMC and adipocytes in response to inflammation and other stimuli. Increased production of proinflammatory cytokines is associated with disease progression and promotes kidney disease.

[1060] Some clinical evidence suggests that anti-inflammatory treatment with anti-TNF-α therapy for patients with rheumatoid arthritis and anti-IL-1β therapy for patients with a prior MI can reduce the incidence of cardiovascular events. The present invention is based in part on the inventors' discovery that the ALPK1 small molecule inhibitors described herein mediate inflammatory responses in model systems associated with kidney disease, as further described in the Examples section below.

[1061] Combination therapy

[1062] The present disclosure also provides methods including combination therapy. As used herein, "combination therapy" or "synergistic therapy" includes administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof with at least one additional therapy or active agent (also referred to herein as an "active pharmaceutical ingredient" ("API")) as part of a treatment regimen, intended to provide a beneficial effect through the combined action of the compound of formula (I) or its pharmaceutically acceptable salt and the additional active agent. According to the embodiments described below, "additional API" should be understood to refer to at least one additional therapeutic agent administered with the compound of formula (I) or its pharmaceutically acceptable salt in a combination therapy regimen. The additional API can be administered in the same or different dosage form as the compound of formula (I) or its pharmaceutically acceptable salt; and the additional API can be administered by the same or different route of administration as the compound of formula (I) or its pharmaceutically acceptable salt. In addition, it should be understood that a variety of additional APIs described below can be used in a combination therapy regimen. The term "combination therapy" or "combination therapy regimen" is not intended to cover the administration of two or more therapeutic compounds as part of a single single therapy regimen, which accidentally and arbitrarily produce unexpected or unpredicted beneficial effects.

[1063] Preferably, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more other APIs described herein to produce a synergistic response in the treated subject. In this context, the term "synergistic" means that the efficacy of the combination is greater than the additive effect of any one monotherapy used alone.

[1064] The synergistic effect of the combination therapy of the present disclosure may allow the use of a lower dose and / or a less frequent administration of at least one of the agents in the combination compared to the dose and / or frequency outside the combination. Additional beneficial effects of the combination may be manifested as the avoidance or reduction of adverse or unwanted side effects associated with the use of either therapy in the combination alone (also referred to as monotherapy).

[1065] In combination therapy, administration of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be simultaneous or sequential with administration of one or more other active agents or APIs. In another embodiment, the frequency of administration of different components of the combination therapy may be different.

[1066] In an embodiment, the additional API can be formulated to be co-administered with a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dosage form. The additional API can also be administered separately from a dosage form comprising a 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, the same or different routes of administration can be used, and / or the administration can be at the same time or at different times.

[1067] In embodiments of methods directed to combination therapies for treating kidney diseases, disorders, and conditions, the methods can include administering a compound of Formula (I) as described herein, or a subembodiment thereof, and at least one additional therapeutic agent selected from SGLT2 inhibitors, phosphate binder drugs, erythropoiesis stimulating drugs, vitamin D analog drugs, vaptan drugs, corticosteroid drugs, aldosterone antagonist drugs, iron supplements, opioid receptor agonist drugs, cholesterol-lowering drugs, antithrombotic agents, and blood pressure-lowering drugs.

[1068] In an embodiment, the present disclosure provides a method for treating kidney diseases, disorders and conditions characterized by excessive or aberrant ALPK1-dependent proinflammatory 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 sub-embodiments thereof as described herein.

[1069] In an embodiment, the compound of formula I, IA, IB, IC or its sub-embodiment is used in combination with a partial adenosine A1 receptor agonist and a mineralocorticoid receptor (MR) antagonist for the treatment and prevention of kidney disease, particularly acute and chronic renal insufficiency and acute and chronic renal failure, and for further protecting the kidney. 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, neladenosone, neladenoson bialanine and capadison.

[1070] In embodiments, the compound of Formula I, IA, IB, IC, or subembodiments 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.

[1071] In an embodiment, the compound of Formula I, IA, IB, IC or a subembodiment thereof is combined with an SGLT2 inhibitor. Exemplary SGL2 inhibitors include, but are not limited to, dapagliflozin, empagliflozin, canagliflozin, ipagliflozin and togliflozin.

[1072] In an embodiment, a compound of Formula I, IA, IB, IC, or a sub-embodiment thereof is combined with an antithrombotic agent. Exemplary antithrombotic agents include, but are not limited to, platelet aggregation inhibitors, anticoagulants, profibrinolytic substances, fat metabolism altering agents, thyroid receptor agonists, cholesterol synthesis inhibitors (e.g., HMG-CoA reductase and squalene synthesis inhibitors), ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPARα, PPARγ, PPARδ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

[1073] In an embodiment, a compound of Formula I, IA, IB, IC, or a sub-embodiment thereof is combined with a blood pressure lowering drug. Exemplary blood pressure lowering drugs 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.

[1074] Pharmaceutical composition

[1075] In an embodiment, the disclosure provides a pharmaceutical composition, which includes a compound of formula I as described herein or its sub-embodiment, and one or more carriers or excipients, preferably a pharmaceutically acceptable carrier or excipient. As used herein, the phrase "pharmaceutically acceptable" refers to a compound, material, composition, carrier and / or dosage form suitable for contacting with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, and with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Excipients for preparing pharmaceutical compositions are generally those known to be safe and nontoxic excipients when applied to humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, sterile liquids, water, buffered saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), oils, detergents, suspending agents, carbohydrates (e.g., glucose, lactose, sucrose or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, and a suitable mixture of any of the above substances. The particular excipient employed in the composition will depend on a variety of factors, including the chemical stability and solubility of the formulated compound and the intended route of administration.

