Alpha protein kinase 1 inhibitors and methods of use

Abstract

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

Description

[01] The present invention relates to compounds that are inhibitors of alpha protein kinase 1 (ALPK1) and related compositions and methods. BACKGROUND OF THE INVENTION

[02] Alpha-kinases display 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, elongated factor-2 kinase (eEF2K), and transient receptor potential cation channel M6 and M7 (TRPM6 and TRPM7). See Ryazanov et al., Cure Biol 9:R43-45 (1999) and Ryazanov et al., Proc Natl Acad Sci USA 94:4884-4889 (1997).

[03] 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 with forkhead-associated domain (TIFA) dependent proinflammatory nuclear factor-kappa-B (NFkB) signaling. See Zimmermann et al. Cell Rep. 20:2384-2395 (2017); Milivojevic et al., PLoS Pathog. 13 :E1006224-E1006224 (2017); and Zhou et al., Nature 561:122-126 (2018).

[04] Inappropriate activation of ALPK1 signaling has been implicated in diseases and disorders associated with excessive or inappropriate inflammation. For example, ALPK1 has been implicated in monosodium urate monohydrate (MSU)-induced inflammation and gout. Lee et al., Sci. Rep. 6:25740-25740(2016). Elevated ALPK1 expression has also been associated with lymph node metastasis and tumor growth in oral squamous cell carcinoma. Chen et al., Am J Pathol 189:190-199 (2019). In addition, genetic mutations in ALPK1 have been associated with spiroandenoma, spiroandenocarcinoma, “Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and migraine Headache” (“ROSAH”) syndrome, and “Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis” (“PFAPA”) syndrome. See e.g., Rashid et al., Nature Communications (2019); Williams et al., Genetics in Medicine 21:2103-2115 (2019); and Sangiorgi et al. Eur. J. Human Genetics (2019). SUMMARY OF THE INVENTION 105] The disclosure provides compounds of Formula 1 and subembodiments of Formula I described herein, that are inhibitors of ALPK1 kinase activity, and related compositions and methods.

[06] In some aspects, provided herein are compounds of Formula I Formula I wherein A, p, Rl, R2, IV, R4 and R5 are as defined herein

[07] In some embodiments, compounds of Formula I are represented by Formula IA Formula IA wherein p, R1, R2, R3, R4,R5, R6, and R9 are as defined herein.

[08] In some embodiments, compounds of Formula I are represented by Formula IA-1 Formula IA-1 wherein p, R1, R2, R3, R4„R\ R6, and R9 are as defined herein.

[09] In some embodiments, compounds of Formula I are represented by Formula IB Formula IB wherein p, R2, R3, R4, R5, R1 J, D, E, F, and G are as defined herein.

[10] In some embodiments, compounds of Formula I are represented by Formula IB-1 Formula IB-1 Wherein p, R2, R3, R4, R5, R!5, R16, and R17 are as defined herein. In some embodiments, compounds of Formula I are represented by Formula IC R3 R5 Formula IC Wherein p, m, R2, R3, R4, R5, R18 are as defined herein.

[12] In some aspects, provided herein are compounds of Formula XI, R3 Mr4) R5 Formula XI wherein X, A, p, R1, R2, R3, R4 and R5 are as defined herein, [131 In some embodiments, compounds of Formula I are represented by Formula XI-A, R3 Formula XI-A wherein X, p, R1, R2, R3, R4,R3, R6, and R9 are as defined herein.

[14] In some embodiments, compounds of Formula I are represented by Formula XI-A-1, R3 Formula XI-A-1 wherein X, p, R1, R2, R3, R4,R5, Rb, and R9 are as defined herein.

[15] In some embodiments, compounds of Formula I are represented by Formula XI-A-1 a. P Formula XI-A-l-a wherein p, R1, R2, R3, R4,R5, Rb, and R9 are as defined herein.

[16] In some embodiments, compounds of Formula I are represented by Formula XI-B, Formula XI-B wherein X, p, R2, R3, R4, R3, Ri3, D, E, F, and G are as defined herein.

[17] In some embodiments, compounds of Formula I are represented by Formula XI-B-1, Formula XI-B-1 wherein X, p, R2, RJ, R4, R3, R15, RlD, and Rl' are as defined herein.

[18] In some embodiments, compounds of Formula I are represented by Formula XI-B-1 - Formula XI-B-l-a wherein p, R2, R3, R4, R5, Rl3, Ri6, and Rj 7 are as defined herein.

[19] In some embodiments, compounds of Formula I are represented by Formula XI-C, Formula XI-C wherein X, p, m, R2, R3, R4, R3, Ri8 are as defined herein.

[20] In some embodiments, compounds of Formula XI are represented by Formula XI-C-1, Formula XI-C-1 wherein p, m, R2, R3, R4, R5, RiS are as defined herein.

[21] In embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a subembodiment thereof, as described herein. In embodiments, the disclosure provides a method for inhibiting ALPK1 kinase activity in a cell or tissue of a subject in need of such therapy, the method comprising administering to the subject a compound of Formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a subembodiment thereof as described herein.

[23] In embodiments, the disclosure provides a method for inhibiting or reducing inflammation in a target tissue of a subject in need of such treatment, the method comprising administering to the subject a compound of Formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a subembodiment thereof, as described herein.

[24] In embodiments, the disclosure provides a method for treating a disease, disorder, or condition characterized by excessive or inappropriate ALPK1 -dependent proinflammatory signaling in a subject in need of such therapy, the method comprising administering to the subject a compound of Formula I, IA, IB, IC, XI, XI-A, XI-B, or XI-C, or a subembodiment thereof, as described herein.

[25] In embodiments, the disease, disorder, or condition is selected from sepsis, cancer, spiroandenoma, spiroandenocarcinoma, “Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and migraine Headache” (“ROSAH”) syndrome, and “Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis” (“PFAPA”) syndrome.

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

[27] In embodiments, the disease or disorder is selected from ROSAH and PFAPA.

[28] In embodiments, the disease or disorder is sepsis.

[29] In embodiments, the disease or disorder is spiradenoma or spiroandenocarcinoma,

[30] In embodiments, the subject in need of such therapy or treatment is a subject carrying one or more genetic mutations in ALPK1. In embodiments, at least one mutation is an activating mutation. BRIEF DESCRIPTION OF THE FIGURES

[31] FIG, 1: Bar graph showing IL-8 secretion (pg / ml) in HEK293 cells transiently transfected with empty vector, or expression vectors encoding human ALPK1 (hALPKl), an activating mutation in hALPKl (T237M, V1092A) or an activating mutation combined with a kinase dead mutation in ALPK1 (hALPKl -T237M-D1194S).

[32] FIG .2: Treatment groups were administered 4, 10 or 25 mg / kg of the ALPK1 inhibitor AOI76 2 hours prior to the agonist, D-glycero-D-manno-6-fluoro-heptose-ip-S-ADP. 3 hours after agonist administration, the kidney tissues were examined for inhibition of gene expression of innate immunity genes including MCP-1 (CCL-2), CCL-7, CXCL-1, CXCL-10, IL-1 P, IL-6 mRNA. AO 176 showed a dose-dependent inhibition of gene expression levels. **p<0.01, ***p<0.001 vs Vehicle-PO+A0176-IP-3hr by two-way-ANOVA

[33] FIG. 3; In the sepsis induced acute kidney injury animal model, compounds C008 and A0176 (20 mg / kg) were administered to treatment groups of animals 2 hours prior to the surgery. Survival was recorded over the following 24 hours. Both compounds improved the animals’ survival rate.

[34] FIG 4: In the sepsis induced acute kidney injury animal model, compounds COOS and A0176 (20 mg / kg) were administered to treatment groups of animals 2 hours prior to the surgery. 24 hours post-surgery, the kidneys were collected for gene expression analysis by Q-PCR. The data show that ALPK1 inhibitors decreased expression of kidney proinflammatory genes including IL6, TNFa, IL-1 b, CCI2 and Keratinocyte chemoattractant (KC) chemokine. *p<0.05, **p<0.01, p<0.001, vs. CLP-Vehicle

[35] FIG 5: In the sepsis induced acute kidney injury animal model, compounds C008 and A0176 (20 mg / kg) were administered to treatment groups of animals 2 hours prior to the surgery . 24 hours post-surgery, plasma MCP-1 concentration was measured by ELISA. ALPK1 inhibitors improved the plasma MCP-1 levels. ***p<0.001 vs. CLP vehicle by oneway ANOVA DETAILED DESCRIPTION

[36] The disclosure provides compounds that are inhibitors of ALPK1, compositions comprising same, and methods for their use in therapy.

[37] The term “ALPK1” is used herein to refer interchangeably to isoform 1 (Q96QP1-1) or the alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB - Q96QP1 (ALPK1HUMAN).

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

[39] As used herein, “alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, Ci-i, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C&. 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, an alkenyl group has 1 double bond. Alkenyl groups can be substituted or unsubstituted.

[40] As used herein, “alkynyl” refers to a straight chain or branched hydrocarbon having 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 Ce. Alkynyl groups can have any suitable number of triple bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. In some embodiments, an alkynyl group has 1 triple bond. Alkynyl groups can be substituted or unsubstituted.

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

[42] As used herein, the term “alkoxy” or “alkoxyl” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxyl groups can have any suitable number of carbon atoms, such as Cl -6. Alkoxyl groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be substituted or unsubstituted.

[43] As used herein, the term “alkenyloxy” or “alkenyloxyl” refers to an alkenyl group, as defined above, having an oxygen atom that connects the alkenyl group to the point of attachment: alkenyl-O-. Alkenyloxyl groups can have any sui table number of carbon atoms, such as Cl-6. Alkenyloxyl groups can be further substituted with a variety of substituents described within. Alkenyloxyl groups can be substituted or unsubstituted.

[44] “Aminoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched mono valent hydrocarbon radical of three to six carbons substituted with -NR’R” where R’ and R” are independently hydrogen, alkyl, haloalkyl, or hydroxyalkyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[45] As used herein, the term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.

[46] As used herein, the term “haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as Ci-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc.

[47] As used herein, the term “haloalkoxyl” or “haloalkoxy” refers to an alkoxyl group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as Ci-6. The alkoxy groups can be substituted with 1, 2, 3, or more halogens.

[48] As used herein, the term “deuteroalkyl” means an alkyl radical as defined above wherein one to six hydrogen atoms in the alkyl radical are replaced by deuterium, e.g., -CI N). -CHIT. -CD3, -CH2CD3, and the like.

[49] As used herein, the term "hydroxyalkyl” refers to an alkyl radical wherein 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.

[50] As used herein, the term “oxo” refers to an oxygen atom connected to the point of attachment by a double bond (=0).

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

[52] As used herein, the term “heteroaryl” refers to a monocyclic or fused bicyclic aromatic ring assembly containing 5 to 12 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, 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 from 5 to 9 ring members and from 1 to 4 heteroatoms, or from 5 to 9 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), purine. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazin.es such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[53] As used herein, “’cycloalkyl” refers to a saturated ring assembly containing from 3 to 10 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8. Cycloalkyl rings can be saturated or unsaturated, when unsaturated cycloalkyl rings can have one or two double bonds. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Cycloalkyl groups can be substituted or unsubstituted.

[54] As used herein, the term“heterocycly 1” or“heterocyclic” refers to a heterocyclic group that is saturated or partially saturated and is a monocyclic or a polycyclic ring; which has 3 to 16, most preferably 5 to 10 and most preferably 1 or 4 ring atoms; wherein one or more, preferably one to four, especially one or two ring atoms are a heteroatom selected from oxygen, nitrogen and sulfur (the remaining ring atoms therefore being carbon). The term heterocyclyl excludes heteroaryl. The heterocyclic group can be attached to the rest of the molecule through a heteroatom, selected from oxygen, nitrogen and sulfur, or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocyclyl include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetra hydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.

[55] As used herein, “spiroheterocyclyT’ refers to a specific bicyclic heterocyclic group wherein the 2 ring systems are connected through a single carbon atom. For example, the term“spiroheterocyclyl” can refer to a 6-10 spiro heterocyclyl. Examples of include, but 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, l-thia-8-azaspiro[4.5]decane 1,1-dioxide, l-oxa-7-azaspiro[4.4]nonane and l-oxa-9-azaspiro[5.5]undecane.

[56] As used herein, “bridged heterocyclyl” refers to a C3-6 cycloalkyl ring or a .3- to 6- memberd heterocyclyl ring, as defined above, where two non-adjacent ring vertices (“bridgehead atoms”) of the cycloalkyl ring or the heterocyclyl ring are linked to form an additional cyclic moiety (a “bridge”). The bridge comprises 1 to 4 ring vertices, not including the bridgehead atoms. Examples include, but not limited to, 2,5-diazabicyclo [2.2. l]heptane, 3,6-di azabicyclo [3.1 ,l]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.

[57] The term “bicyclic heterocyclyl” refers to a heterocyclic group as defined above where the two ring systems are connected through two adjacent ring vertices (e.g., a fused ring system). Typical “bicyclic heterocyclyl” rings include 6 to 11 ring members having 1 to 4 heteroatom ring vertices selected from N, O, and S (the remaining ring atoms therefore being carbon). Examples include, but not limited to, benzodioxolyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, chromanyl, cmnoiiny!, dihydrobenzofuryl, dihydroisobenzofuranyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, naphthyridinyL pyrazolopyridinyl, quinazolinyl, quinolinyi, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl.

[58] As used herein, “saturated or unsaturated” refers to a cyclic system where two of the atoms in the group may be bound to one another by a single bond, a double bond, or a triple bond. Saturated moieties are those having only single bonds, where moieties having multiple bonds (e.g., at least one double bond or at least one triple bondare referred to as unsaturated,

[59] When needed, any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group cycloalkoxyl means that a cycloalkyl group is attached to the parent molecule through an oxyl group.

[60] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When 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 suffi cient 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 deri ved from pharmaceutically-acceptable organic bases include salts of primary , secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring 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, hydrabamine, 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids Hke acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., 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.

[61] The neutral forms of the compounds may 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 otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[62] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomer, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. In some embodiments, the compounds of the present invention are a particular enantiomer, anomer, or diastereomer substantially free of other for ms.