[1076] The pharmaceutical composition may be provided in bulk or unit dosage form. Formulating the pharmaceutical composition in unit dosage form is particularly advantageous for ease of administration and uniformity of dosage. The term "unit dosage form" refers to physically discrete units suitable as unit doses for the subject to be treated; each unit contains 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, intravenous bag, or a single pump on an aerosol inhaler.

[1077] In therapeutic applications, dosages may vary depending on the chemical and physical properties of the active compound and the clinical characteristics of the subject, including, for example, age, weight, and comorbidities. Typically, the dosage should be a therapeutically effective amount. An effective amount of a pharmaceutical composition refers to an objectively identifiable improvement observed by a clinician or other qualified observer. For example, a symptom of a condition, disorder, or illness is alleviated.

[1078] 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.) to be administered by any desired route (e.g., pulmonary, inhalation, intranasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, transdermal, transmucosal, rectal, etc.). In an embodiment, the pharmaceutical composition is an oral acceptable dosage form, including but not limited to capsules, tablets, buccal forms, lozenges, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions, or solutions. Capsules may contain excipients, such as inert fillers and / or diluents, including starch (e.g., corn, potato, or tapioca starch), sugar, artificial sweeteners, powdered cellulose (e.g., crystalline cellulose and microcrystalline cellulose), flour, gelatin, gum, etc. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, may also be added.

[1079] In an embodiment, the pharmaceutical composition is in the form of a tablet. The tablet may include a unit dose of a compound described herein and an inert diluent or carrier, such as a sugar or sugar alcohol, such as lactose, sucrose, sorbitol or mannitol. The tablet may also include a non-sugar derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starch, such as corn starch. The tablet may also include a binder and a granulating agent, such as polyvinyl pyrrolidone, a disintegrant (e.g., a swellable cross-linked polymer, such as cross-linked carboxymethyl cellulose), a lubricant (e.g., stearate), a preservative (e.g., paraben), an antioxidant (e.g., butylhydroxytoluene), a buffer (e.g., a phosphate or citrate buffer) and an effervescent agent, such as a citrate / bicarbonate mixture. The tablet may be a coated tablet. The coating may be a protective film coating (e.g., wax or varnish) or a coating for controlling the release of an active compound, such as delayed release (release of an active substance after a predetermined lag time after ingestion) or release at a specific location in the gastrointestinal tract. The latter can be achieved, for example, by using an enteric film coating, such as those sold under the brand name Enteric film coating for sale.

[1080] Tablet formulations can be made by conventional compression, wet granulation or dry granulation methods, and use pharmaceutically acceptable diluents, adhesives, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers, including but not limited to magnesium stearate, stearic acid, talcum powder, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethyl cellulose, polyvinyl pyrrolidone, gelatin, alginic acid, gum arabic, xanthan gum, sodium citrate, composite silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talcum powder, dry starch and powdered sugar. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include but are not limited to poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, polyhexetol emulsifying wax, sorbitol esters, colloidal silicon dioxide, phosphates, sodium lauryl sulfate, magnesium aluminum silicate and triethanolamine.

[1081] In an embodiment, the pharmaceutical composition is in the form of a hard or soft gelatin capsule.Depending on the formulation, the compound of the invention may be in solid, semi-solid or liquid form.

[1082] In an embodiment, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion suitable for parenteral administration. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[1083] In an embodiment, the pharmaceutical composition is in the form of a sterile aqueous solution or dispersion, suitable for intravenous infusion administration by direct injection or addition to a sterile infusion solution, and comprises a solvent or a dispersion medium, wherein the solvent or the dispersion medium comprises water, ethanol, a polyol (such as glycerol, propylene glycol and liquid polyethylene glycol), a suitable mixture thereof or one or more vegetable oils. The solution or suspension can be prepared in water by means of a cosolvent or a surfactant. The example of a suitable surfactant includes polyethylene glycol (PEG)-fatty acid and PEG-fatty acid monoester and diester, PEG glyceride, alcohol-oil transesterification product, polyglycerol fatty acid, propylene glycol fatty acid ester, sterol and sterol derivatives, polyethylene glycol sorbitol fatty acid ester, polyethylene glycol alkyl ether, sugar and derivatives thereof, polyethylene glycol alkylphenol, polyoxyethylene-polyoxypropylene (POE-POP) block copolymer, sorbitol fatty acid ester, ionic surfactant, fat-soluble vitamins and salts thereof, water-soluble vitamins and amphiphilic derivatives thereof, amino acids and salts thereof, organic acids and esters thereof and anhydrides thereof. Dispersions can also be prepared, for example, in a mixture in glycerol, liquid polyethylene glycol and oil.

[1084] The present disclosure also provides packaging and kits comprising pharmaceutical compositions for use in the methods described herein. The kit may include one or more containers selected from bottles, vials, ampoules, blister packs, and syringes. The kit may also include one or more instructions for use, one or more syringes, one or more applicators, or a sterile solution suitable for reconstitution of a compound or composition described herein.

[1085] All percentages and ratios used herein are by weight unless otherwise specified.

[1086] The present invention is further described and illustrated by the following non-limiting examples.

[1087] example

[1088] In embodiments, the compounds of Formula I or subembodiments described herein are inhibitors of ALPK1, such as in in vitro kinase assays or assays designed to measure activation of downstream targets of ALPK1 pathway activation, such as NFkB transcriptional activation and secretion of proinflammatory cytokines and chemokines, such as IL-8, which is also known as CXCL-8.