[63] As used herein, the term “substantially tree” 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 form. In some embodiments, the isomer is a stereoisomer. Detailed Description of the Embodiments

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

[65] The present invention discloses novel heterocyclic compounds as inhibitors of ALPK1. The compounds are represented by formula I Formula I wherein A, p, R1, R2, IV, R4 and R5 are as defined herein: A is selected from a bond, azetidinyl, -0-, -N(R6)-, -CH2--N(R6)-, -CHR9-N(RD)-, wherein R6 is selected from H, D, -OH, optionally substituted Ci-Cs alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted Ci-Ce aminoalkyl, optionally substituted Ci-Ce alkoxyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, and optionally substituted saturated or unsaturated C3-C6 cycloalkoxyl, wherein the optionally substituted Rb moieties comprise 0-3 substituents independently selected from -D, halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci~C6 hydroxy-duterated alkyl, Ci-Ce haloalkyl, Cj-Ce aminoalkyl, and Cj-Ce alkoxyl; R9 is selected from optionally substituted Ci-Ca alkyl, C1-C6 haloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, ptionally substituted saturated or unsaturated C3-C6 cycloalkoxyl, wherein optionally substituted R9 moieties comprise 0-2 substituents independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci~C6 hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, Ci-Cehaloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHRVR8^ -OR'1, -OC(O)(R7f), -C(O)(R7f), -C(O)N(R7<R8f), -C(O)O(R7f), -S(O)2(R7f), -S(O)ON(R7fR8f) and -N(R7fR8f) wherein each R7f and R8f are independently selected from H, Ci-O, alkyl, Ci-Cs alkenyl, C1-C6 hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Cr, alkoxyl, Ci-Cshaloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-Cc, cycloalkoxy; Rj is selected from H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce hydroxyalkyl, optionally substituted C1-C6 hydroxy duterated alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted Ci-Cehaloalkoxyl, optionally substituted Ci-Ce aminoalkyl, optionally substituted Ci-Cf, alkoxyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted saturated or unsaturated C3-C6 cycloalkoxyl, optionally substituted mono or bicyclic aryl, optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 711 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; and optionally substituted saturated or unsaturated 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; wherein optionally substituted R1 moieties comprise 0-4 substituents independently selected from -D, halo, -OH, -COOH, -Nib. (). -CN, CrG> alkyl, C-G, alkenyl, C1-C6 hydroxyalkyl, Ci-Ce hydroxy-duterated alkyl, Ci-Ce haloalkyl, Ci-Cr, aminoalkyl, Cj-C6 alkoxyl, Cj-Cghaloalkoxyl, -R7a, -X’-R73, CHR73 R8a, -OR73, -O-XkR73, -X^O-XkR73, -OC(O)(R7a), -O-X1-C(O)(R7a), -((()){R’j. -C(O)N(R7aR8a), -NR7a(CO)R8a, -C(O)O(R7a), S(O)2R7a, -S(O)2N(R7aR8a), -N(R7aR8a), saturated or unsaturated Cs-Ce cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, mono or bicyclic aryl, 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected fromN, 0, and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, and 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; wherein each X1 is independently Cj-6 alkylene; each R7a and R8a are independently selected from H, Ci-Ce alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-C6 aminoalkyl, C1-C& alkoxyl, Ci-C6haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the aryl and 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; and the C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 5-10 membered heteroaryl, the saturated or unsaturated 7-8 membered bridged heterocyclyl, the saturated or unsaturated 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, C1-C6 alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Cs alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, -CHR7bR8b, -OR7b, -OC(O)( R'D), -C(O)( R7b), -C(O)N(R7bR8b), -NR7b(CO)R8b, -C(O)O(R7b), -S(O)2 N(R7bR8b) and -N(R7bR8b), wherein each R'D and R8b are independently selected from H, Ci-Ce alkyl, Ci-Cc, alkenyl, Ci-Ce hydroxyalkyl, (3-(.7 haloalkyl, Ci-Cc, aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; or R1 and R6 combine to form a 3-6 membered heterocycloalkyl substituted with 0-3 moieties independently selected from the group consisting of halo, -OH,-COOH, -NH2, =0, -CN, Ci-C6 alkyl, C1-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, and Ci-Ce alkoxyl; R3 is selected from H, deuterium, halo, Ci-Ce alkyl, Ci-Cg deuteroalkyl, and Ci-Cg haloalkyl; R2 and R3 are each independently selected from H, OH, Ci-Ce alkyl,C2-C6 alkynyl, C3-C6 cycloalkyl, and the mono or bicyclic aryl,wherein Ci-Cs alkyl,C2-C6 alkynyl, C3-C6 cycloalkyl, and the mono or bicyclic aryl are each substituted with 0-3 moieties independently selected from halo, -OH, Ci-Ce alkyl, C1-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci-Cb haloalkyl, C1-C6 aminoalkyl, Cj-Ce alkoxyl, saturated or unsaturated Cs-Ce cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -OC(O)(R7c), -C( ())( R7c), C(O)O(R7c), S(O)2N(R7cR8c), and M( R ' Rs k wherein each R7c and R8c are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxy, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; provided that R2 and R3 are not both H; or R2 and RJ combine to form a C3-C6 cycloalkyl ring or a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices independently selected from N, O, and S, wherein the ring formed can be optionally substituted with 1-2 substituents independently selected from Ci-Cc, alkyl, Ci-Ce alkenyl, Cj-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, halo, -OH , =0, -CN, OC(O)( R7d), -C(O)( R7d), C(O)O(R7d), S(C))2N(R7dR8d) and N(R7dR8d), wherein each R7d and Rsd are independently selected from H, C1-C6 alkyl, Ci-Ce alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; each R4 is independently selected from halo, -OH, -NH2, CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, CH R7eR8e, OR7s, OC(O)( R7e), C(O)( R7s), C(O)N(R7eR8e), C(O)O(R7e), S(O)2N(R7eR8e) and N(R7eR8e) wherein each R7e and Ree are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci~C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, and the subscript p is 0,1, 2 or 3.

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

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

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

[69] In some embodiments, A in Formula I is -N(R6)-.

[70] In some embodiments, A in Formula I is -at~N(Rb)*-

[71] In some embodiments, A in Formula I is -CHR9-N(R6)-.

[72] In some embodiments, the compound of formula I is represented by the compound of formula IA, formula IA-1, formula IA-2 and / or a stereoisomer, a stable isotope, or a pharmaceuti cally acceptable salt thereof Formula IA-2 Wherein p, R1, R2, R3, R4,R5, R6, and R9 are as defined above.

[73] In some embodiments Rb in formula I, IA, IA-1, or IA-2 is H, Ci-Ce alkyl or C j -Ce hydroxyalkyl.

[74] In some embodiments R9 in formula I and 1A is CH3 or CH2OH.

[75] In some embodiments R9 in formula I and 1A is saturated C3-C6 cycloalkyl.

[76] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is selected from H and optionally substituted Ci-Ce alkyl, wherein optionally substituted C1-C6 alkyl comprises 0-4 substituents independently selected from halo, -OH,-COOH, -NH2, =0, -CN, C1-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci-Cf, alkoxyl, Cj-Cehaloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7aRea, -OR7a, -OC(O)(R7a), -G;OH R a). -C(O)N(R7aRSa), -C(O)O(R7a), -SiObif. -S(O)2N(R7aR8a) and -N(R7aR8a), wherein each R7a and R8a are independently selected from H, Cj-Ce alkyl, Cj-C6 alkenyl, C1-C6 hydroxyalkyl, Ci-Ca haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, C1-Co haloalkoxy 1, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. [771             some embodiments R1 in formula I, IA, IA-1, or IA-2 is optionally substituted saturated or unsaturated C3-C6 cycloalkyl, wherein optionally substituted ( -(. .> cycloalkyl comprises 0-4 substituents independently selected from halo, -OH,-COOH, -NH2, =0, -CN, C1-C6 alkenyl, Ci-Ca hydroxyalkyl, Cj-Ce alkoxyl, and Ci-Ckhaloalkoxyl.

[78] In some embodiments R1 in formula I, IA, IA-1, or IA-2 combines with R6 to form a 3-6 membered heterocycloalkyl substituted with 0-3 moieties independently selected from the group consisting of halo, -OH,-COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxyl,

[79] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is Ci-Ce alkyl substituted with 0-4 substituents independently selected from -OH, Ci-Ce hydroxyalkyl, Ci-Ce alkoxyl, -OC(O)( R / a), -S(O)2N(R / aR8a) and -N(R'aR8a), wherein each R7a and R8a are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Cj-Ce haloalkyl, C1-C6 aminoalkyl, Cj-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[80] In some embodiments R! in formula I, IA, IA-1, or IA-2 is Cj-Ce alkyl substituted with 0-2 substituents independently selected from -OH, Ci-Ce hydroxyalkyl, and -S(O)2N(R7aR8a), wherein each R7a and R8a are independently selected from H, and Ci-Ce alkyl.

[81] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is optionally substituted Ci-Ce hydroxyalkyl.

[82] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S, the 5-10 membered bicyclic heteroaryl is substituted with 0 to 3 moieties selected from halo, -OH,-COOH, -NH2, -CN, Cj-C6 alkyl, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, 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 cycloalkoxyl, -CHR7bR8b, -OR7b, -OC(O)(R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R / b and R8b are independently selected from H, C1-C6 alkyl, Ci-C6 alkenyl, Cs-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. [831          In some embodiments R1 in formula I, IA, IA-1, or IA-2 is pyridiyl substituted with 0 to 3 moieties selected from halo, -OH,-COOH, -NH2, -CN, Ci-Ce alkyl, Ci-Cg alkenyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the 3-7 membered heterocyclyl is substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, C1-C6 alkyl, Ci-Cs alkenyl, Ci-Cs haloalkyl.

[84] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is a saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the 7-8 membered bridged heterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, Ci-Co haloalkyl, Ci-Cs aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated 0---(.7 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -0R7b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Cr, hydroxyalkyl, Ci-Ce haloalkyl, Cj-C6 aminoalkyl, Ci-Cs alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[85] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is a saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the 7-11 membered spiroheterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -COOH, -NH2, O. -CN, Cj-C6 alkyl, C:-C(. alkenyl, Ci-C6 hydroxyalkyl, Ci-Co haloalkyl, Ci-Cs aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated (' ---(.7 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, OR7b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and Rsb are independently selected from H, Ci-Ce alkyl, C1-C6 alkenyl, Ci~C6 hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. 1861          In some embodiments, R1 in formula I, IA, IA-1, or IA-2 is aryl substituted with 0-3 substituents selected from halo, a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; a 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 7-1I membered spiroheterocyclyl are substituted with from 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, C1-C6 alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -0R7b, -0C(0)(R7b), -C(O)(R7b), -C(0)N(R7bR8b), -C(O)O(R7b), -S(O)2R7b, -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R / b and R8b are independently selected from H, Cj-Ce alkyl, Cj-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl

[87] In some embodiments R1 in formula I, IA, IA-1, or IA-2 is aryl substituted with 0-3 moieties selected from halo -OH,-COOH, -NH2, =0, -CN, Ci-Ce alkyl, Cs-Ce alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Cs alkoxyl, and a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, the 3-7 membered heterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Cs-Ce alkenyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-Cr, cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -0R7b, -OC(O)(R7b), -C(0)(R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(0)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ca alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci~C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. 188]          In some embodiments R1 in formula I, IA, IA-1, or IA-2 is aryl substituted with 0-3 moieties selected from halo and a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the 3-7 membered heterocyclyl is further substituted with 0-3 moieties selected from -OH,-COOH, -NH2, =0, -CN, and -Ci-C6 alkyl.

[89] In some embodiments, the compound of formula I is represented by the compound of Formula IB and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof Formula IB wherein p, R2, RJ, R4 and R3 are as defined above; and D is CR10 or N; Eis CR14 orN; F is CR12 or N; G is CRl! or N; provided that no more than three of D, E, F, and G are N; Rj0, Rn , R?' , R13 and Ri4, when present, are each independently selected from H, halo, -OH, -COOH, -NHz, =0, -CN, Ci-Cs alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Cehaloalkoxyl, ~R / a, -Xl-R7a, X^O-X^R73, -CHR7aR8a, -OR7a, -O-X^R73, -OC(O)( R7a), -O-X1-C(O)(R7a), -C(O)(R7a), -C(O)N(R7aR8a), -C(O)O(R7a), S(O)2R7a, -Si())2N(R dCG. -N(R7aRSa), saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; mono or bicyclic aryl, a 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, 0, and S; and saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; wherein each X1 is independently C1-6 alkylene; each R7a and R8a are independently selected from H, Ci-Cs alkyl, Ci-Ce alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated Cs-Ce cycloalkoxyl; and the 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 9-10 membered bicyclic heteroaryl, the 7-8 membered bridged heterocyclyl, the 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 2 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Cb alkyl, Cj-Ce alkenyl, Ci-Cc, hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR'sR8g, -OR / g, -OC(O)( R7g), -C(O)( R7g), -C(O)N(R7gR8g), -NR7g(C0)R8g, -C(O)O(R7g), -S(O)2N(R7gR8g) and -N(R7gR8g), wherein each R7g and RSg are each independently selected from H, Ci-Cb alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl;

[90] In some embodiments, D, E, F and G in Formula IB are CR10, CR14, CR12, and CR11, respectively. [91J         In some embodiments, F and G in Formula IB are CR14 and CR11, respectively, E is N or CR14 and D is N or CR10.

[92] In some embodiments, R10 and R11 in Formula IB are each H, R12 and R14 are each independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Cb alkyl, Ci-Ce alkenyl, Ci-Cs hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, Ci-Cs alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bRsb, -0R7b, -0C(0)( R7b), -C(0)( R7b), -C(0)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein R / D and R8b are each independently selected from H, C1-C6 alkyl, Cj-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Cb alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; R13 is 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 spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Cs-Cb alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl.

[93] In some embodiments, R12 and R!4in Formula IB are H, R10 and R11 are each independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Cj-Ce hydroxyalkyl, Ci-Cc, haloalkyl, Cj-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -OR7b, -OC(O)( R7b), -C(0)( R7b), -C(O)N(R7bR8b), -0(0)0(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein R / D and R8b are each independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Cs hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, Ci-Cs alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; R13 is 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Cj-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl.

[94] In some embodiments, R10, R11, R12 and R14 in Formula IB are all H; Rlj is saturated or unsaturated Cs-Ce cycloalkyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moleties independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, C1-C6 hydroxyalkyl, Ci-Ca haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl.

[95] In some embodiments, R10, R11, R12 and R14 in Formula IB are each H; R13 is 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S w substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci- Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[96] In some embodiments, R10, R11, R12 and R14in Formula IB are each H; R13 is optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S substituted with 0-2 substituents selected from -OH,-COOH, -NH2, =0, -CN, and-Ci-Cb alkyl.

[97] In some embodiments, the compound of formula IB is represented by the compound of formula IB-1 or IB-2, and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof Formula IB-2 Wherein p, R2, RJ, R4 and R5 are as defined above; and R16 and R?7 are each independently selected from halo and C1-C6 alkyl; R15 is selected from -OH, C1-C6 alkyl, C1-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci~C6 haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, Ci-Ce haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR / bR8b, -C(O)( R7b), -C(0)N(R7bR8b), -C(O)O(R7b), -S(0)2 R7b and -S(0)2 N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci- Cb hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl,

[98] In some embodiments, R15 in formula IB-1 or IB-2 is selected from Ci-Ce alkyl, C1-C6 alkenyl, Ci-Ce hydroxyalkyl, Cj-Cs haloalkyl, Ci-Ce aminoalkyl, Cj-Cs alkoxyl, Ci-Ce haloalkoxyl; saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR / 0R8b, wherein each R7b and Rsb are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce haloalkyl, C1-C& aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[99] In some embodiments, R15 in formula IB-1 or IB-2 is Cj-Ce alkyl.

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

[101] In some embodiments, R2 and R1 in formula IB-1 or IB-2 are each independently a methyl or an ethynyl group,

[102] In some embodiments, IB-1 is represented by Formula IB-1 -a, or Formula IB- 2-a or a pharmaceutically acceptable salt thereof.

[103] In some embodiments, IB-1 is represented by Formula IB-1 -b, or Formula IB- ]104]         In some embodiments, IB-1 is represented by Formula (IB-l-c), or Formula IB-2-c or a pharmaceutically acceptable salt thereof.

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

[106] The present invention discloses novel heterocyclic compounds as inhibitors of ALPK1. The compounds are represented by formula IC Formula IC Wherein R2, R3, R4 and R5 are as defined above formula I; and m is an integer from 0-6; R18 is selected from H, halo, -OH, -COOH, -NIT, -CN, Ci-Cs alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Ce haloalkoxyl, -R7a, -X'-R / v CHR7a R8a, -OR7a, -O-XJ-R7a, X^O-X’-R73, - OC(O)(R7a), -O-XkC(O)(R7a), -C(O)(R7a), -C(O)N(R7aR8a), -NR7a(CO)R8a, -C(O)O(R7a), S(O)2R7a, -S(OkN(R7aR8a), -N(R7aRSa), saturated or unsaturated Cs-Ce cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, mono 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 fromN, O, and S; wherein each X1 is independently Cj-6 alkylene; each R7a and R8a are independently selected from H, Ci-Ce alkyl, saturated or unsaturated Cs-Cc, cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, Ci-Ce alkenyl, C1 -Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Cy aminoalkyl, Cj-C6 alkoxyl, Cj-Cehaloalkoxyl, saturated or unsaturated CVCv cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the aryl and 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, O. -CN, Ct-C6 alkyl, G-G, alkenyl, Cf-C6 hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated (.7-(.1, cycloalkyl, and saturated or unsaturated Cs-Ce cycloalkoxyl; and the C3-C6 cycloalkyl, (.7-(.1, cycloalkoxyl, 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 9-10 membered bicyclic heteroaryl, the saturated or unsaturated 7-8 membered bridged heterocyclyl, the saturated or unsaturated 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, C1-C6 alkyl, C1-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci~C6 haloalkyl, Ci-CG aminoalkyl, Cj-Cs alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, -CHR7bR8b, -0R7b, -0C(0)( R7b), -C(0)( R7b), -C(0)N(R7bR8b), -NR7b(C0)R8b, -C(0)0(R7b), -S(0)2 N(R / bR8D) and -N(R7bR8b), wherein each R / b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci~C6 hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; In some embodiments, m in formula IC is 1;

[107] In some embodiments, R18 in formula IC is H.