[1089] The following examples also provide additional evidence for ALPK1 as a therapeutic target for kidney disease, and for the small molecule ALPK1 inhibitors described herein for the treatment of 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, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, intradialytic hypotension, obstructive urinary tract disease, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, renal disease (e.g., primary and congenital kidney disease), nephritis, Alport syndrome, renal inflammation, immune kidney disease, renal transplant rejection, immune complex-induced kidney disease, renal viral agents, contrast-induced nephropathy; minimal change glomerulonephritis (lipidic), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal Cysts, hypertensive nephrosclerosis and nephrotic syndrome (whose diagnostic features include, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, changes in urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilatation, hyperphosphatemia and / or the need for dialysis), uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD), chronic uric acid nephropathy and syndrome of inadequate antidiuretic hormone 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 can inhibit NF-kB reporter gene activity in HEK293 cells stimulated by the ALPK1 agonist D-glycero-D-mannose-6-fluoro-heptose-1β-S-ADP. The following examples also include ALPK1 transgenic HEK293 cells showing SNPs ALPK1 of rs2074380 or rs2074381 can reduce the kinase activity of ALPK1 when activated by the ALPK1 agonist D-glycerol-D-mannose-6-fluoro-heptose-1β-S-ADP. The following examples also include studies on in vivo rat models of chronic kidney disease induced by UUO, in which the ALPK1 inhibitor C008 showed anti-fibrotic efficacy. The following examples also include studies on in vivo rat models of chronic kidney disease induced by adenine diet, in which the ALPK1 inhibitor C008 showed the efficacy of protecting glomerular function and anti-fibrosis.

[1090] ALPK1 in vitro kinase assay

[1091] ALPK1 kinase activity was measured in an in vitro assay. ADP-Heptose was used as an ALPK1 activator to activate kinase activity. Since phosphorylated TIFA proteins oligomerize, protein-protein interactions between HA-tagged TIFA proteins were measured using homogeneous time-resolved fluorescence (HTRF) as an indicator of TIFA phosphorylation.

[1092] In brief, dose response studies were performed in 384-well assay plates. Each well contained 0.1 mg TIFA, ALPK1 (final concentration in the reaction mixture was 2 nM) and kinase buffer (100 mM HEPES pH 7.4, 4 mM DTT, 40 mM MgCl2, 20 mM β-glycerophosphate disodium salt, 0.4 mM Na3VO4, 0.16 mg / mL). Titration of the test compound was prepared in dimethyl sulfoxide (DMSO). The reaction was initiated by adding ATP and ADP-Heptose.

[1093] For HTRF, the RT-PCR was performed according to the manufacturer's instructions (PerkinElmer TM 、CisBio TM ), the samples were incubated with Tb cryptate-labeled anti-HA antibodies to capture the HA-tagged protein, and the fluorescence signal was quantified (Tecan Infinite FNANO+). The HTRF signal was calculated as the HTRF ratio (fluorescence ratio measured at 665nm and 620nm) × 104 (thus using the signal at 620nm as an internal standard).

[1094] In this assay, all compounds showed a dose-dependent decrease in TIFA phosphorylation. IC50 values ​​were determined by 3 or 4 parameter logistic equations using GraphPadPrism version 6.00. Reference compound A027 was used as a positive control for each plate. In this assay, the IC50 of this compound was ~50 nanomolar (nM). The IC50 values ​​of the test compounds ranged from 1 to 1000 nM, as shown in Table 1. Table 4-7 shown.

[1095] NFκB alkaline phosphatase reporter gene detection method

[1096] Inhibition of ALPK1-dependent NFκB reporter gene activation was measured using an alkaline phosphatase reporter gene assay system. Briefly, HEK293 cells stably expressing the NF-kB reporter gene (referred to herein as "G9 cells") were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Hyclone TMFor the assay, cells were seeded at a density of 10,000 cells / well in Freestyle TM 293 expression medium (ThermoFisher) in 96-well plates and allowed to attach overnight. Cells were pretreated with serial dilutions of the compounds for 30 minutes and then stimulated with D-glycero-D-mannose-6-fluoro-heptose-1β-S-ADP. This compound is an analog of ADP-heptose and exhibits higher stability in vitro while having similar ability to activate ALPK1 kinase activity. NFkB gene activation was detected using the chromogenic substrate p-nitrophenyl phosphate (pNPP) according to the manufacturer's protocol (pNPP phosphatase assay, Beyotime Biotechnology). In this assay, all compounds showed a dose-dependent reduction in NFkB promoter-driven gene expression. IC50 values ​​ranged from 1-10 micromolar (μM), as shown in Table 4-7 shown.

[1097] ALPK1 SNPs are associated with chronic kidney disease

[1098] The rs2074380 and rs2074381 SNPs of ALPK1 are significantly associated with chronic kidney disease in patients with diabetes (Yamada Y, Nishida T, Ichihara S, Kato K, Fujimaki T, Oguri M, Horibe H, Yoshida T, Watanabe S, Satoh K, Aoyagi Y, Fukuda M, Sawabe M. Chromosome 3q28 and ALPK1 identified as susceptibility loci for chronic kidney disease in Japanese individuals 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 result in amino acid changes in G870S and N916D. Both SNPs were found to be protective against chronic kidney disease. To examine whether the mutated amino acid affects the activity of ALPK1, we overexpressed wild-type ALPK1 and its mutant forms ALPK1-G870S and ALPK1-N916D in the renal cell line HEK293 cells and treated them with 100nM D-glycero-D-mannose-6-fluoro-heptose-1β-S-ADP (a derivative of ADP-heptose) to stimulate ALPK1 activation. ELISA analysis of IL8 in the supernatant showed that both ALPK1-G870S and ALPK1-N916D resulted in a decrease in IL8 compared with wild-type ALPK1. These results suggest that mutations G870S and N916D reduce the activity of ALPK1 in activating downstream IL8 expression. ( Figure 1 ) Therefore, we speculated that these changes may lead to reduced ALPK1 protein activity in chronic kidney disease, and inhibiting ALPK1 activity may have a protective effect on chronic kidney disease. We tested this hypothesis by treating chronic kidney disease model rats with the ALPK1 inhibitor C008.