[108] The present invention also discloses novel heterocyclic compounds as inhibitors of ALPK1. The compounds are represented by formula XI, Formula XI wherein A, p, Rj , R2, R3, R4 and R3 are as defined herein; and X is selected from -S-, -O-, -NRa-, -CH=N-, and -CH=CH-, wherein Ra is H, or Ci-C6 alkyl.

[109] In some embodiments, X in Formula XI is S.

[110] In some embodiments, X in Formula XI is O. [Ill]        In some embodiments, X in Formula XI is NH.

[112] In some embodiments, A in Formula XI is a bond.

[113] In some embodiments, A in Formula XI is azetidinyl.

[114] In some embodiments, A in Formula XI is -0-.

[115] In some embodiments, A in Formula XI is -N(R6)-.

[116] In some embodiments, A in Formula XT is -CH2-N(Rb)-.

[117] In some embodiments, A in Formula XII is -CHR9-N(R6)-.

[118] In some embodiments, the compound of formula I is represented by the compound of formula XI-A, formula XI-A-1, formula XI-A-2 and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof. <>0 nA        -7   R1__N-X R6 H X^'R5 Formula XI-A Hx S n-ZAJ R Formula XI-A-2 : / p ^X^R5 Formula XI-A-1

[119] In some embodiments, the compound of formula XI is represented by the compound of formula XI-A-l-a, and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof Formula XI-A-l-a X, p, R1, R2, R3, R4,R5, Rb, and R9 are as defined above.

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

[121] In some embodiments R6 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is H, Ci-C6 alkyl or Ci-Ce hydroxyalkyl.

[122] In some embodiments R9 in formula XI and XI-A is CH3 or CH2OH.

[123] In some embodiments R9 in formula XI and XI-A is saturated C3-C6 cycloalkyl.

[124] In some embodiments R! in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is selected from H and optionally substituted C1-C6 alkyl, wherein optionally substituted Ci-Ce alkyl comprises 0-4 substituents independently selected from halo, -OH,-COOH, -NH2, =0, -CN, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 alkoxyl, Ci-Cehaloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR / aR8a, -OR / a, -OC(O)(R7a), -C(O)(R7a), -C(O)N(R7aR8a), -C(O)O(R7a), -S(()bR’ . -S(O)2N(R7aR8a) and -N(R7aR8a), wherein each R7a and R8a are independently selected from H, Ci-Co alkyl, Ci-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, Ci-Cehaloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[125] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is optionally substituted saturated or unsaturated C3-C6 cycloalkyl, wherein optionally substituted C3-C6 cycloalkyl comprises 0-4 substituents independently selected from halo, -OH,-COOH, -NH2, O. -CN, Ci-Cr, alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce alkoxyl, and Ci-Cehaloalkoxyl.

[126] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a combines with R6 to form a 3-6 membered heterocycloalkyl substituted with 0-3 moieties independently selected from the group consisting of halo, -OH,-COOH, -NHz, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, and Ci-Ce alkoxyl.

[127] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a is Ct-C6 alkyl substituted with 0-4 substituents independently selected from -OH, Ci-Cc, hydroxyalkyl, Ci-Ce alkoxyl, -OC(O)( R7a), -S(O)2N(R7aR8a) and -N(R7aR8a), wherein each R7a and R8a are independently selected from H, Ci-C6 alkyl, Ci-C6 alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[128] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a is Ci-Co alkyl substituted with 0-2 substituents independently selected from -OH, Ci-Ce hydroxyalkyl, and -S(O)2N(R7aR8a), wherein each R'a and R8a are independently selected from H, and Ci-Cs alkyl.

[129] In some embodiments R! in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-1-a is optionally substituted Ci-Ce hydroxyalkyl.

[130] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S, the 5-10 membered bicyclic heteroaryl is substituted with 0 to 3 moieties selected from halo, -OH,-COOH, -NH2, -CN, Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, 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 C Afo cycloalkoxyl, -CHR7bR8b, -OR7b, -OC(O)(R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ca alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci~C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. [131 ]         In some embodiments R1 in formula XL XI-A, XI-A-1, XI-A-2, or XI-A-l-a is pyridiyl substituted with 0 to 3 moieties selected from halo, -OH,-COOH, -NH2, -CN, Ci-Ce alkyl, Cs-Ce alkenyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the 3-7 membered heterocyclyl is substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, -CN, Ci-Ce alkyl, Ci-Co alkenyl, Ci-Ce haloalkyl.

[132] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is a saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1 -2 heteroatom ring vertices selected from N, O, and S, wherein the 7-8 membered bridged heterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -COOH, -NH2, O. -CN, Ci-C6 alkyl, Cs-C6 alkenyl, Ci-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -OR7b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ca alkenyl, Ci-Cs hydroxyalkyl, Cj-C6 haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl. 1133] In some embodiments R1 in formula XL XI-A, XI-A-1, XI-A-2, or XI-A-l-a is a saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the 7-11 membered spiroheterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, OR7b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ca alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci~C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[134] In some embodiments, R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is aryl substituted with 0-3 substituents selected from halo, a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; a 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 substituted with from 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ct-Cc, haloalkyl, Cj-Cr, aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -0R7b, -OC(O)(R7b), -C(O)(R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2R7b, -S(O)2N(R7bR8b) and -N(R'DR8b), wherein each R7b and R8b are independently selected from H, C1-C6 alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, C1-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl

[135] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is aryl substituted with 0-3 moieties selected from halo -OH,-COOH, -NH2, =0, -CN, Ci-Ce alkyl, C1-C6 alkenyl, Ci-Ca hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ca aminoalkyl, Ci-Ce alkoxyl, and a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, the 3-7 membered heterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, C1-C6 alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, Ci-Cs alkoxyl, saturated or unsaturated C3-Ce cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR?bRsb, -0R / b, -OC(O)(R7b), -C(O)(R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Cr, hydroxyalkyl, Ci-Ce haloalkyl, Cj-C6 aminoalkyl, Ci-Cs alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[136] In some embodiments R1 in formula XI, XI-A, XI-A-1, XI-A-2, or XI-A-l-a is aryl substituted with 0-3 moieties selected from halo and a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the 3-7 membered heterocyclyl is further substituted with 0-3 moieties selected from -OH,-COOH, -NH2, O. -CN, and -C1 -C6 alkyl.

[137] In some embodiments, the compound of formula XI is represented by the compound of Formula XI-B and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof, Formula XI-B wherein X, p, R2, R3, R4 and R5 are as defined above; and DisCR10orN; E is CR14 or N; Fis CR12orN; G is CR11 or N; provided that no more than three of D, E, F, and G are N; R10, R11 , R12 , R1J and R14, when present, are each independently selected from H, halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ca alkenyl, Ci-Co hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Cehaloalkoxyl, -R7a, -X!-R?a, X^O-XkR7a, -CHR7aR8a, -OR7a, -O-Xl-R7a, -OC(O)( R7a), -O-XkQOXR73), -C(O)(R7a), -C(O)N(R7aR8a), -C(O)O(R7a), S{()} jGv -S(ObN(R^R88), -N(R7aR8a), saturated or unsaturated Cs-Ce cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; mono or bicyclic aryl, a 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, 0, and S; and saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S; wherein each X1 is independently C1-6 alkylene; each R7a and R8a are independently selected from H, Ct-Cc, alkyl, Ci-Ce alkenyl, Cj-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; and the 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 9-10 membered bicyclic heteroaryl, the 7-8 membered bridged heterocyclyl, the 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 2 moieties selected from halo, -OH, -COOH, -NH2, (). -CN, C1-C6 alkyl, Ct-Cc, alkenyl, Cj-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR'8R8g -OR7g, -OC(O)( R7g), -C(O)( R7g), -C(O)N(R7gR8g), -NR7g(CO)R8g, -C(O)O(R7g), -S(O)2N(R7sR8g) and -N(R7gR8g), wherein each R'g and R8g are each independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci~C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated CVCe cycloalkoxyl; 1138] In some embodiments, D, E, F and G in Formula XI-B are CR10, CR14, CR12, and CR11, respectively.

[139] In some embodiments, F and G in Formula XI-B are CR14 and CR11, respectively, E is N or CR14 and D is N or CR10.

[140] In some embodiments, R!0 and R11 in Formula XI-B are each H, R12 and R14 are each independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Cs-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR'DR8b, -OR7b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R / DR8b), wherein R7b and R8b are each independently selected from H, Ci-Cg alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; R1J is 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 fromN, O, and S, 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 with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =O, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated Cs-Ce cycloalkoxyl. [141 ]        In some embodiments, R12 and R14in Formula XI-B are H, Rj0 and Rn are each independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, C1-C6 alkenyl, Cj-Ce hydroxyalkyl, C1-C6 haloalkyl, Cj-Cs aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR'DR8b, -OR7b, -00(0)( R7b), -0(0)( R7b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2N(R7bR8b) and -N(R'DR8b), wherein R7b and Reb are each independently selected from H, Ci-Ce alkyl, C1-C6 alkenyl, Cj-Ce hydroxyalkyl, Ci-Cc, haloalkyl, Cj-Cs aminoalkyl, Ct-Cc, alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; R!j is 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, 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, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Co alkyl, C1-C6 alkenyl, Ci-Ca hydroxyalkyl, Ci-Ce haloalkyl, Cj-Cr, aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated Cs-Ck cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl.

[142] In some embodiments, R!0, Rn,R12 and R!4in Formula XI-B are all H; R13 is saturated or unsaturated C3-C6 cycloalkyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, saturated or unsaturated 7-1I membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moieties independently selected from halo, -OH, -COOH, -NH2, O. -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ca aminoalkyl, Ci-Cr, alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl.

[143] In some embodiments, R10, R11, R12 and R14 in Formula XI-B are each H; R13 is 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S w substituted with 0-2 moieties independently selected from halo, -OH, -COOH, ~NH2, ~0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated Cb-Ce cycloalkoxyl.

[144] In some embodiments, R10, R11, R12 and R14 in Formula XI-B are each H; R13 is optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S substituted with 0-2 substituents selected from -OH,-COOH, -NH?, =0, -CN, and-Ci-Ce alkyl. ^145]        In some embodiments, the compound of Formula XI-B is represented by the compound of Formula XI-B-1 or XI-B-2, and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof Formula XI-B-1 Formula XI-B-2.

[146] In some embodiments, the compound of Formula XI-B-lor XI-B-2 is represented by the compound of formula XI-B-l-a, XI-B-2-a and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof Formula XI-B-l-a Formula XI-B-2-a wherein p, R2, R3, R4 and R5 are as defined above; and R16 and R1' are each independently selected from halo and Ci-Ce alkyl; Rl3 is selected from -OH, Ci-Cs alkyl, Cj-Ce alkenyl, O.-C6 hydroxyalkyl, Ci-Cs haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Ce haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR7bR8b, -C(O)( R / b), -C(O)N(R7bR8b), -C(O)O(R7b), -S(O)2R7b and -S(0)2 N(R7bR8b), wherein each R7b and R8b are independently selected from H, Cj-C6 alkyl, Ci-Cc, alkenyl, Ci- Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ca aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[147] In some embodiments, R13 in Formula XI-B-1 or XI-B-2 is selected from Ci- Cs alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Cs-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Co haloalkoxyl; saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, -CHR / DR8b, wherein each R'b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Cr, hydroxyalkyl, Ci-Ce haloalkyl, Cj-C6 aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated Cs-Ce cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl.

[148] In some embodiments, R15 in formula XI-B-1 or XI-B-2 is Ci-Ce alkyl.

[149] In some embodiments, both R2 and RJ in formula XI-B-1 or XI-B-2 are methyl groups.

[150] In some embodiments, R2 and RJ in formula XI-B-1 or XI-B-2are each independently a methyl or an ethynyl group.

[151] In some embodiments, XI-B-l-a is represented by Formula XI-B-l-a-I, and XI-B-2-a is represented by Formula XI-B-2-a-I or a pharmaceutically acceptable salt thereof, wherein R4 is halo.

[152] In some embodiments, XI-B-l-a is represented by Formula XI-B-l-a-II, and XI-B-2-a is represented by Formula XI-B-2-a-II or a pharmaceutically acceptable salt thereof.

[153] In some embodiments, XI-B-l-a is represented by Formula XI-B-l-a-III, and XI-B-2-a is represented by Formula XI-B-2-a-III or a pharmaceutically acceptable salt thereof.

[154] In some embodiments, XI-B-l-a is represented by Formula XI-B-l-a-IV, and XI-B-2-a is represented by Formula XI-B-2-a-IV (XI-B-l-a-IV) J ny~O~c! hAA-r5 R^               pis                                   n, -, ,-, ~ R                            (Xl-B-2-a-IV) or a pharmaceutically acceptable salt thereof.

[155] In some embodiments, R3 in formula XI-B-1 or XI-B-2 is H or methyl.

[156] The present invention discloses novel heterocyclic compounds as inhibitors of ALPK1. The compounds are represented by formula XI-C p3 o2 n ,—_ rha \ / m n VZXnS fl X R5 Formula XI-C Wherein X, R2, R3, R4 and R5 are as defined above formula XI; and m is an integer from 0-6; R18 is selected from H, halo, -OH, -COOH, -NH2, -CN, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Ce haloalkoxyl, -R7a, -X^R73, CHR7a R8a, -OR73, -O-X^R73, X^O-X’-R73, - OC(O)(R7a), -O-X; ~C( <))(R ;-C(O)(R7a), -C(O)N(R7aR8a), -NRZ(.'O)RZ -C(O)O(R / a), S(O)2R7a, -S(O)2N(R7aR8a), -N(R7aR8a), saturated or unsaturated Cs-CX cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected fromN, O, and S, mono 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 each X1 is independently Cue, alkylene; each R7a and R8a are independently selected from H, Ci-Ce alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-C6 aminoalkyl, C1-C& alkoxyl, Ci-C6haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated Cs-Cc, cycloalkoxyl, aryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the aryl and 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl; and the C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 9-10 membered bicyclic heteroaryl, the saturated or unsaturated 7-8 membered bridged heterocyclyl, the saturated or unsaturated 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Cs-Ce hydroxyalkyl, CVG, haloalkyl, Ci-Cs aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C0 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, -CHR7bR8b, -OR / b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -NR7b(CO)R8b, -C(O)O(R7b), -S(O)2 N(R7bR8D) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ce alkyl, Ci-Ce alkenyl, C1-C6 hydroxyalkyl, Ci-Ce haloalkyl, Ci-Cc, aminoalkyl, Cj-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl,

[157] In some embodiments, the compound of formula XI-C is represented by the compound of formula XI-C-1, and / or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt thereof, Formula XI-C-1 wherein R\ R3, R4 and R5 are as defined above formula I; and m is an integer from 0-6; R18 is selected from H, halo, -OH, -COOH, -NH2, -CN, C1-C6 alkenyl, Cj-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, Ci-Ce haloalkoxyl, -R7a, -X^R73, CHR7a Rs\ -OR7a, -O-X’-R \ X^C-X^R73, -OC(O)(R7a), -O-X!-C(O)(R7a), -C(O)(R7a), -C(0)N(R7aR8a), -NR7a(CO)R8a, -C(O)O(R7a), S(O)2R7a, -S(O)2N(R7aR8a), -N{ R ’ Rx'saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, mono 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 each X1 is independently C1-6 alkylene; each R7a and RSa are independently selected from H, Cj-Ce alkyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, C1-C& alkenyl, Ci-Ce hydroxyalkyl, C1-C6 haloalkyl, Ci-Ce aminoalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, aryl , saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, 0, and S, wherein the aryl and 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, -OH, -COOH, ~NH2, =0, -CN, Ci-Ce alkyl, Ci-Ca alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated Cj-Cc, cycloalkoxyl; and the C3-C6 cycloalkyl, C3-C6 cycloalkoxyl, 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 9-10 membered bicyclic heteroaryl, the saturated or unsaturated 7-8 membered bridged heterocyclyl, the saturated or unsaturated 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 3 moieties selected from halo, -OH, -COOH, -NH2, =0, -CN, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce hydroxyalkyl, Ci-Ce haloalkyl, Ci-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated C3-C6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, -CHR7bR8b, -OR7b, -OC(O)( R7b), -C(O)( R7b), -C(O)N(R7bR8b), -NR7b(CO)R8b, -C(O)O(R7b), -S(O)2 N(R7bR81’) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, Ci-Ca alkyl, Ci-Ce alkenyl, C1-C6 hydroxyalkyl, Ci-Cf, haloalkyl, Ct-Cr, aminoalkyl, Cj-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, and saturated or unsaturated C3-C6 cycloalkoxyl;

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

[159] In some embodiments, R18 in formula XI-C or XI-C-1 is H. 1160]         In some embodiments, R2 and R3 in each of the formulas described herein are both Ci-Ce alkyl groups;

[161] In some embodiments, R2 is methyl and R3 is CH2OMe in each of the formulas described herein.