[1099] Inhibition of ALPK1 in the kidney

[1100] We investigated whether ALPK1 inhibitors could inhibit the activation of ALPK1-dependent genes in rats. Animals were orally administered compound C008, and ALPK1-dependent gene expression was induced by intraperitoneal injection of the ALPK1 agonist D-glycerol-D-mannose-6-fluoro-heptose-1β-S-ADP. Kidneys were collected and gene expression was analyzed as described in more detail below. Thirty-six male Sprague-Dawley (SD) rats were randomly divided into 6 groups. The first control group (“normal”) was orally administered with vehicle (0.5% MC) and PBS was injected intraperitoneally (ip) 21 hours later. The second control group (“vehicle”) was orally administered with vehicle (0.5% MC) and 21 hours later with an intraperitoneal injection of the ALPK1 agonist D-glycerol-D-mannose-6-fluoro-heptose-1β-S-ADP (50 μpk). The treatment groups were orally administered with ALPK1 inhibitors (2, 5, 10, 20 mpk) and 21 hours later with an intraperitoneal injection of ALPK1 agonists. Three hours after administration of the ALPK1 agonist, kidneys were collected from each group. RNA was isolated and the expression of MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1β and IL-6 mRNA in the samples was analyzed by RT-PCR. In brief, total RNA was extracted according to the protocol of the RNeasy Mini Kit (QIAGEN, Germany). Messenger RNA was reverse transcribed into cDNA using the HiScriptQ RT SuperMix for qPCR Kit (Vazyme, Nanjing, China). Quantitative PCR was performed on a QuantStudio 5 Applied Biosystem (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 normalization of gene expression. The data are presented as gene fold changes relative to their respective expressions in the control group. As Figure 2 As shown, the mRNA expressions of CCL-2, CCL-7, CXCL-1, CXCL-10, IL-1β, and IL-6 were significantly decreased in the C008-treated group compared with the vehicle group.

[1101] Inhibition of ALPK1 in the unilateral ureteral obstruction (UUO) model

[1102] Renal fibrosis is a common pathway in most progressive renal diseases. The unilateral ureteral obstruction (UUO) model is widely used to study renal fibrosis. Moreover, experimental UUO in rodents is thought to mimic human chronic obstructive nephropathy in an accelerated manner. (Martínez-Klimova E, Aparicio-Trejo OE, Tapia E, Pedraza-Chaverri J. Unilateral ureteral obstruction as a model to study fibrosis-attenuating treatments. Biomolecules. 2019 Apr 8;9(4):141. doi:10.3390 / biom9040141. PMID:30965656; PMCID:PMC6523883.) Here we tested the effects of the ALPK1 inhibitor C008 (2, 7, 20 mg / kg) on ​​the rat UUO model. Briefly, we ligated the left ureter of rats and then started daily oral treatment for 7 days immediately after surgery, and then measured renal fibrosis by hydroxyproline content measurement and Sirus red staining. Due to the extent of renal inflammation, we used hydroxyproline (OH-P) content as an indicator of total protein to explain UUO-induced fibrosis and the efficacy of the compound ( Figure 3A ) For completeness, we also analyzed the OH-P content as an indicator of tissue quality ( Figure 3B ). UUO increased renal cortical OH-P compared with sham-operated controls. ALK5i and C008 (7 mpk and 20 mpk) attenuated the UUO-induced increase in renal cortical OH-P. Sirius Red staining composite data represent the average of 3 anatomically different depths (10 images / depth / rat / group = approximately 60-65% of renal cortical area). Renal cortical fibrosis (measured as collagen volume fraction (CVF; by quantifying Sirius Red-stained tissue sections) was increased in UUO-obstructed kidneys receiving vehicle compared with sham-operated controls. ALK5i and C008 (7 mpk and 20 mpk) attenuated the UUO-induced increase in renal cortical CVF ( Figure 4A , 4B ). All these results indicate that C008 can inhibit UUO-induced renal fibrosis in a dose-dependent manner. We also examined the renal gene expression of different doses of C008 (5, 10, 20 mg / kg) in another study and found that C008 inhibited genes related to fibrosis and inflammation ( Figure 5 ).

[1103] Inhibition of ALPK1 in adenine-induced chronic kidney disease

[1104] A 0.25% adenine diet produces pathophysiological changes that resemble the structural and functional changes seen in human chronic kidney disease (CKD), characterized by renal dysfunction, renal inflammation, elevated fibrotic and oxidative markers, and increased tubulointerstitial fibrosis, tubular epithelial cell apoptosis, and 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.) We tested the effects of the ALPK1 inhibitor C008 (7, 20 mg / kg) on ​​an adenine diet-induced rat CKD model. We dosed the compound starting on day 14 after initiation of the adenine diet and continued for 6 weeks. During the study, we collected plasma weekly and measured blood urea nitrogen (BUN) ( Fig. 6A ) and creatine ( Figure 6B ) levels. Adenine ingestion increased plasma BUN and creatinine on days 7 to 56 compared with the control group. ALK5i attenuated the increases in plasma BUN and creatinine induced by adenine on days 35-56. C008 attenuated the increases in plasma BUN induced by adenine on days 42 (20mpk), 49 (7&20mpk), and 56 (20mpk), as well as the increases in plasma creatinine induced by adenine on days 35 (20mpk), 49, and 56 (7&20mpk). At the end of the study, we collected rat kidneys to quantify renal fibrosis by measuring hydroxyproline content. The results showed that adenine consumption increased renal cortical OH-P content indexed by tissue mass compared with the control group. ALK5i attenuated the adenine-induced increase in renal cortical OH-P content indexed by tissue mass. C008 (7mpk) attenuated the adenine-induced increase in renal cortical OH-P content indexed by tissue mass. ( Figure 7 ) Sirius red staining composite data represent the average of 3 anatomically different depths (10 images / depth / rat / group = approximately 60-65% of renal cortical area) Adenine depletion increased renal cortical fibrosis compared with non-diseased controls, expressed as collagen volume fraction (CVF; by quantitative PSR staining of tissue sections). ALK5i attenuated adenine-induced increase in renal cortical CVF. C008 (7 and 20 mpk) attenuated adenine-induced increase in renal cortical CVF ( Fig. 8A , B). The results showed that C008 could significantly inhibit renal dysfunction and renal fibrosis caused by adenine diet.