[162] In some embodiments, R2 and R3 are each methyl in each of the formulas described herein.

[163] In some embodiments, R2 is methyl and RJ is ethynyl in each of the formulas described herein.

[164] In some embodiments, R2 is methyl and RJ is C3-C6 cycloalkyl.

[165] In some embodiments, R2 is methyl, and R3 is phenyl.

[166] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R4 is attached to the phenyl ring as shown below: wherein the wavy line represents the point of attachment to the remainder of the formula. 1167]         In some embodiments, in each of the formulas described herein, the subscript p is 1, and R4 is halo attached to the phenyl ring as shown below: wherein the wavy line represents the point of attachment to the remainder of the formula.

[168] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R4 is chloro attached to the phenyl ring as shown below: wherein the wavy line represents the point of attachment to the remainder of the formula.

[169] In some embodiments, in each of the formulas described herein, the subscript p is 1, and R4 is methoxy attached to the phenyl ring as shown below: 5 wherein the wavy line represents the point of attachment to the remainder of the formula.

[170] In some embodiments, R5 in each of the formulas described herein is H.

[171] In some embodiments, R5 in each of the formulas described herein is deuterium.

[172] In some embodiments, R5 in each of the formulas described herein is C1-C6 deuteroalkyl. In some embodiments, R5 in each of the formulas described herein is selected from the group consisintg of-CH2D, -CHD2, and -CD3.

[173] In some embodiments, the carbon atom attached to R2 and R ' in each of the formulas described herein is chiral. In such embodiments, it is understood that R2 and R3 are not the same. In some embodiments, the carbon atom attached to R2 and R3 in each of the formulas described herein is the S isomer, referring to the absolute stereochemistry at this carbon atom. In some embodiments, the carbon atom attached to R2 and R3 in each of the formulas described herein is the R isomer, referring to the absolute stereochemistry at this carbon atom. In some embodiments, R2 is methyl and R3 is ethynyl. In some embodiments, R2 is methyl and R’ is C3-C6 cycloalkyl. In some embodiments, R2 is methyl, and R2 is phenyl. In some embodiments, R3 is methyl and R2 is ethynyl. In some embodiments, RJ is methyl and R2 is C3-C6 cycloalkyl. In some embodiments, R3 is methyl, and R2 is phenyl.

[176] In some embodiments, the compound is selected from the examples provided herein. Preparation of Compounds of Formula I and Exemplary Compounds ANALYTICAL DETAILS

[177] NMR: Measurements were performed on a Broker Ultrashield TM 400 (400 MHz) spectrometer using or not tetramethylsilane (TMS) as an internal standard. Chemical shifts (8) are reported ppm downfield from TMS, spectra splitting pattern are designated as single (s), doublet (d), triplet(t), quartet (q), multiplet, unresolved or overlapping signals (m), broad signal (br). Deuterated solvent are given in parentheses and have a chemical shifts of dimethyl sulfoxide (52.50 ppm), chloroform (8 7.26 ppm), methanol (83.31 ppm), or other solvent as indicated in NMR spectral data. [ 178 ]        LC-MS: Shimadzu20A-2010MS Detection: SPD-M20A Column: MERCK, RP-18e 25-2mm; Wavelength: UV 220nm, 254nm ; Column temperature: 50°C; MS ionization: ESI Mobile Phase: L5ML / 4LTFA in water (solvent A) and 0.75ML / 4LTFA in acetonitrile (solvent B),using the elution gradient 5%-95% (solvent B) over 0.7 minutes and holding at 95% for 0.4 minutes at a flow rate of 1.5 ml / min;

[179] Flash Column Chromatography System System: CombiFlash Rf+ Column: Santai Technologies, Inc, SEPAFLASH ® Samples were typically adsorbed on isolute HPLC separation conditions System : TRILUTION LC 4.0 Detection: Gilson 159 UV-VIS Condition 1: Column: Phenomenex Gemini-NX 80*40mm*3um Eluent A: water (0.05%NH3H2OH0mM NH4HCO3) Eluent B: CH3CN Begin B: 20-45%, End B: 80-20%, Gradient Time (min): 8 Condition 2: Column: Xtimate Cl 8 1 Op. 250 mm *50mm; Eluent A: water (0.04%NH3H20+10mM NH4HCO3). Eluent B: CH3CN 50%-80%; Gradient Time (min): 8 SFC Chiral Seperation Conditions Mobile phase: [0.1%NH3H2O ETOH]; B%: 30%-30%, 35%-35% or 45-45% Column: DAICEL CHIRALCEL OJ-H(250mm*30mm,5um); Mobile phase: [0J%NH3H2O ETOH];B%: 30%-30%, 40%-40%; Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Mobile phase: [0.1%NH3H2O ETOH]; B%: 35%-35%; Column: DAICEL CHIRALPAK AS (250mm*30mm,10um); Mobile phase: [0.1%NH3H2O ETOH]; B%: 35%-35%

[180] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary’ skill in the art.

[181] Below is the abbrivation table for chemistry'': Ac Acetyl ACN Acetonitrile Cbz Benzoxycarbonyl GDI N,N-Carbonyldiimidazole Com. Compound DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMP Dess-Martin Periodinane DMSO Dimethyl sulfoxide EA Ethyl Acetate EDC I 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electron Spray Ionization Et Ethyl HATU 2-(7~Azabenzotriazol~l-yl)-N,N,N\NMetramethyluronium hexafluorophosphate HBTU O-Benzotriazole-N,N,N\NMetramethyl-uronium-hexafluorophosphate HOBt 1-Hydroxybenzotri azole HPLC High Performance Liquid Chromatography Int Intermediate LCMS Liquid Chromatography-Mass Spectrometry LiHMDS Bis(trimethylsilyl)amine lithium salt Me Methyl MS Mass Spectrometry Ms Methanesulfonyl NMR Nuclear Magnetic Resonance Pd2(dba)3 Tris(dibenzyli den eacetone)di palladium PE Petroleum Ether PyBOP Benzotriazol-l-yl-oxytripyrrolidinophosphonium hex afluoropho sphate RT Room Temperature TBAF Tetrabutylammonium fluoride TBDPS t-buty 1 di phen y 1 s i 1 yl TBME tert-Butyl Methyl Ether t-Bu tert-butyl TEA Triethylamine TFA Trifluoroacetic Acid THF Tetrahydro furan TLC Thin Layer Chromatography TMS Tetramethylsilane Ts p-Toluenesulfonyl X-phos (2-(2,4,6-triisopropylphenethyl)phenyl)dicyclohexylphosphine Reaction Scheme 1: Bromination Ri R2 M4

[182] Appropriately substituted compound Ml wherein R are suitable 1-3 groups like halo or Ci-Cc, alkyl, etc, and Ri and R2 are suitable groups like independently selected from H, Ci-Ce alkyl and C2-C6 alkynyl, converted to acid chloride with SOCI2 or (COC1)2 under heating or room temperature. Weinreb amide was formed by the reaction of N,O-dimethylhydroxylamine hydrochloride with the acid chloride at 0°C. Grignard reagent in THF was added to the Weinreb amide at 0°C to give the ketone, which was converted to M5 by bromination. The cyclization with thiourea under basic condition gave the intermediate M6. Example 1: Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazoI-2-amine fwwvwwwwwwwwwwwwwwwwwvwwwwwwwwwwwwwwwwwwwvwwwwwvwwwwwwwwwwvwwwwwwvwwwwwvwwwwvwwwwwwWwMwwvwwwwwwwwwwwwwvwwwww (Intermediate 1)

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

[184] Compound 2-(4-bromophenyl)-2-methylpropanoic acid (100 g, 411 mmol, 1.0 eq) in SOCI2 (175 mL, 6 eq) was warmed to reflux for 2 h. Then the solution was cooled to RT, the mixture was concentrated under reduced pressure to get dry acid chloride (yellow oil) which was used in next step without further purification.

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

[186] The solution of compound N,O-dimethylhydroxylamine HC1 salt (48.2 g, 49 mmol, 1.2 eq) in DCM (300 mL) was cooled to 0 °C. Then to the mixture was added crude acid chloride obtained from step 1 above (1.0 eq) in DCM (200 mL) and TEA (114 mL, 2 eq), and the mixture was stirred at RT overnight. The reaction mixture was quenched with H2O (200 mL). The mixture was extracted with DCM (200 mL x 3), the combined organic layers were washed with water (200 mL x 3), brine (200 mL x 3), dried over Na2SO4, filtered and concentrated to give a residue. The desired compound (108 g, pure) was obtained as a pale yellow oil which was used in next step without further purification.

[187] NMR (400 MHz, CDCh) d 7.42 (d, J= 8.8 Hz, 2H), 7.12 (d,   8.8 Hz, 2H), 3.08 (s, 3H), 2.71 (s, 3H), 1.49 (s, 6H). [ 188] Step 3. Preparation of compound 3-(4-bromophenyl)-3-methylbutan-2-one [ 189]         The solution of compound obtained from step 2 above (54 g, 189 mmol, 1 eq) in dry THF (500 mL) was cooled to 0°C. CHsMgBr (3 M in THF, 253 mL, 757.8 mmol, 4 eq) was added dropwise. The mixture was stirred at RT overnight. The reaction mixture was quenched with sat. NH4CI (200 mL) and extracted with EA (300 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered and concentrated to give a residue. The desired compound (90.4 g, pure) was obtained as a pale yellow'' oil which was used into the next step without further purification.

[190] NMR (400 MHz, CDCh) 4 7.45 (d, J 8.4 Hz, 2H), 7.11 (d, J === 8.4 Hz, 2H), 1.90 (s, 3H), 1.44 (s, 6H).

[191] Step 4. Preparation of compound l-bromo-3-(4-bromophenyl)-3-methyIbutan- 2-one

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

[193] NMR (400 MHz, CDCh) 3 7.48 (d, J= 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 3.82 (s, 2H), 1.52 (s, 6H).

[194] Step 5. Preparation of 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine 50 °C, 1.5 h

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

[196] !H NMR (400 MHz, DMSO-» 5 7.39 (d, >8.0 Hz, 2H), 7.14 (d, >8.0 Hz, 2H), 6.78 (s, 2H), 6.22 (s, 1H), 1.50 (s, 6H). MS (ESI) m / z (M+H)+=297.0. Example 2: 4-(l-(4-bromophenvI)cvclopentvI)thiazoL2-amine (Intermediate 2)

[197] Step 1. Preparation of compound ethyl l-(4-bromophenyl)cyclopentane-l- carboxylate

[198] To a solution of compound ethyl 2-(4-bromophenyl)acetate (10 g, 41,3 mmol) in DMF (50 mL), NaH (8.3 g, 207 mmol) was added slowly at 0°C and then the reaction was stirred at RT for 30 min. 1,4-dibromobutane (8.8 g, 41.3 mmol) was added slowly at RT. The mixture was stirred at RT overnight. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE: EA =1:0 to 5: 1). The title compound (7.8 g, yield: 63.8%) was obtained. MS (ESI) m / z (M+H)’ =297.0

[199] Step 2, Preparation of compound l-(4-bromophenyl)cyclopentane-l- carboxylic acid

[200] To a solution of compound ethyl l-(4-bromophenyl)cyclopentane-l-carboxylate (7.8 g, 26.3 mmol) in THF (25 mL) were added NaOH (3.2 g,79 mmol) and H2O (5 mL) and the reaction was stirred at 40 °C overnight. After cooling down, the PH value of the reaction solution was adjusted to 6. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE: EA = 1: 0 to 1: 2). The desired compound (5.6 g, yield: 79.4%) was obtained. MS (ESI) m / z (M ■ Ilf 269.0 The synthesis of following steps was similar as described in intermediate 1. Example 3: 4-(2-(5-bromopyridin-2-yl)propan-2-yl)thiazoI-2-amine (Intermediate 3) [f 1 ¥ y-NH2 Br -         &

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

[202] 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, 3.5eq) at 0°C. The resulting mixture was stirred for 20 min at 0°C. The mixture was added CH3I (2 mL, 3.5 eq) at 0°C and stirred for 6 h. The reaction mixture was quenched with water (50 mL), extracted with EA (25 mL x 2) and wushed with brine (10 mL x 2), then dried over Na2S(X filtered and evaporated to dryness. The resulting residue was purified by column chromatography on a silica gel to obtain the desired compound (1.95 g, yield: 93 %).

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

[204] A mixture of 2-(5-bromopyridin-2-yl)-2-methylpropanoate (1.95 g, 7.56 mmol, l.Oeq) and KOH (1.9 mL, 2M in H2O, 3.0eq) was heated to reflux for 1 h. The reaction was cooled to RT and quenched with 0.1M HC1 extracted with EA, washed by brine, dried over Na2SO4, filtered and evaporated to dryness to obtain the desired compound (1.82 g, yield: 98%).

[205] The next few steps are similar as described for intermediate 1.

[206] The following examples were synthesized analogous to the procedure of intermediate 1 using the appropriate starting materials and thiourea:

[207] Table 1 Corn. ID Structure Name HNMR LCMS ([M+H]M Intermediate 4 H2N~^ g f |f s-J 4-(2-(3-bromophenyl)propan-2-yl)thiazol-2-amine ‘H NMR (400MHz, CDCI3) d 7.67 (t, J = 1.88 Hz, 1 H), 7.43 (d, J = 7.78 Hz, 1 H), 7.33 - 7.39 (m, 1 H), 7.14 - 7.22 (m, 1 H), 6.48 (s, 1 H), 4.87 (br s, 2 H), 2.57 (s, 1 H), 1.91 (s, 3 II). 297.0 Intermediate 5 / o X 4-(2-(3-methoxyphenyl)propan-2-yl)thiazol-2-amine 249.1 Intermediate 6 T L T s- 4-(2-(4-bromo-3-methoxyphenyl)propan-2-yl)thiazol -2-amine 327.0 Intermediate 7 T 1 o \ 4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-amine 249.1 Intermediate 8 h2n-^ ft f 4 S-J NX 4-(2-(4- cyclopropylphenyl)propan-2-yl)thiazol-2-amine 259.1 Intermediate 9 4-(1 -phenyl etbyl)thiazol-2-amine 205.0 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh Uh Intermediate 10 h2n-^ Y S-U 4-(2-(4-fluorophenyl)propan-2-yl)thiazol-2-amine 237.0 Intermediate 11 H2N-f J S"" O c5 4-(2-(4-chIorophenyl)propan-2-yl)thiazol-2-amine 253.0 Intermediate 12 h2n--^ Y s-'J F 4-(2-(4-bromo-3- fluorophenyl)propan-2-yl)thiazol-2-amine 314.9 Intermediate 13 N .. z' ii S'" y^ci F 4-(2-(4-chloro-3- fluorophenyl)propan-2-yl)thiazol-2-amine 271.0 Intermediate 14 h2n—jr 4-(2-(4-iodophenyl)propan-2-yl)thiazol-2-amine 344.9 Intermediate 15 h2n-( / Y S'"' Br 4-(1-(4- bromophenyl)ethyl)thiazol-2- amine 282.9 Intermediate 16 N. X H2N—^ T -^0-^ 4-(2-(4-ethoxyphenyl)propan-2-yl)thiazol-2-amine 263.1 Intermediate 17 '          i T JM X 4-(2-(4-bromophenyl)propan-2-yl)-5-methylthiazol-2-amine 311.0 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh Intermediate 18 nUUx II            |           |1 °             Br 4-(2-(4-bromophenyl)butan-2-yl)thiazol-2-amine 311.0 Intermediate 19 H2N—jj | |j s F'^^^Br 4-(2-(4-bromo-2- fluorophenyl)propan-2-yl)thiazoi- 2-amine 315.0 Intermediate 20 \ / s'   ^^ocfs 4-(2-(4- (trifluorometho xy)phenyl)propan- 2 -y l)thi azol-2 -amine 303.0 Intermediate 21 H2N-y P 1 H s-^ 4-(2-(p-tolyl)propan-2-yl)thiazol-2-amine 233.1 Intermediate 22 11 JO H2N   S 4-(1-(4- bromophenyl)cyclobutyl)thiazol-2-amine NMR (400MHz, CDC13) <5 7.45 - 7.41 (m, 2H), 7.22 - 7.17 (m, 2H), 6.05 (s, 1H), 4.88 (s, 2H), 2.74 - 2.65 (m, 2H), 2.62 - 2.51 (m, 2H), 2.20 ■ 2.04 (m, 1H), 1.97 - 1.85 (m, HI). 309.0 Intermediate 23 V / F N H2N—T H 4 V W-Br 4-(2-(4-bromo-2- fluorophenyl)propan-2-yl)thiazol- 2-amine 314.9 Intermediate 24 h2n—y H । Br 4-(1-(4- bromophenyl)cyclopropyl)thiazol- 2-amine 294.9 Intermediate 25 H2N-y y t । s- Br 4-(2-(3-bromo-4-methoxyphenyl)propan-2-yl)thiazol-2-amine 327.0 WO 2022 / 063152                                                 PCT / CN2021 / 119801

[208] Appropriately substituted compound M7 wherein R was suitable 1-3 groups like halo or Ci-Ce alkyl, etc, was acetylated with lithium base at lower than -60°C condition. M9 wus obtained by alkyl substitution like C1-C6 alkyl group, of M8 under base condition at 50-70°C. After bromination, MIO was obtained. The cyclization of MIO with thiourea under base condition gave the thiazole intermediate Ml 1. An appropriate protection group was introduced to protect amine. The reduction of ester into alcohol was performed by LiBI R at 0°C yielding Ml 3, which was oxidized to the corresponding aldehyde by using Dess-Martin Periodinane (DMP) reagent. The alkynylthiazole amine intermediate M15 was obtained by Seyferth-Gilbert Homologation with treating M14 with 1-diazo-l-dimethoxyphosphoryl-propan-2-one under base condition at RT. The final de-protection gave the intermediate Ml6. Example 4; Preparation of 4-(2-(4-chIt)rophenyl)but-3-vn-2-vl)thiazol-2-amine (Intermediate 27) Cl

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

[210] To a solution of compound methyl 2-(4-chlorophenyl)acetate (10g, 54.2 mmol, 8.77 ml) in THF (80 mL) v / as added dropwise LiHMDS (IM, 65.0 mL) at -78°C. The mixture was stirred at -78°C for 20 min. Then acetyl acetate (5.53 g, 54.17 mmol, 5.07 mL) was added at -78°C. The mixture was warmed to 0°C and stirred for 2 h at 0°C. The mixture was quenched with sat. NH4CI (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 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 5: 1). The desired compound (7.47 g, yield: 60.9%) was obtained as a pale yellow oil.

[211] MS (ESI) m / z (M ■ H) 227.1.

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

[213] To a solution of 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 h. The mixture was filtered and the filtrate was concentrated to give a residue. The desired compound (7.79 g, yield: 98.2%) v / as obtained as a pale yellow oil which was used into the next step without further purification.

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

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

[216] To a solution of compound obtained from step 2 above (7.79 g, 32.4 mmol) in CHCI3 (80 mL) w’as added Br2 (4.66 g, 29.1 mmol, 1.50 mL). The mixture was stirred at 75 °C for 16 h. The reaction mixture was adjust to PH = 6-7 with NaOH (1 N), and then washed w'ith H2O (100 mL), brined (100 mL), dried over anhydrous NaaSO^ filtered and concentrated to give a residue. The desired compound (9.91 g, yield: 95.8%) wns obtained as a pale brown oil, which wns used into the next step without further purification.

[217] MS (ESI) m / z {M Hi 319.0.

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

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

[220] MS (ESI) m / z {M 111 297.().

[221] Step 5. Preparation of compound methyl 2-(2-acetamidothiazol-4-yl)-2-(4- chl orophenyl )propan oate

[222] To a solution of 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. The second batch of acetyl chloride (794 mg, 10.1 mmol, 721 uL) and TEA (1.53 g, 15.2 mmol, 2.11 mL) was added at 0°C, the mixture was stirred at 25 °C for 1 h. The 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) was added at 0°C, the mixture was stirred at 25 °C for 1.5 h. The reaction mixture wus quenched with H2O (3 mL) and then added anhydrous Na2SO4, 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 pale yellow solid. [223 ]          MS (ESI) m / z (M • H! 3 39.1.

[224] Step 6. Preparation of compound N-(4-(2-(4-chlorophenyl)-l-hydroxypropan-2- yl)thiazoI-2-yl)acetamide

[225] To a solution of compound obtained from step 5 above (1.4 g, 4.13 mmol) in THE (50 mL) was added partly LiBEL (450 mg, 20.66 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with sat. NU4CI (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 give 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 pale yellow solid.

[226] MS (ESI) m / z (MU) 311.1.

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

[228] To a solution of compound obtained from step 6 above (970 mg, 3.12 mmol) in DCM (30 mL) was added partly 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), quenched with sat. Na2S2O3. / sat. NaHCOj (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 sat. Na2.S2.O3 / sat. NaHCO.3 (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 which was used into the next step without further purification.

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

[230] To a solution of compound obtained from step 7 above (1.03 g, 3.34 mmol) and 1 ■ diazo-1-dimethoxyphosphoryl-propan-2-one (961 mg, 5.00 mmol) in MeOH (40 mL) was added K2CO3 (922 mg, 6.67 mmol). The mixture was stirred at 25 °C for 12 h. 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 prep-HPLC (column: Venusil ASB Phenyl 150 x 30 mm x 5 um; mobile phase: [water (0.05% HC1)-ACN]; B%: 55%-85%, 9 min). The desired compound (219 mg, yield: 21.54%) was obtained as a white solid.

[231] Tl NMR (400MHz, CDCI3) d 9.98 (br s, 1H), 7.45 (d, J 8.5 Hz, 2H), 7.30 (d, J- 8.5 Hz, 2H), 6.88 (s, 1H), 2.63 (s, 1H), 2.25 (s, 3H), 1.99 (s, 3H). MS (ESI) m / z (M+H)M05.1.

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

[233] To a solution of compound obtained from step 8 above (180 mg, 591 umol) in MeOH (10 mL) was added methanesulfonic acid (284 mg, 2.95 mmol, 210 pL). The mixture was stirred at 80 °C for 16 h. The reaction mixture was adjusted pH == 9-10 with solid NallCOs 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 (137 mg, yield: 88.3%) was obtained as a pale yellow solid.

[234] !H NMR (400MHz, CDCb) 3 7.39 - 7.32 (m, 2H), 7.20 - 7.16 (m, 2H), 6.35 (s, 1H), 4.90 (hr s, 2H), 2.46 (s, 1H), 1.82 (s, 3H). MS (ESI) m / z (M • i 1) 263.0.

[235] The following examples were synthesized analogous to the procedure of example 4 (intermediate 27) using the appropriate starting materials and thiourea:

[236] Table 2 Com. ID Structure Name HNMR LCMS ([M+H]+=) Intermediate 28 X INS 0 (7 0 \ 2-(2-aminothiazol-4-yl)-2-(4-methoxyphenyl)propan-1 -ol 265.1 Intermediate 29 \ 0 X 4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-amine 259.1 Intermediate 30 h2n-^ IT i il 4-(2-(4-bromo-2-fluorophenyl)but-3 -yn-2-yl)thiazol-2-amine 'H NMR (400 MHz, DMSO-J6) d 7.52 -7.46 (m, 1H), 7.45 - 7.39 (m, 2H), 6.93 (s, 2H), 6.42 (s, III), 3.44 (s, III), 1.84 (s, 3H). 19F NMR (376 MHz, DMSO-d6) 8 -107.657 324.9 Intermediate 31 Br h2Zs 4-(3 -(4-bromophenyl)pent-1 -yn-3 -yl)thiazol-2-amine Tl NMR (400MHz, DMSO-r / 6) d 7.60 -7.58 (m, 2 H), 7.43 - 7.39 (m, 2 H), 6.74 (s, 1 H), 3.77 (s, 1 H), 2.32 - 2.23 (m, 1 H), 2.18 - 2.11 (m, 1 H), 0.83 (t, J =7.2 Hz, 3 H) 321.0 Intermediate 32 U / 4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-amine 306.9 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Example 5: 4-(2-(4-bromophenyI)-l -methoxypropan-2-yI) thiazol-2-amine (Intermediate 33)

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

[238] To a solution of N-(4-(2-(4-bromophenyl)-l-hydroxypropan-2-yl)thiazol-2-yl) acetamide (200 mg, 563 umol, synthesized in the similar method described in intermediate 46) and Nl,Nl,N8,N8-tetramethylnaphthalene-l,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 LLO (30 mL), HC1 (1 N, 20 mL), sat. NaHCOs (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 (41 mg, yield: 19.72%) was obtained as a white solid.

[239] ’ll NMR (400 MHz, CDCL) S 8.69 (br s, 1H), 7.39 (d, J === 8.5 Hz, 2H), 7.10 (d, J 8.5 Hz, 2H), 6.69 (s, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 2.20 (s, 3H), 1.68 (s, 3H). MS (ESI) m / z (M+Hy=371.0.

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

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

[242] ’H NMR (400 MHz, CDCL) <5 7.42 - 7.36 (m, 2H), 7.18 - 7.13 (m, 2H), 6.22 (s, 1H), 4.83 (br s, 2H), 3.84 - 3.73 (m, 2H), 3.34 (s, 3H), 1.65 (s, 3H). MS (ESI) m / z (M+HI   327.0. [243| The following intermediates were synthesized analogous to the procedure of example 5 (intermediate 33) using the appropriate starting materials and thiourea:

[244] Table 3 Com. ID Structure Name HNMR LCMS (1M+H]]=) Intermediate 34 \ o 1 CM X 4-( 1 -methoxy-2-(4-methoxyphenyl)propan-2-yl)thiazol-2-amine 279.1 Intermediate 35 zd h2n— / 1        J s-J FAABr 4-(2-(4-bromo-2-fluorophenyl)-l-methoxypropan-2-yl)thiazol-2-amine 345.0 Intermediate 36 HgN"—Il      il 1 4 ■ (1 -methoxy-2-phenylpropan-2 ■■ yl)thiazol-2-amine 248.1 Intermediate 37 o ---o cz? 4-(2-(4-chlorophenyl)-1 -methoxypropan-2-yl)thiazol-2-amine 282.1 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Example 6: l-(2-aminothiazol-4-yI)-l-(4-bromophenyI)ethan-l-oI (Intermediate 38)

[245] Step 1, Preparation of compound l-(4-bromophenyl)propane-1,2-dione O

[246] To a solution of compound l-(4-bromophenyl)propan-2-one (2.0 g, 9.4 mmol, 1.0 eq) in dioxane (20 mL) was added SeO2 (3.12 g, 28.1 mmol, 3.0 eq). The mixture was stirred at 110 °C for 4 h. .After cooling down, 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.

[247] Step 2. Preparation of compound 3-bromo-l-(4-bromophenyl)propane-l,2- dione O                      O Br2,60 °C 0 CH^CIAcoiT            0

[248] To a solution of compound obtained from step 1 above (960 mg, 4.23 mmol, 1.0 eq) in CH3CI (20 mL) was added Br2 (1.05 g, 6.34 mmol, 1.5 eq) and AcOH (3 drops). The mixture was stirred at 60°C for 16 h. The reaction mixture was quenched by ■w / .Na2SO ' (aq) (20 mL), extracted with DCM (20 mL x 2) and washed with brine (15 mL), then dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE: EA =94%: 6%). The desired compound (800 mg, yield: 74%) was obtained as a yellow oil.

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

[250] To a solution of 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 NaHCOs. The mixture was stirred at 50 °C for 1.5 h. 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 NaaSCh, filtered and concentrated to give a residue, which was purified by flash silica gel chromatography (PE: EA=3: 1) to get the desired group (680 mg, yield: 90%).

[251] Step 4 Preparation of compound l-(2-aminothiazol-4-yl)-1-(4- bromophenyl)ethan-1 -ol ?                         HOx / f| ] T                    j J y-NH2 -1O'C-r.t, THF                  ~"s

[252] The solution of compound (2-aminothiazol-4-yl)(4-bromophenyl)methanone (200 mg, 0.71 mmol, 1.0 eq) in dry THF (4 mL) was cooled to 0°C, and was added CHsMgBr (3 M in THF, 1.6 mL, 4.9 mmol, 7.0 eq) dropwise. The mixture was stirred at RT overnight. The reaction mixture was quenched with sat. NH4CI (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 Na2SO4, filtered and concentrated to give a residue. The resulting residue was purified by Prep-TLC to give the desired compound (40 mg, yield: 20%).

[253] NMR (400 MHz, DMSO) 5 7.45 - 7.38 (m, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.12 (t, J === 7.3 Hz, 1H), 6.77 (s, 2H), 6.30 (s, 1H), 5.37 (s, 1H), 1.67 (s, 3H).

[254] MS (ESI) m / z (M+H)‘=221.0 Example 7:4-(2-(4-chlorophenyl)but-3~yn-2-yI)thiazol-5-d-2-amine D C!

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

[256] The mixture of N-[4-[l-(4-chlorophenyl)-l-methyl-prop-2-ynyl]thiazol-2- yl]acetamide (1 g, 3.28 mmol ) and NBS (700.74 mg, 3.94 mmol) in DMF (10 mL) was stirred at 50 °C for 2 h. The reaction was cooled to room temperature and then diluted with H?O (50 mL), extracted with EtOAc (30 mL x 3), the organic phase was combined and washed with brine (50 mL x 3), concentrated to give a residue. The 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.

[257] NMR (400MHz, CDC13) d 8.89 (br. s, 1H), 7.33-7.41 (m, 2H), 7.24-7.32 (m, 2H), 2.61 (s, 1H), 2.29 (s, 3H), 2.00 (s, 3H). MS (ESI) m / z (MH) 384.8.

[258] Step 2. Preparation of compound 4-[l-(4-chlorophenyl)-l-methyl-prop-2- ynyI]-5-deuterio~thiazoI-2-amine

[259] The mixture of compound obtained from step 1 above (600 mg, 1.56 mmol) and MsOH (751.43 mg, 7,82 mmol) in CD3OD (8 mL) was stirred at 80 °C for 16 h. The reaction was adjusted to pH = 8-9 with sat. NaHCOs aqueous, and then extracted with EtOAc (30 mL x 3), the organic phase was combined and washed with brine (30 mL), concentrated to give a residue. The residue was purified by silica gel chromatography (PE: EA=1:0 to 3:1) to give the products, which was re-purified by Pre-TLC (PE: EA=3:1). The desired compound (100 mg, yield: 20.8 %) was obtained as a yellow oil.