[1105] MRL / MpJ-Fas lpr Inhibition of ALPK1 in the mouse lupus nephritis model

[1106] The MRL / MpJ-Faslpr / J mouse model is similar to human systemic lupus erythematosus. This mouse model also develops kidney damage and is valuable for studying the efficacy of drugs to treat lupus nephritis. To evaluate the efficacy of the ALPK1 inhibitor C008 in the treatment of lupus nephritis, 12 vehicle-treated non-disease control mice ("MRL / MpJ") and 12 vehicle-treated disease control mice ("MRL / MpJ-Fas lpr / J, vehicle”) were orally administered with vehicle (0.1% MC) every day, 36 MRL / MpJ-Fas lpr / J mice (12 per group) were orally treated with C008 3mg / kg or 10mg / kg daily, and another group was intraperitoneally injected with cyclophosphamide 50mg / kg once a week. The animals were sacrificed after 8 weeks of treatment, and urine was collected and proteinuria was assessed using urine protein test strips ( Fig. 9 The right kidney was removed and stained with hematoxylin and eosin (H&E) for pathological evaluation ( Fig. 10A -G). In addition, qPCR was used to quantify the mRNA expression levels of Ccl2, Ccl4, Ccl5, Ccr1 and IL-6 in the left kidney ( Fig.11 ).

[1107] In summary, the proteinuria score in the C008 10 mg / kg group was significantly reduced compared with the control group. In terms of renal pathology, the pathological scores of glomerular diameter, crescents, interstitial inflammation, protein casts, and lupus nephritis activity index in mice in the 10 mg / kg C008 group were significantly reduced. In terms of gene expression, the mRNA expression of Ccl2, Ccl4, Ccl5, Ccr1, and IL-6 in the C008 group was significantly reduced compared with the control group. These results indicate that C008 can improve renal function in the lupus nephritis disease model and alleviate the renal morphological changes caused by the disease.

[1108] Hotspot kinase analysis

[1109] The assay is based on the transfer of 33P-labeled phosphate from ATP to the kinase substrate. ALPK1 kinase activity can be measured by detecting the remaining radioactive phosphorylated substrate TIFA. Briefly, the substrate TIFA is prepared in freshly prepared reaction buffer (buffer conditions: 20mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.01% Brij35, 0.02mg / ml BSA, 0.1mM Na3VO4, 2mM DTT, 1% DMSO). The required cofactors are delivered to the above substrate solution. The kinase ALPK1 is delivered to the substrate solution and mixed gently. C008 in DMSO is added to the kinase reaction mixture using acoustic technology (Echo550). 33P-ATP (final specific activity 0.01 μCi / μl) was injected into the reaction mixture to initiate the reaction. The kinase reaction was incubated at room temperature for 60 minutes. The reactants were dropped onto P81 ion exchange paper (Whatman #3698-915). The filter was thoroughly washed with 0.75% phosphoric acid and the residual radioactive phosphorylated substrate on the filter paper was measured. Data analysis: Kinase activity data are expressed as the percentage of the remaining kinase activity in the test sample reacted with the carrier (dimethyl sulfoxide). IC50 values ​​and curve fitting were obtained using Prism4 software (GraphPad).

[1110] Equivalent

[1111] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

[1112] All references cited herein are incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety and for all purposes.