[260] H NMR (400MHz, CDCI3) d 8.89 (br. s, 1H), 7.33-7.41 (m, 2H), 7.24-7.32 (m, 2H), 2.61 (s, 1H), 2.29 (s, 3H), 2.00 (s, 3H). MS (ESI) m / z (M ■ Hf 263.8.

[261] At the same time, the byproduct 5-bromo-4-[l-(4-chlorophenyl)-l-methyl- prop-2-ynyl]thiazol~2-amine (300 mg, yield: 52.2%) was obtained as a yellow solid.

[262] MS (ESI) wvAiHf343.1. General Method I

[263] To a solution of thiazole amines (1 eq) and in appropriate organic solvent like DMF was added NaH (1.2-1,5 eqiv.) at 0-10°C, the resulting mixture was stirred for 5-30 mins. The mixture was added activated amine by CDI and stirred for 4-16 hours. Once the reaction was completed, the resulting suspension was diluted with organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by trituration / Prep-TLC / chromatography / Prep-HPLC to give the product. Example 8: Preparation of tert-butyl 4-(4-((3-(4-(2-(4-chloro-3-fluorophenyl)propan-2- yI)thiazol-2-yl)ureido)methyl)phenyl)piperazine-l-carboxyIate Boc ]264] To a solution of 4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazol-2-amine (40 mg, 0.15mmol, 1 eq) and in DMF (5 mL) was added NaH (7 mg, 0.3mmol, 2 eq) at 10°C. The resulting mixture was stirred for 5min. The mixture was added tert-butyl 4-(4-((1 H-imidazole-l-carboxamido)methyl)phenyl)piperazine-l-carboxylate (58 mg, 0.15 mmol, leq), and stirred overnight. The reaction was quenched with water, extracted with EA and combined organic layers were washed with brine then dried (Na2SO4), filtered and evaporated to dryness. The resulting residue was purified by Prep-TLC (PE: EA=3: 1) to give the title compound 35 mg (0.06 mmol) with the yield 40%. MS (ESI) m / z (M+H)+=588.2 General Method II 1265]         To a solution of amine fragment (1 eq) and pyridine in appropriate solvent like dry DCM was added phenyl carbonochloridate (2 eq) below 20°C slowly. The mixture was stirred at RT for 4-6 h. Once the reaction was completed, the resulting reaction was diluted with organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by trituration / Prep-TLC / chromatography / Prep-HPLC to give the product. Example 9: Preparation of tert-butvl 4-(5-((3-(4-(2-(4-bromophenvl)propan-2-yl)thiazol-2-vI) ureido)methy])pyrimidin-2-yl)piperazine-l-carboxvIate

[266] Phenyl carbonochloridate (336mg, 2.2 mmol, 269.0 uL) was added to the mixture of tert-butyl 4-(5-(aminomethyl)pwmidin-2-yl)piperazine-l-carboxylate (600 mg, 2.1 mmol), pyridine (194 mg, 2.5 mmol, 198pL) in CH3CN (15 mL) at - 20°C. After addition, the mixture was allowed to warm to 25 °C and stirred at 25 °C for 0,25 h. The solvent was removed under vacuum. The residue was triturated with ice water (15 mL). White solid was precipitated from the mixture. The mixture was filtered and the solid was collected, dried under vacuum. Tert-butyl 4-(5-(((phenoxycarbonyl)amino)methyl)pyrimidin- 2-yl)piperazine-l-carboxylate (420 mg, yield: 38.2%) was obtained as a white solid. MS (ESI) m / (Mil) = 414.2.

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

[268] MS(ESI)mA(M+H)M16.2. General Method III

[269] To a solution of substituted thiazol-2-amine and hunig base or pyridine in appropriate solvent like DCM or CH3CN, or DCM / water was added phenyl carbonochloridate (2 eq) at 0°C-RT slowly. The mixture was stirred 2-4 h at RT and the resulting reaction was diluted with organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by chromatography to give the substituted thiazol-2-amine carbamate.

[270] The mixture of the substituted thiazol-2-amine carbamate, amine and DMAP in appropriate solvent like THF was heated to reflux for 1-2 h. After cooling down, the resulting reaction evaporated and diluted with appropriate organic solvent like EA and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by trituration / Prep-TLC / chromatography / Prep-HPLC to give the product. Example 10: Preparation of l-(4-(4-((tert-bMtvldimethvIsiIvl)oxv)piperidin-l-vl)benzyl)- 3 ~(4-(2-(4~methoxYphenyI)propan”2-Yl)thiazoI-2~yI)urea [271 ]         To a solution of 4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-amine (100 mg, 0.34 mmol, 1 eq) and triethylamine in dry DCM (5 mL) was added phenyl carbonochloridate (106 mg, 0.68 mmol, 2 eq) at 0°C-RT slowly and the mixture was stirred for 4 h at RT. Quenched by brine, extracted with EA, the combined organic layers were washed with brine, dried over Na^SCL, filtered and concentrated to give a residue, which was purified by column chromatography on a silica gel to afford phenyl (4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)carbamate (112 mg).

[272] The mixture of phenyl (4-(2-(4-bromophenyl)propan-2-yl)thiazol-2- yl)carbamate (112 mg, 0.27 mmol, 1 eq), tert-butyl ((l-(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 hour. Cooled down to RT, the reaction mixture was participated 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 column chromatography on a silica gel to afford tert-butyl ((1-(4-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)phenyl)piperidin-4-yl)methyl)carbamate (42 mg) as a white powder. General Method IV

[273] The mixture of amine and isocyanate-alkanes in THF was stirred at RT overnight. Once the reaction w'as completed, the resulting suspension was diluted with organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by trituration / Prep-TLC / Prep-HPLC to give the product. Example 11: Preparation of l-ethyl-3-(4-(2-(4-methoxyphenyl)propaH-2-yi)thiazol-2-yl)urea o—

[274] To a solution of 4-(2-(4-methoxyphenyl)propan-2-yl)thiophen-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 RT overnight. The mixture was concentrated at 45°C with reduce pressure to remove THF. The resulting suspension was diluted with EtOAc and washed with brine and then dried (NawO filtered and evaporated to dryness. The resulting residue was purified by Prep-TLC to give the desired compound (164 mg, yield: 65.4%) as a pale yellow' solid. MS (ESI) m / z (M+H ) + = 367.1.

[275] De-BOC General Method

[276] The Boc compounds w'ere dissolved in HCl / MeOH, the reaction mixture was stirred for 1-2 h at RT. The solution was concentrated to dryness to give the final compound. Example 12: Preparation of compound l-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6-(piperazin-l-yI)pyridin-3-yI)methyl)urea hydrochloride

[277] 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~l-carboxylate (70.0 mg, 113.71 pmol) in MeOH (2 mL) was added HCI / MeOH (4 M, 2 mL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuum. The desired compound (47.0 mg, yield: 74.1%, HC1) was obtained as a white solid.

[278] NMR (400MHz, DMSCWe) d 10.90 (br s, 1H), 9.66 (br s, 2H), 8.05 - 7.92 (m, 2H), 7.48 - 7.28 (m, 4H), 7.21 - 7.10 (m, 2H), 6.75 (s, 1H), 4.30 - 4.20 (m, 2H), 4.04 -3.92 (m, 4H), 3.24 (br s, 4H), 1.57 (s, 6H). MS (ESI) m / z (Mil) 517.2.

[279] The following examples were synthesized analogous to the procedure of example 8, 9, 10, 11 and 12 using the appropriate intermediates and the corresponding fragments:

[280] Table 4 Com. ID Structure Name HNMR LCMS (IM-HI ) Kinase assay 1C50 nM NFkB assay IC50pM A001 y-OMe I 0 N-A K 'N SZ j] J H H HN.^ 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-( 1 -(6-(piperazin-l- yi)pyridin-3-yl)ethyl)urea 481.0 58 0.67 A002 y~OMe F ( 0 N-A 1A A A) if A N N S JI J H H F 1 -(1 -(2,5-difluoro-4-(piperazin-1 -yi)phenyl)ethyl)-3 -(4-'(2-(4-methoxyphenyl)propan-2 -y l)th iazo 1-2 -y 1) ure a 516.1 63 0.70 A003 XI> T V N N S il | H H HNxA F 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(l-(3,5-difluoro-4-(piperazin-1-yl)phenyl)ethyl)urea 564.0 45 1.20 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A004 - / J V-Br 0 JI J / 7 II J H H 1-(4-(2-(4- bromophenyl)propan-2-yl)thiazol-2 -yl)-3 -(pyrimidin-5-ylmethyl)urea 432.1 240 2.03 A005 I ^<rBr I 1 > SZ [1 J H H 0 N H 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3-(3-(piperazin-1 -yl)benzyl)urea 514.0 97 3.15 A006 HN^s^ JT^ H2N 1-(4-((3-(4-(2-(4-bromophenyl)propan-2.-yl)thiazol-2-yl)ureido)methyl)phenyi )piperidine-4-carboxamide 556.1 104 A007 _[yf~\-~QMe J o n-A JJ » > NUNN'S M H H 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(pyrazin-2-ylmetbyljurea 384.0 91 5.58 A008 n        n n H H d 4-((3-(4-(2-(4-bromophenyl)propan-2-yi)thiazol-2-yl)ureido)methyl)benza mi de 473.1 8 0.70 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh A009 - y         Br JI ! H H HO-Xn l-(4-(2"(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(3 -hydroxypyrrolidin-1 -yl)benzyl)urea 515.1 154 3.15 AOK) jry* / "Xt—J 0 NXk A A > N       N "n S II J H H hct^ 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-vl) ■ 3 -((6-( 4 ■ (2-hydroxyethyl)piperazin-l-yl)pyridin-3-yl)methyi)urea 559.0 200 3.95 AO 11 ACX o nA jf II > l| 1 H H HA 1-((6-(3- (dimetbylamino)pyrrolid in-1 -yi)pyridin-3 -yl)methyl)-3 -(4-(2-(4-methoxyphenyl)propan-2 -y l)thiazo 1-2 -y 1) ure a 495.1 49 1.37 AO 12 '-.L— 1J3 N       N N S II           H H \      A< A N-Z^ N / VJ 1-((2-(3-(dimethylamino)pyrrolid in-1 -yl)pyrimidin-5 -yi)methyl)-3 -(4-(2-(4-m eth oxyphenyl )pr op an -2-yI)thiazol-2-yl)urea 496.0 40 2.21 AO 13 J?— O M e O    O N-^ X  A A? / 1 xX^N  N S °      H   H 1-(4-(2-(4-meth oxyphenyl )prop an -2-yi)thiazol-2-yl)-3-(2-(methylsulfonyl)ethyl)ur ea 398.1 316 2.97 WO 2022 / 063152                                                 PCT / CN2021 / 119801 AO 14 OMe 0 .. ~ I H > N   'N^N^S HOX A J H H x' N H 1-((6-((2-h ydroxy ethyl) amino)pyr idin-3-vllmethyl)-3-(4- " (2-(4-‘ ' methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 442.0 160 0.88 AO 15 OMe s H J J H H ( T Y o 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-N-( 1 -methylpiperidin-4-yl)picolinamide 523.0 24 0.88 AO 16 uJU H H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazo!-2-yl)-3-(4-((4-methylpiperazin-1 ■■ yl)methyl)benzyl)urea 542.1 27 2.34 AO 17 4__£A-b, o n-4 _ _ a X> if A-^-N N S II J H H 6i 1-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-3 -(3 chloro-4-fluorobenzyl)urea 482.1 204 0.97 AO 18 OMe / ={ / > j PY d 1 J H H Pf Y 4-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazoi-2-yl)ureido)methyl)-N-( 1 -methylpiperidin-4-yl)benzamide 522.1 29 1.28 WO 2022 / 063152                                                 PCT / CN2021 / 119801 AO 19 0 s- O PVNp' jl i H H HN' 0 1 1-(4-(2-(4-methoxyphenyl)propan-2-yi)thiazol-2-yl)-3 -((6-((1 -methylpiperidin-4 ■ yl)amino)pyridin-3 -yl)methyl)urea 495.1 32 1.29 A020 A A^-Br 0 nA A Ae / N N S H H 1-(4-(2-(4-bromophenyl)propan-2 ■ yl)thiazol-2-yl)-3 -(2-fluoroethyl)urea H NMR (400 MHz, CDC13) d 7.40 - 7.35 (m, 2H), 7.15-7.10 (m, 2H), 6.42 (s, 1H), 4.54-4.49 (m, 1H), 4.41 -4.37 (m, 1H), 3.55 (ddd, J == 28.1, 10.0, 5.2 Hz, 2H), 1.63 (s, 6H). 386.0 144 6.79 A021 / ^O \ A z M 1 p / o % 1 -(2-fluoroethyl)-3 -(4-(2-(4- ' methoxyphenyl)propan-2-yl)thiazol-2-yl)urea lH NMR (400 MHz, DMSO-A) d 10.53 (s, 1H), 7.12 - 7.00 (m, 2ID, 6.83 -6.68 (m, 2H), 6.60 (s, 1H), 6.48 (s, 1H), 4.40 (dt, J = 47.5, 5.0 Hz, 2H), 3.72 -3.58 (m, 3H), 3.37 (ddd, J = 26.8, 10.6, 5.2 Hz, 2H), 1.60 - 1.46 (m, 6H). 338.1 104 1.39 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A022 &• X O Q *=< o=< XX b $ o SE 1-((6-((2-hydroxyethyl)amino)pyr idin- 3 -yl)methyl)-3 -(4- * (2-(4-m eth oxyphenyl )pr op an -2-yl)thiazol-2-yl)urea lH NMR (400 MHz, CD3OD) 4 7.85 (dd, J = 9.3, 1.9 Hz, 1H), 7.75 (s, 1H), 7.20 - 7.15 (m, 2H), 7.08 (d, J === 9.3 Hz, 1H), 6.87 - 6.81 (m, 2H), 6.78 (s, 1H), 4.31 (s, 2H), 3.85 -3.78 (m, 2H), 3.78 - 3.73 (m, 3H), 3.55 - 3.48 (m, 2H), 1.67 (s, 6H). 442.1 232 0.96 A023 o nA A AJ N      N N S HO^ Aj H H 1 1-((6-((2-hydroxyethyl)(methyl)a mino)pyridin-3 -yl)methyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea lH NMR (400 MHz, CD3OD) S 7.94 (dd, J = 9.5, 2.1 Hz, 1H), 7.84 (d, J === 1.6 Hz, 1H), 7.31 (d, J === 9.5 Hz, 1H), 7.21 - 7.16 (m, 2H), 6.88 -- 6.85 (m, HI), 6.85 (d, J = 2.1 Hz, 1H), 6.84 (s, 1H), 4.35 (s, 2H), 3.85 (t, J === 4.8 Hz, 2H), 3.80 -3.77 (m, 211),3.77 (s, 3H), 3.29 (s, 3H), 1.68 (s, 6H). 456.0 229 1.32 A024 X(y« 0 N-A "" nK / x A H H 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2 -yl)-3 -(2-cyanoethyl)urea ‘H NMR (400MHz, CDCh) <5 7.44 - 7.37 (m, 2H), 7.30 -7.24 (m, 2H), 6.75 (s, 1H), 3.55 - 3.40 (m, 2H), 2.58 -2.51 (m, 3Hl. 1.92 (s, 3H). 359.1 13 1.25 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A025 O O rr" s HoY 1-(4-(2-(4-cyc] opropylphenyl)prop an-2-yl)thiazol-2-yl)-3-(4-(piperazin-l -yl)benzyl)urea 476.0 334 8.58 A026 Br o HN'^>   ff^r^N'^'N'^'N P' ow h h 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-ylmethyl)benzyl)urea 528.0 117 1.25 A027 ■J / Ver . 1 Jo fYp s 1-(4-(2-(4-bromophenyl)propan-2 ■ yl)thiazol-2-yl)-3 -(4-(piperazin-1-yl)benzyl)urea 514.0 46 1.45 A028 4-0 o n-4 ^^x,^-nAnAs> H H 1 -(4-aminobutyl)-3-(4-(2-(4-^ bromophenyl)propan-2-yl)thiazol-2-yi)urea 411.1 53 2.56 A029 OXO-Br / NO' O NO ACnv* Ht4> 1-(4-(2-(4- bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(2-methylpiperazin-1 -yl)benzyl)urea 528.1 73 A030 00-8^ % IV ~ JI J H H 1-(4-(2-(4- bromophenyl)propan-2-yl)-5 -methylthiazol-2-y 1)-3-(4 -(piperazin-1 -yl)benzyl)urea 528.1 23? 4.11 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 o A031 HN              / ° V F hn-A || L 1 S'"     'Z a b(442-(4-chk)ro-3-fiuorophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea 488.0 345 1.45 A032 —i_ / ~ V-Br x H Ji i H H 1-(4-(3-aminopyrrolidin-1 -yl) benzyl)-3 -(4 -(2 ■ (4 -bromophenyl)propan-2-yl)thiazol-2-yl)urea 514.0 291 0.58 A033 AA A A? i .1 H H 0 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(2-oxo-2-(piperazin-1 -yl)ethoxy)benzyl)urea 572.0 80 3.19 A034 U AVar J-VA o n-4 .      / s / x A A? HN 1     Q H H “ 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(2-(piperazin-1 ■■ yl)ethoxy)benzyl)urea 558.0 114 0.73 A035 tAO-8' I f^V^NH NH S l h 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(3 ■■ (piperazin-1-yl)propoxy)benzyl)urea 572.0 52 2.03 A036 R^JJ> “ T j H H A'’y'Y HN^X F l-((5-fluoro-6-(piperazin-1 -yl)p yridin-3-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 485.1 24 0.62 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A037 F ■^4— O N-4 A A? N N S H H l-(3-fluoro-4- (piperazin-1-ylmethyl)benzyl)-3-(4 -(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 498.1 57 2.51 A038 XT HN^J F ACT o nA A At hT N S H H 1-(4.(2-(4-bromophenyl)propan-2 ■ yl)thiazol-2-yl)-3-((5-fluoro-6-(piperazin-l -yl)pyridin-3-yl)methyi)urea 533.1 30 1.66 A039 4Q"Br J Y / N N S H H 1-(4-(2-(4-bromophenyl)butan-2-yl)thiazol-2-yl)-3-(4- (piperazin-1 ■ yl)benzyl)urea 528.1 189 0.711 A040 / £X hO f ACT“ A A > N N' S H H l-(3,5-difluoro-4-(piperazin-1 -yl)benzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 502.1 45 0.50 A041 H!H Ct H OMe ci o s-\ yA x-v. A A / —A X N N N A H H 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperidin-4-ylamino)benzyl)urea 480.0 23 1.86 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A042 MeO f-s 0 H H L 1 d 0 4-((3-(4-(2-(4-m eth oxyphenyl )pr op an -2-yl)thiazol-2-yl)ureid o)methyl)-N -(piperidin-4-yl)benzamide 508.0 15 A043 OMe HN'^        q 8-¾ y^n-^nA? y U H H 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3 -((6-(piperazin-1 -yl)p yridin-2-yl)methyl)urea 467.0 165 A044 X r$ M N x s l| J H H 1-.(4-.(1..(4.. bromophenyl) ethyl)thiaz ol-2-yl)-3-(4-(piperazin-1 -yl)benzyl)urea i 1 NMR (400 MHz, CD3OD) S 7.45 (d. J - 6.9 Hz, 2H), 7.22 (s, 2H), 7.14 (s, 2H), 6.97 (s, 3H), 4.32 (s, 2H),4.18(s, 1H), 3.37 (s, 411),3.33 (s, 4H), 1.59 (s, 3H). 500.0 147 1.11 A045 UN        —\ O N— / \=- / hnA nA HN~<J M 3   \   / 1-(4-(1-(4-bromophenyl)cyclopent yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea lH NMR (400 MHz, DMSO-O S 9.28 (s, 1H), 7.39 (d, J - 8.3 Hz, 2H), 7.19 (d, J 8.5 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.76 (s, lH),4.18(d, J = 4.4 Hz, 2H), 3.31 (s, 411),3.16 (s, 4H), 2.41 (d, J - 12.9 Hz, 2H), 1.95 (s, 2H), 1.59 (d, J = 9.0 Hz, 4H). 540.1 24 1.07 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A046 0  N-\ H H 1-(4-(2-(4-chlorophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1 ■ yl)benzyl)urea lI-I NMR (400 MHz, DMSO-cfc) <5 8,99 (s, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.12 (d, J === 8.2 Hz, 2H), 6.91 (d, J === 8.7 Hz, 3H), 6.70 (s, 1H), 4.17 (d, J = 5.8 Hz, 2H), 3.28 (s, 4H), 3.17 (s, 4H), 1.54 (s, 6H). 470.0 79 1.06 A047 Q o x > XX "n 1-(4-(2-(4-fiuorophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea 1H NMR (400 MHz, DMSO-Je) d 7.18 (dd, J = 8.1,5.7 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 6.89 (d, J === 8.1 Hz, 2H), 6.84 (s, HI), 6.66 (s, HI), 4.17 (d, J 5.6 Hz, 2H), 3.24 (d, J = 5.3 Hz, 4H), 3.13 (d, J = 5.0 Hz, 4H), 1.54 (s, 6H). 454.0 167 2.10 A048 Q 2!—\ Q X ■4-ZyBr ,.115 = >rMs H H 'Cl 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(2-chloro-4-(piperazin-l -yl)benzyl)urea 'H NMR (400 MHz, DMSO-16) ¢5 9.24 (s, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.19 (d, J === 8.6 Hz, 1H), 7.12 (d, J === 8.6 Hz, 3H), 7.01 (d, J === 2.3 Hz, 1H), 6.90 (dd, J = 8.7, 2.3 Hz, 1H), 6.70 (s, 1H), 4.25 (d, J === 5.7 Hz, 2H), 3.43 - 3.28 (m, 4H), 3.13 (s, 4H), 1.54 (s, 6H). 548.0 138 1.53 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A049 O / \= / I T $ JI J H H cfs 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3 -(4-(piperazin-1 -yl) - 3 -(trifluoromethyl)benzyl) urea lI-I NMR (400 MHz, DMSO-A) <5 9.11 (s, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.38 (d, J === 8.5 Hz, 2H), 7.19 (s, 1H),7.11 (d, 1===8.5 Hz, 2H), 6.70 (s, 1H), 4.30 (d, J = 5.7 Hz, 2H), 3.10 (d, J == 17.0 Hz, 4H), 3.01 (d, J = 3.9 Hz, 4 Hl 1.56 (d, J = 22.5 Hz, 6H). 582.0 119 0.8 A050 AO* o N-i 0    « 2 AVA' VA 1      1 H H A^=o^ HN^A F 1-(4-(2-(4- bromophenyl)propan-2-yl)lhiazol-2-yl)-3-(3-fluoro-4-(piperazin-l -yl)benzyl)urea ’H NMR (400 MHz, DMSO-A) ¢5 9.31 (s, 1H), 7.31 (d, J === 44.6 Hz, 3H), 7.04 (d, J ==== 44.4 Hz, 4H), 6.68 (s, HI), 4.18 (s, 2H), 3.15 (s, 8H), 1.51 (s, 6H). 532.1 26 1.21 A051 O__^ ^-Br o n-4 / . A A J OOn N^s J MH 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3 -(2-methyl-4-(piperazin-1 -yl)benzyl)urea A NMR (400 MHz, DMSO-A) <5 10.54 - 10.45 (m, 1H), 9.02 (s, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.5 Hz, 1H), 6.78 (s, 2H), 6.74 (d, J === 8.5 Hz, HI), 6.70 (s, HI), 4.17 (d, 1====5.4 Hz, 2H), 3.28 (d, J = 5.5 Hz, 4H), 3.16 (s, 4H), 2.20 (s, 3H), 1.54 (s, 6H). 528.1 125 0.29 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 Ul A054 A055 5-((3-(4-(2-(4-bromophenyl)propan-2-yi)thiazol-2-yl)ureido)methyl)-2-(piperazin-1 ■ yl)benzamide 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea l-(3-fluoro-4-(piperazin-1 -yl)benzyl)-3-(4-(2-(4-m eth oxyphenyl )pr op an -2-yl)thiazol-2-yl)urea 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(3-(2-meth oxyethoxy) -4-(piperazin-1-yl)benzyl)urea lH NMR (400 MHz, DMSO-O 3 9.35 (s, HI), 8.04 (s, 1H), 7.54 - 7.32 (m, 3H), 7.23 (d, J = 29.5 Hz, 2H), 7.09 (d, J === 19.3 Hz, 3H), 6.70 (s, 1H), 3.13 (d, J == 46.5 Hz, 8H), 2.66 (d, J = 17.4 Hz, 2H), 1.53 (s, 6H). Hl NMR (400 MHz, DMSO4) <5 9.15 (s, HI), 7.09 (d, J = 18.4 Hz, 4H), 6.90 (s, 2H), 6.75 (s, 2H), 6.61 (s, 1H), 4.17 (s, 2H), 3.65 (s, 3H), 3.28 (s, 4H), 3.15 (s, 411), 1.52 (s, 6H), lH NMR (400 MHz, CD3OD) d 10.12 (s, 2H), 8.12 (s, 1H), 7.81 (d, J === 23.1 Hz, 5H), 7.53 (s, 2H), 7.39 (s, 1H), 4.97 (s, 2H), 4.43 (s, 3H), 3.93 (s, 8H), 2.29 (s, 6H). 'H NMR (400 MHz, CD3OD) J 7.48 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 7.1 Hz, 2H), 7.11 (s, 1H), 7.00 (s, 2H), 6.93 (s, HI), 4.38 (s, 2H), 4.19(8, 4H), 3.77 (s, 4H), 3.43 (s, 4H), 3.40 (s, 3H), 1.69 (s, 6H). 557.1 466.1 484.1 588.1 24       1.96 30       0.88 182      4.70 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A056 OH / =\ CO N 3 F 1-(4--(1--(4-bromophenyl) -1 ■■ hydroxyethyl)thiazol-2-yl)-3-(3-fluoro-4-(piperazin-1-yl)benzyl)urea lH NMR (400 MHz, CD3OD) 3 7.46 (d, J - 8.4 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.04 (t, J = 9.9 Hz, 4H), 4.36 (d, J == 6.7 Hz, 2H), 3.29 (s, 8H), 1.84 (d, J = 13.6 Hz, 3H). 534.1 176 1.06 A057 p ^--32 >o \ 1 o 1 1-(4-(2-(5-bromopyridin-2-yl)propan-2-yl)thiazol-2-yl)-3 -(3 -fluoro-4-(piperazin-1-yl)benzyl)urea ‘H NMR (400 MHz, CD3OD) S 8.48 (d, J = 2.3 Hz, HI), 7.80 - 7.73 (m, 11:1),7.08 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 4.2 Hz, 2H), 6.99 (s, 1H), 6.73 (s, 1H), 4.30 (s, 2H), 3.25 (s, 4H), 3.23 (s, 4H), 1.64 (s, 6H). 