[1113] The present invention is not limited to the scope of the specific embodiments described herein. In fact, various modifications of the present invention, in addition to those described herein, will become apparent to those skilled in the art based on the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for treating kidney diseases, disorders and conditions in a subject in need of such treatment, the method comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein A is selected from a bond, azetidinyl, -O-, -N(R 6 )-、-CH2-N(R 6 )-、-CHR 9 -N(R 6 )-,in R 6 is selected from H, -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 alkoxy, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, and optionally substituted saturated or unsaturated C3-C6 cycloalkoxy, wherein Optionally substituted R 6 The moiety includes 0-3 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, and C1-C6 alkoxy; R 9 is selected from optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkoxy, wherein Optionally substituted R 9 The moiety contains 0-2 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 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7f R 8f 、-OR 7f 、-OC(O)(R 7f )、-C(O)(R 7f )、-C(O)N(R 7f R 8f )、-C(O)O(R 7f )、-S(O)2(R 7f )、-S(O)ON(R 7f R 8f ) and -N(R 7f R 8f ) of a substituent, wherein Each R 7f and R 8f Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; 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 haloalkoxy, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 alkoxy, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkoxy, optionally substituted monocyclic or bicyclic aryl, optionally substituted containing 1-4 selected from N, O and S 5-10 membered heteroaryl with heteroatom ring vertices; 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; wherein the optionally substituted R 1 The moiety contains 0-4 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 alkoxy, C1-C6 haloalkoxy, -R 7a , -X 1 -R 7a , CHR 7a R 8a 、-OR 7a 、-OX 1 -R 7a , -X 1 -OX 1 -R 7a 、-OC(O)(R 7a ),-OX 1 -C(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a ),-NR 7a (CO)R 8a 、-C(O)O(R 7a )、S(O)2R 7a 、-S(O)2N(R 7a R 8a )、-N(R 7a R 8a ), a saturated or unsaturated C3-C6 cycloalkyl, a saturated or unsaturated C3-C6 cycloalkoxy, a saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, a monocyclic or bicyclic aryl, a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S, 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 a 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; wherein Each X 1 Independently for C 1-6 Alkylene; Each R 7a and R 8a independently selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, containing 1- 2 saturated or unsaturated 3-7 membered heterocyclic groups with 2 heteroatom ring vertices selected from N, O and S, wherein the aryl and 3-7 membered heterocyclic groups are substituted with 0-3 substituents 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 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and The C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 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 substituted with 0 to 3 moieties selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, -C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b ),-NR 7b (CO)R 8b 、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in Each R 7b and R 8b independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; or R 1 and R 6 Combined to form a 3-6 membered heterocycloalkyl substituted with 0-3 moieties independently selected from the group consisting of halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy; R 5 is selected from the group consisting of H, deuterium, halo, C1-C6 alkyl, C1-C6 deuterated alkyl and C1-C6 haloalkyl; R 2 and R 3 each independently selected from H, OH, C1-C6 alkyl and C2-C6 alkynyl, wherein C1-C6 alkyl and C2-C6 alkynyl are each substituted by 0-3 moieties independently selected from the following: halo, -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -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 ),in Each R 7c and R 8c Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; The condition is R 2 and R 3 Not all H; or R 2 and R 3 The 3-7 membered heterocyclic group is combined to form a C3-C6 cycloalkyl ring or a 3-7 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O and S, wherein the formed ring may be optionally substituted by 1-2 independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 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 ) is substituted by a substituent, wherein Each R 7d and R 8d Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; Each R 4 independently selected from halo, -OH, -NH2, CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, CHR 7e R 8e , OR 7e 、OC(O)(R 7e )、C(O)(R 7e )、C(O)N(R 7e R 8e )、C(O)O(R 7e )、S(O)2N(R 7e R 8e ) and N(R 7e R 8e ),in Each R 7e and R 8e independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, and The subscript p is 0, 1, 2, or 3.

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

3. The method according to claim 1, wherein A is azetidinyl. The method according to claim 1 , wherein A is —O—.

5. The method of claim 1, wherein A is -N(R6)-.

6. The method of claim 1, wherein A is -CH2-N(R6)-.

7. The method according to claim 1, wherein A is -CHR 9 -N(R6)-.

8. The method according to claim 1, which has formula IA or a pharmaceutically acceptable salt thereof.

9. The method according to claim 1, which has the formula IA-1 or a pharmaceutically acceptable salt thereof.

10. The method according to claim 1, which has the formula IA-2 or a pharmaceutically acceptable salt thereof.

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

12. The method according to any one of claims 1 to 8, wherein R 9 Selected from CH3 and CH2OH.

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

14. The method according to any one of claims 1 to 13, wherein R 1 is selected from H and optionally substituted C1-C6 alkyl, wherein The optionally substituted C1-C6 alkyl group comprises 0-4 independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7a R 8a 、-OR 7a 、-OC(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a )、-C(O)O(R 7a )、-S(O)2R 7a 、-S(O)2N(R 7a R 8a ) and -N(R 7a R 8a ) of a substituent, wherein Each R 7a and R 8a Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

15. The method according to any one of claims 1 to 13, wherein R 1 is an optionally substituted saturated or unsaturated C3-C6 cycloalkyl group, wherein The optionally substituted C3-C6 cycloalkyl includes 0-4 substituents independently selected from halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

16. The method according to any one of claims 1 to 13, wherein R 1 With R 6 Combine to form a 3-6 membered heterocycloalkyl substituted by 0-3 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxy.

17. The method according to any one of claims 1 to 13, wherein R 1 is a C1-C6 alkyl group substituted by 0-4 substituents independently selected from the following: -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -OC(O)(R 7a )、-S(O)2N(R 7a R 8a ) and -N(R 7a R 8a ),in Each R 7a and R 8a Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

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

19. The method according to any one of claims 1 to 13, wherein R 1 is an optionally substituted C1-C6 hydroxyalkyl group.

20. The method according to any one of claims 1 to 13, wherein R 1 is a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S at the vertices of the ring, The 5-10 membered bicyclic heteroaryl is substituted by 0 to 3 moieties selected from the following: halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

21. The method according to any one of claims 1 to 13, wherein R 1 is a pyridyl group substituted by 0 to 3 moieties selected from the group consisting of halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, a 3-7 membered heterocyclic group containing 1-2 heteroatoms selected from N, O and S, wherein The 3-7 membered heterocyclic group is substituted by 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, C1-C6 alkenyl, and C1-C6 haloalkyl.

22. The method according to any one of claims 1 to 13, wherein R 1 is a saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatoms selected from N, O and S, wherein The 7-8 membered bridged heterocyclic group is substituted by 0-3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

23. The method according to any one of claims 1 to 13, wherein R 1 is a saturated or unsaturated 7-11 membered spiro heterocyclic group containing 1-2 heteroatoms selected from N, O and S, wherein The 7-11 membered spiro heterocyclic group is substituted by 0-3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b , OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

24. The method according to any one of claims 1 to 13, wherein R 1 is an aryl group substituted with 0-3 substituents selected from the following: a halo group, a 3-7 membered heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, a 7-8 membered bridged heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S; and a saturated or unsaturated 7-11 membered spiroheterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, wherein The 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl and 7-11 membered spiroheterocyclyl are substituted by 0 to 3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2R 7b 、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

25. The method according to any one of claims 1 to 13, wherein R 1 is an aryl group substituted by 0-3 moieties 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, C1-C6 alkoxy, and a 3-7 membered heterocyclyl group containing 1-2 heteroatom ring vertices selected from N, O and S, The 3-7 membered heterocyclic group is substituted by 0-3 moieties 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, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

26. The method according to any one of claims 1 to 13, wherein R 1 It is an aryl group substituted by 0-3 moieties selected from the following: a halo group and a 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, and the 3-7 membered heterocyclic group is further substituted by 0-3 moieties selected from -OH, -COOH, -NH2, =O, -CN and -C1-C6 alkyl.

27. The method of claim 1 having formula IB or a pharmaceutically acceptable salt thereof, wherein D is CR 10 or N; E is CR 14 or N; F is CR 12 or N; G is CR 11 or N; The condition is that no more than three of D, E, F and G are N; R 10 , R 11 , R 12 , R 13 and R 14 , when present, are each independently selected from H, halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -R 7a , -X 1 -R 7a , X 1 -OX 1 -R 7a 、-CHR 7a R 8a 、-OR 7a 、-OX 1 -R 7a 、-OC(O)(R 7a ),-OX 1 -C(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a )、-C(O)O(R 7a )、S(O)2R 7a 、-S(O)2N(R 7a R 8a )、-N(R 7a R 8a ), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, saturated or unsaturated 3-7 membered heterocyclic group 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 heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S; and saturated or unsaturated 7-11 membered spiro heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S; 6-11 membered bicyclic heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S; wherein Each X 1 Independently for C 1-6 Alkylene; Each R 7a and R 8a independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and The 3-7 membered heterocyclyl, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, 7-8 membered bridged heterocyclyl, 7-11 membered spiroheterocyclyl and 6-11 membered bicyclic heterocyclyl are each independently substituted by 0 to 2 moieties selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7g R 8g 、-OR 7g 、-OC(O)(R 7g )、-C(O)(R 7g )、-C(O)N(R 7g R 8g ),-NR 7g (CO)R 8g 、-C(O)O(R 7g )、-S(O)2N(R 7g R 8g ) and -N(R 7g R 8g ),in Each R 7g and R 8g Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

28. The method according to claim 27, wherein D, E, F and G are CR 10 , CR 14 , CR 12 and CR 11 .

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

30. The method according to any one of claims 27 to 29, wherein R 10 and R 11 Each is H; R 12 and R 14 Each is 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 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in R 7b and R 8b Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; R 13 is selected from a 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, a saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, and a saturated or unsaturated 7-11 membered spiroheterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, wherein The 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl and 7-11 membered spiroheterocyclyl are optionally substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

31. The method according to any one of claims 27 to 29, wherein R 12 and R 14 is H; R 10 and R 11 Each is 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 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ),in R 7b and R 8b Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and R 13 is selected from a 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, a saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, and a saturated or unsaturated 7-11 membered spiroheterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, wherein The 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl and 7-11 membered spiroheterocyclyl are optionally substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

32. The method according to any one of claims 27 to 29, wherein R 10 , R 11 , R 12 and R 14 , when present, are each H; and R 13 is selected from saturated or unsaturated C3-C6 cycloalkyl, 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, saturated or unsaturated 7-11 membered spiroheterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, wherein The 3-7 membered heterocyclyl, 7-8 membered bridged heterocyclyl and 7-11 membered spiroheterocyclyl are optionally substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

33. The method according to any one of claims 27 to 29, wherein R 10 , R 11 , R 12 and R 14 , when present, are each H; and R 13 It is a 3-7 membered heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, which is substituted by 0-2 moieties independently selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

34. The method according to any one of claims 27 to 29, wherein R 10 , R 11 , R 12 and R 14 , when present, are each H; and R 13 It is an optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclic group containing 1-2 heteroatom ring vertices selected from N, O and S, which is substituted by 0-2 substituents selected from -OH, -COOH, -NH2, =O, -CN and -C1-C6 alkyl.

35. The method of claim 27, having formula IB-1 or 1B-2 or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from -OH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-C(O)(R 7b )、-C(O)N(R 7b R 8b )、-C(O)O(R 7b )、-S(O)2R 7b and -S(O)2N(R 7b R 8b ),in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

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

37. The method according to claim 35 or 36, wherein R 15 Selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b ,in Each R 7b and R 8b Independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

38. The method according to claim 35 or 36, wherein R 15 Selected from C1-C6 alkyl.

39. The method according to any one of claims 35 to 38, which has formula IB-1-a or formula IB-2-a or a pharmaceutically acceptable salt thereof.

40. The method according to any one of claims 35 to 38, which has formula IB-1-b or formula IB-2-b or a pharmaceutically acceptable salt thereof, wherein R 4 It is a halo group.

41. The method according to any one of claims 35 to 38, which has formula IB-1-c or formula IB-2-c or a pharmaceutically acceptable salt thereof.

42. The method according to claim 1, which has the formula IC or a pharmaceutically acceptable salt thereof, wherein m is an integer between 0 and 6; R 18 is selected from H, halo, -OH, -COOH, -NH2, -CN, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -R 7a , -X 1 -R 7a , CHR 7a R 8a 、-OR 7a 、-OX 1 -R 7a , X 1 -OX 1 -R 7a 、-OC(O)(R 7a ),-OX 1 -C(O)(R 7a )、-C(O)(R 7a )、-C(O)N(R 7a R 8a ),-NR 7a (CO)R 8a 、-C(O)O(R 7a )、S(O)2R 7a 、-S(O)2N(R 7a R 8a )、-N(R 7a R 8a ), a saturated or unsaturated C3-C6 cycloalkyl, a saturated or unsaturated C3-C6 cycloalkoxy, a saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S, a monocyclic or bicyclic aryl, a 9-10 membered bicyclic heteroaryl containing 1-4 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 a 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O and S; wherein Each X 1 Independently for C 1-6 Alkylene; Each R 7a and R 8a independently selected from H, C1-C6 alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, containing 1-2 a saturated or unsaturated 3-7 membered heterocyclic group with a heteroatom ring vertex selected from N, O and S, wherein the aryl and 3-7 membered heterocyclic groups are substituted by 0-3 substituents selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy; and The C3-C6 cycloalkyl, C3-C6 cycloalkoxy, 3-7 membered heterocyclyl, monocyclic or bicyclic aryl, 9-10 membered bicyclic heteroaryl, saturated or unsaturated 7-8 membered bridged heterocyclyl, saturated or unsaturated 7-11 membered spiroheterocyclyl, 6-11 membered bicyclic heterocyclyl are each independently substituted by 0 to 3 moieties selected from the following: halo, -OH, -COOH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxy, -CHR 7b R 8b 、-OR 7b 、-OC(O)(R 7b )、-C(O)(R 7b )、-C(O)N(R 7b R 8b ),-NR 7b (CO)R 8b 、-C(O)O(R 7b )、-S(O)2N(R 7b R 8b ) and -N(R 7b R 8b ), where R 7b and R 8b Each is independently selected from H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxy.

43. The method of claim 42, wherein m is 1.

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

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

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

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

48. The method according to any one of claims 1 to 44, wherein R 2 is methyl and R 3 It is CH2OMe.

49. The method of any one of claims 1 to 38 or 42 to 48, wherein the subscript p is 1, and R 4 Attached to the phenyl ring as follows: The wavy lines represent points of attachment to the rest of the formula.

50. The method of any one of claims 1 to 38 or 42 to 48, wherein subscript p is 1, and R 4 is a halide attached to a phenyl ring as shown below: The wavy lines represent points of attachment to the rest of the formula.

51. A method according to any one of claims 1 to 38 or 42 to 48, wherein the subscript p is 1, and R 4 is a chlorine attached to a phenyl ring as shown below: The wavy lines represent points of attachment to the rest of the formula.

52. The method of any one of claims 1 to 38 or 42 to 48, wherein subscript p is 1, and R 4 is a methoxy group attached to a phenyl ring as shown below: The wavy lines represent points of attachment to the rest of the formula.

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

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

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

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

57. The method according to any one of claims 1 to 52, wherein R 5 Selected from -CH2D, -CHD2 and -CD3.

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

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

60. The method according to claim 1, wherein the compound of formula I is selected from 61. The compound of claim 1 selected from the Tables or Examples disclosed herein.

62. The method of claim 1, wherein the compound is selected from the Tables or Examples disclosed herein.

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

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

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

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

67. The method of claim 66, wherein the kidney disease, disorder or condition is one or more of lupus nephritis, membranous nephropathy, non-diabetic chronic kidney disease (ndCKD), diabetic nephropathy (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, lytic hypotension, obstructive dialysis, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial disease. Primary and congenital kidney disease, nephritis, Alport syndrome, kidney inflammation, immune nephropathy, renal transplant rejection, nephropathy caused by immune complexes, nephropathy caused by toxic substances, nephropathy caused by contrast agents and other kidney diseases; subtle change glomerulonephritis (lipidic), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis, nephrotic syndrome, uremia, anemia, electrolyte disorders, hyperkalemia, hyponatremia, bone and carbohydrate metabolism disorders, polycystic kidney disease (PCKD), chronic uric acid nephropathy and syndrome of insufficient ADH secretion (SIADH).

68. The method of any one of claims 1 to 67, comprising administering to a subject the compound in combination with one or more drugs.

69. The method of claim 68, wherein 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 drugs, and any combination thereof.

70. The method of claim 69, wherein the MR antagonists include spironolactone, eplerenone, adalactone, carlopir, and fenidone.

71. The method of claim 69, wherein the partial adenosine A1 receptor agonists include naladenosine, naladenosine dipropionate, and kappadenosine.

72. The method of claim 69, wherein: Diuretics include thiazide diuretics, thiazide-like diuretics, carbonic anhydrase inhibitors, and potassium-sparing diuretics.

73. The method of claim 69, wherein the SGL2 inhibitor comprises dapagliflozin, empagliflozin, canagliflozin, empagliflozin, and topagliflozin.

74. The method of claim 69, wherein the antithrombotic agent comprises a platelet aggregation inhibitor, an anticoagulant, a fibrinolytic substance, a fat metabolism altering agent, a thyroid receptor agonist, a cholesterol synthesis inhibitor, an ACAT inhibitor, a CETP inhibitor, an MTP inhibitor, a PPARα, PPARγ, PPARδ agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a polymeric bile acid adsorbent, a bile acid reabsorption inhibitor, and a lipoprotein (a) antagonist.

75. The method of claim 69, wherein the blood pressure lowering drugs include ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, diuretics, beta-blockers, endothelin antagonists, renin inhibitors, alpha-blockers, and mineralocorticoid co-receptor antagonists.

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

77. The method of any one of claims 68 to 75, wherein the compound is administered with one or more drugs.

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