533.1 246 A058 -1.. / JV-O6S® O Np HN. J k OH 1 -(3 -(hydroxymethyl)-4 ■ (piperazin-1 -yDbenzyl)-3-(4-(2-(4- methoxyphenyl)propan-2-yl)thiazol -2-yl)urea Hl NMR (400 MHz, CD3OD) d 7.41 (d, J = 4.2 Hz, 2H), 7.21 (s, HI), 7.15 (d, J = 6.7 Hz, HI), 7.12 (d, J = 5.9 Hz, 2H), 6.88 (s, 1H), 6.85 (s, 1H), 6.82 (d, J = 5.7 Hz, 2H), 4.67 (s, 2H), 4.38 (s, 2H), 3.74 (s, 3H), 3.25 - 3.22 (m, 411),3.17-3.11 (m, 4H), 1.63 (s, 6H). 496.1 130 3.10 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A059 o n-A I 11 > ~ J J H H An 1-(4-(2-(4-eth oxyphenyl )propan-2-yl)thiazol-2-yl)-3 -(4-(piperazin-1-yl)benzyl)urea lH NMR (400 MHz, CD3OD) ¢5 7.17 (t, J = 5.9 Hz, 2H), 7.09 (dd, J = 9.4, 2.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.78 -- 6.73 (m, 2H), 6.58 (s, 1H), 4.28 (s, 2H), 3.96 (q, J = 7.0 Hz, 2H), 3.34 (d, J = 3.6 Hz, 4H), 3.33 (s, 4H), 1.57 (s, 6H), 1.37- 1.29 (m, 3H). 480.0 269 A060 J / / ”Y-OMe J 0  N"4 A A J AV N N S 1         H H rff o^nh2 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yI)ureido)methyl)-2-(piperazin-1-yl)benzamide lH NMR (400 MHz, DMSO A) <5 9.35 (s, 2H), 8.05 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.48 (s, 1H), 7.30 (d.J 10.1 Hz, 2H), 7.08(1, J = 8.0 Hz, 311), 6.78 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 4.24 (d, J = 5.2 Hz, 2H), 3.66 (s, 3H), 3.20 (s, 4H), 3.08 (s, 4H), 1.54 (s, 6H). 509.0 8 4.80 A061 £ / v w a: A CM X 1 -(3-aminopropvl)-3-(4-(2-(4-' bromophenyl)propan-2-yl)thiazol-2-yl)urea lH NMR (400 MHz, DMSO-A) 8 8.08 (s, 3H), 7.49 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.11 (d.J 8.2 Hz, 2H), 6.78 (s, HI), 3.14 -3.12 (s, 2H), 2.73 (s, 2H), 1.70 (s, 2H), 1.53 (s, 6H). 397.0 195 1.99 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 00 A062 a-, ? HN V             H ® 1-(4-(2,5-diazabicyclo[2.2 J ]hepta n-2-yl)benzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea lH NMR (400 MHz, CD3OD) <5 7.22 - 7.15 (m, 4H), 7.09 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.5 Hz, 2H), 4.62 (s, 1H), 4.46 (s, 1H), 4.30 (s, 2H), 3.75 (s, 3H), 3.69 (dd, J = 10.7, 2.2 Hz, 1H), 3.31 -3.27 (m, 3H), 2.25 (d, J = 11.0 Hz, 1H), 2.04 (d, J = 11.2 Hz, 1H), 1.68 (s, 6H). 478.1 60 1.33 A063 —1—^ £ J H H /    Y hm     X 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-2-(3-methylpiperazin-1 -yl)benzamide 'H NMR (400 MHz, CD3OD) J 7.70 (d, J = 2.0 Hz, 1H), 7.50 (dd, J === 8.3, 2.0 Hz, III), 7.28 (d, J ==== 8.3 Hz, HI), 7.23 (s, 1H), 7.20 (s, 1H), 7.14 (s, HI), 6.93 (d, J = 8.8 Hz, 2H), 4.47 (s, 2H), 3.79 (s, 3H), 3.56 -3.48 (m, 1H), 3.46-3.41 (m, 1H), 3.38 (d, J === 11.9 Hz, HI), 3.17 (d, J === 12.7 Hz, HI), 3.00 (d, J = 13.9 Hz, 1H), 2.97 - 2.91 (m, iH). 2 90 2.84 (m. 1H), 1.72 (s, 6H), 1.40 (d, 1===6.6 Hz, 3H). 523.0 29 2.91 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 MO A064 o=A 2-(2,5-diazabicyclo[2.2.1 ]hepta n-2-yl)-5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)benza mi de lH NMR (400 MHz, DMSO-Aj ¢5 10.70 (s, 1H), 9.72 (s, 1H), 8.89 (s, 1H), 7.68 (s, 1H), 7.37 (s, 1H), 7.23 (d, J === 1.9 Hz, 1H), 7.18 (dd, J === 8.5, 1.9 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.80 (dd, J = 14.2, 8.7 Hz, 3H), 6.68 (d, J = 1.1 Hz, 1H), 5.44 (s, 5H), 4.48 (s, 1H), 4.35 (s, 1H), 4.22 (d, J === 5.1 Hz, 2H), 3.71 (s, 3H), 3.17(s, 111),3.11 (d, J = 10.7 Hz, 1H), 2.04 (d, J == 10.5 Hz, 1H), 1.95-1.89 (m, 1H), 1.58 (s, 6H). 521.0 41 19.73 A065 1 J > ~ II           H H H 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido (methyl) -N-methyl-2-(piperazin-l -yl)benzamide 'H NMR (400 MHz, DMSO-J6) ¢5 9.42 (s, 1H), 8.45 (s, 1H), 7.51 (d, J ==== 28.5 Hz, 2H), 7.28 (d, J === 8.0 Hz, HI), 7.07 (t, J ==== 10.0 Hz, 3H), 6.78 (d, J === 8.4 Hz, 2H), 6.67 (s, 1H), 4.23 (s, 2H), 3.66 (s, 3H), 3.18 (s, 4H), 3.06 (s, 4H), 2.77 (d, J ==== 3.7 Hz, 3H), 2.46 (s, 1H), 1.54 (s, 6H). 523.0 30 4.44 A066 y-yy* °" / I rt H H 1-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-3-(2-(methylsulfonyl)ethyl)ur ea 446.0 126 10.50 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A067 o A y > H H s o *X 1-(4-(2-(4-iodophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)benzyl)urea 562.0 28 1.11 A068 p 1 J H H h2n- / ^ 4Q-° x$ 1-((2-(3-aminopyrrolidin-1 ■ yl)pyrimidin-5-yl)methyl)-3 -(4-(2-(4-chlorophenyl)propan-2-yl)thiazol-2-vl)urea 472.0 269 A069 q H H HO—f N ac>o“ T> s 1-(4-(3-hydroxypyrrolidin-1 -yl)benz^l)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 467.0 269 A070 u          O zx N x-x z-.„ A fT 7 “ " * OMe 15 -^s 4-(3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)-N-(l-methylpiperidin-4-yl)butanamide 474.0 140 16.91 A071 / ) tz Ao zez: ~^_^V-OMe A 4-(3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazoi-2-yl)ureido)-N-(piperidin-4-yl)butanamide 460.1 64 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A072 1-(2-(2-(3-aminopyrro lidin-1 -y l)ethoxy) ethyl) -3 -(4 -(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 448.1 143 1.45 A073 HN.^ 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(l -(4-(piperazin-1-yl)phenyl) ethyl)urea 528.1 85 2.79 A074 - / #“V0Me 1 -(3-hydroxy-2-oxopropyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 364.1 61 A075 HN,^ l-(4-(piperazin-l-yl)benzyl)-3-(4-(2-(p-toIyl)propan-2-yl)thiazol-2-yl)urea 450.1 25 0.267 A076 yA- / OMe HN,^J 1-(4-(2-(4-methoxyphenyl)butan-2-yl)thiazol-2-yl) -3 -(1 -(4 -(piperazin-1-yl)phenyl) ethyl)urea 494.1 147 4.48 A077 1-(4-(3-aminopyrro lidin-1 -yl)butyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 432.1 180 2.97 WO 2022 / 063152                                                 PCT / CN2021 / 119801 to AO / 8 h2n J] J H H 1-((2-(3- aminopyrro lidin-1 - yl)pyrimidin-5-yl)methyl)-3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea lI-I NMR (400 MHz, DMSO-A) d 8.46(br, 5H), 7A9(d, J = 8.8Hz, 2H), 7.32(s, 1H), 7,10(d, J = 8.8Hz, 2H), 6.73(s, 1H), 4.15(s, 2H), 3.70-3.59(m, 5H), 2.30-2.27(m, 1H), 2,16-2,13(m, 1H), 1.53(s, 6H). 516.1 8 A079 HO- AAA* o n-A N'V "'NT N^'S A J H H \J 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(3-hydroxypyrrolidin-1 ■■ yl)pyrimidin-5-yl)methyl)urea ‘H NMR (400MHz, Ci X ! 0 d 8.13 (s,2H), 7.34 (d,J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6 48 (s, 1H), 4,49 (br s, 1H), 4.07 (br d, J == 4.0 Hz, 2IT), 3.85 - 3.50 (m, 4H), 2.22 - 1.92 (m, 3H), 1.59 (s, 6H), 1.26 (s, 1H). 519.2 170 1.68 A080 cr i AO »W«A X J H H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazoI-2-yl)-3-((2-methoxypyrimidin-5 -yl)methyl)urea di NMR (400 MHz, DMSO-A) d 10.72 (s, 1 H), 8.49 (s, 2 H), 7.39 (d, 1=8.56 Hz, 2 H), 7.14 - 7.07 (m, 2 H), 6.85 - 6.79 (m, 1 H), 6.70 (s, 1 H), 4.20 (s, 2 H), 3.82 - 3.87 (m, 3 IT), 1.53 (s, 6 H). 461.9 172 13.30 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A081 O s-^ A N'N N N H H H 1-((2-((2-aminoethyl)amino)pyri midin-5 -yl)methyl)-3 -(4-(2.-(4-bromophenyl)propan-2-yl)thiazoi-2-yl)urea lI-I NMR (400 MHz, DMSO-de) <5 8.44 (s, 2 H), 8.06 (br s, 3 H), 7.43 (d, .1=8.56 Hz, 2 H), 7.24 (br s, 1 H), 7.14 (d, J 8.56 Hz. 2 H), 6.75 (s, 1 H), 4.17 (br d. .1=5.38 Hz, 2 H), 3.52 -3.65 (m, 2 H), 2.88 - 3.04 (m, 2 H), 1.57 (s, 6 H). 492.1 17 1.84 A082 4 / y* 115 Ji J H H ho'Ax~ / 1-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-3-((2-(4-hydroxypiperidin-1 -yl)pyrimi din-5 -yl)methyl)urea !H NMR (400MHz, DMSOA) d’ 10.65 (s, 1H), 8.27 (s,2H), 7.42 (d, J =8.6 Hz, 2H), 7.14 (d, J= 8.8 Hz, 2H), 6.77 ■ 6.67 (m, 2H), 4.74 - 4.68 (m, HI), 4.27-4.19 (m,2H), 4.12-4.06 (m, 2H), 3.75 - 3.66 (m, U B. 3.26 - 3.18 (m, 2H), 1.79 - 1.71 (m, 2H), 1.57 (s, 6H), 1.31 - 1.24 (m, 2H). 533.0 125 6.15 A083 4-CK s n L h H H HO-^? 1-((2-(3-hydroxypyrrolidin-1 -yl)pyrimidin-5-yl)methyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol -2-yl)urea 'H NMR (400 MHz, CDCh) 8.16 (s, 2 H), 7.15 - 7.03 (m, 2 H), 6.79 - 6.77 (m, 1 H), 6.83 - 6.72 (m, 1 H), 6.46 - 6.38 (m, 1 H), 4.55.4.49 (m; 1 H), 4.15 -4.06 (m, 2 H), 3.77 (s, 3 H), 3.71 - 3.59 (m, 4 H), 2.13 ■ 2.02 (m, 2 H), 1.58 (s, 6 H) 469.2 111 0.68 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A084 H i H H 1-(4-(2-(4-chlorophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)urea lI-I NMR (400 MHz, DMSOp6)d9.17(s, 1H), 8.34 (s, 2H), 7.25 (d, J === 8.0 Hz, 2H), 7.16 (d, J === 8.0 Hz, 2H), 7.02 (s, 1H), 6.69 (s, 111),4.11 (s, 21-1),3.90 (s. 4H), 3.09 (s, 4H), 1.53 (s, 6H). 472.0 22 0.34 A085 iUL. n, H* ZE O=( SIS / s—< Q 1-(4-(2-(4-fluorophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1 ■ yl)pyrimidin-5-yl)methyl)urea 1H NMR (400 MHz, DMSO-ae) 8 9.34 (s, HI), 8.35 (s, 1H), 7.22 (d, J === 40.8 Hz, 2H), 7.01 (s, 2H), 6.69 (s, 1H), 4.11 (s,2H), 3.91 (s, 4H), 3.08 (s, 4H), 1.54 (s, 6H). 456.0 85 0.49 A086 d p sp ji j h h 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3 -((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)urea 1H NMR (400 MHz, CD3OD) 8 8.47 (s, 2H), 7.17 (s, 2H), 7.09 (s, 1H), 6.88 (s, 2H), 4.32 (s, 2H), 4.09 (s, 3H), 3.74 (s, 4H), 3.32 (d, J === 5.5 Hz, 4H), 1.67 (s, 6H). 468.0 16 0.39 A087 ._ / / b"os / \= / o 1 JL > II J H H 1-(4-(2-(4-ethoxyphenyl)propan-2-yl) thiazol-2 -yl) - 3 -((2 -(piperazin-1-yi)pyrimidin-5-yl)methyl)urea 'H NMR (400 MHz, CD3OD) 8 8.57 (s, 2H), 7.15 (d, J === 8.2 Hz, 2H), 7.11 (s, 1H), 6.87 (d, J == 8.2 Hz, 2H), 4.37 (s, 2H), 4.14 (s, 4H), 3.99 (q, J = 6.9 Hz, 2H), 3.34 (d, J === 12.6 Hz, 4H), 1.68 (s, 6H), 1.34 (t, J == 6.9 Hz, 3H). 482.1 89 1.74 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh A088 n n' hM 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)urea compound with methane (1:1) lH NMR (400 MHz, CD3OD) 8 8.51(s, 2H), 7.53-7.5 l(m, 2H), 7.24-7.22(m, 2H), 7.15(s, 1H), 4.36(s, 2H), 4.14-4.12(m, 4H), 3.34-3.33(m, 41A 1.73 (s, 6H). 518.0 13 1.45 A089 0 NZVXN^N'^S 1)      1 H H HN^ 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((4-methyl-2-(piperazin-l -yl)pyrimidin-5-yl)methyl)urea 11 NMR (400MHz, DMSO-t / e) 8 10.70 (br s, 1H), 9.37 (brs,2H), 8.21 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.34 - 7.26 (m, 1H), 7.14 (d, J - 8.6 Hz, 2H), 6.75 (s, 1H), 4.20 (br d, J = 5.1 Hz, 2H), 4.01 - 3.91 (m, 4H), 3.12 (br s, 4H), 2.37 (s, 3H), 1.57 (s, 6H) 532.0 26 1.19 A090 H H Z^AA.N. >L « Y   8 Q Vo- 1-(4-(2-(4-bromophenyl)propan-2 ■ yl)thiazol-2-yl)-3-((2-(piperazin-1-yl)pyrimidin-4-yl)methyi)urea H NMR (400MHz, DMSO-^6) 8 9.45 (br s, 2H), 8.35 (d, 1==5.1 Hz, 1H), 7.41-7.47 (m, 3H), 7.24-7.34 (m, 2H), 7.11-7.21 (m, 3H), 6.75 (s, HI), 6.67 (d, J 5.1 Hz, 1H), 4.28 (brs, lH),4.27(brs, 1H),4.O5 (s, 1H), 3.05 (s, 1H), 1.58 (s, 6H) 516.1 178 1.11 WO 2022 / 063152                                                 PCT / CN2021 / 119801 O> A091 N''%x HN     J Br o S- 0 H H 1 -((2-(1,4-diazepan-1 -yl)pyrimidin-5-yl)methyl)-3 -(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea 11 NMR (400MHz, DMSO-4) 3 9.24 (br s, 2H), 8.31 (d, J = 5.0 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 3.3 Hz, 2H), 7.29 (s, 1H), 7.17 (d, J = 1.8 Hz, 2H), 7.15 - 7.14 (m, 1H), 6.74 (s, 1H), 6.64 (d, J = 5.0 Hz, 1H), 4.28 (br d, J = 5.3 Hz, 2H), 4.01 (br s, 2H), 3.20 (br s, 2H), 3.16 - 3.08 (m, 2H), 2.09 - 2.01 (m, 2H), 1.58 (s, 6H), 1.26- 1.19 (m, 2H). 530.0 135 3.45 A092 HN^ o n-A 117 A'V S H H 1-(4-(2-(4-bromophenyl)propan-2.-yl)thiazol-2-yl)-3-((6-(piperazin-1 -yl)pyridin-3 -yl) methyi)urea 4l NMR (400MHz, DMSO-4) 3 10.90 (br s, 1H), 9.66 (br s, 2H), 8.05 -7.92 (m, 2H), 7.48 - 7.28 (m, 4H), 7.21 - 7.10 (m, 2H), 6.75 (s, 1H), 4.30 -4.20 (m, 2H), 4.04 - 3.92 (m, 4H), 3.24 (br s, 4H), 1.57 (s,6H). 517.2 20 0.57 A093 iAA^ Y»-An HN,0 40' ? «4 N N^S H H 1-(4-(2-(4- bromophenyl)propan-2-yl) thiazol-2-yl) -3 -((5 -(piperazin-1 -yl)pyrazin-2-yl)methyl)urea 41 NMR (400MHz, DMSO-cfc) 3 9.26 (s, 2H), 8.30 (s, 1H), 8.07 (s, 2H), 7.41 - 7.36 (m, 2H), 7.13 -7.11 (m, 3H), 6.72 (s, HI), 4.29 - 4.28 (m, 2H), 3.76 -3.74 (m, 4H), 3.16-3.14 (m, 4H),1.54 (s, 6H). 516.1 9 0.32 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A094 O N-4 N O N H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6-(piperazin-1-yi)pyrimidin-4-yl)methyl)urea H NMR (400MHz, DMSOA) 6 11.05 (br s, 1H), 9.70 (br s, 2H), 8.86 (s, 1H), 7.48 - 7.43 (m, 2H), 7.39 - 7.33 (m, 1H), 7.21 ■■ 7.14 (m, 3H), 6.78 (s, 1H), 4.45 (br d, J = 6.0 Hz, 2H), 4.11 (brs, 4H), 3.25 (brs, 4H), 1.59 (s, 6H). 518.2 73 1.29 A095 0 N-i A JLy X -Anns H H 6 hT H 1-(4-(2-(4- bromophenyl)propan-2-yl)thiazol-2-yl)-3-((2-methyl-6-(piperazin-l -yl)pyrimi din-4-yl)methyl)urea 1H NMR (400 MHz, DMSO-i / 6) ¢5 7.40 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.8Hz, 2H), 6.87(s, 1H), 6.70(3, HI), 6.43( s, 1H), 4.12(8, 2H), 3.46-3.39(m, 4H), 2.69-2.67(m, 4H), 2.30(s, 3H), 1.55 (s, 6H). 532.1 32 A096 <V n n s l| । H H 1-(4.(2-(4-bromophenyl)propan-2-yI)thiazol-2-yl)-3-(3-methyl-4-(piperazin-l -yl)benzyl)urea H NMR (400MHz, DMSO-< / 6) 8 10.61 (br s, 1H), 9.04 (br s, 2H), 7.40 (d, J - 8.8 Hz, 2H), 7.12 (d, J === 8.8 Hz, 2H), 7.07 - 6.99 (m, 2H), 6.95 (br d, J === 7.6 Hz, 2H), 6.71 (s, III), 4.18 (hr d.. / 5.6 Hz. 2H), 3.17 (br s, 4H), 2.97 (br d, J=4.4 Hz, 4H), 2.19 (s, 3H), 1.54 (s, 6H). [M+Na]+=55 2.0 69 1.43 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A097 X ’-O xz O I l-(3-bromo-4-(piperazin-1 -vi)benzyl)-3-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)urea lH NMR (400 MHz, CDCh) 3 9.18 (brs, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.57-7.29 (m, 1H), 7.18-7.13 (m, 4H), 6.75 (s, 1H), 4.24 (s, 2H), 3.23 - 3.14 (m, 8H), 1.58 (s, 6H). 593.0 87 1.42 A098 -y av-bf o nA HI H H HN^J NH2 l-(3-amino-4-(piperazin-1 -vl)benzyl)-3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea ‘H NMR (400 MHz, DMSO-A) 3 10.76(br, 1H), 9.22(br, 2H), 7.42-7.39(m, 2H), 7.26-7.12(m, 6H), 6 71 (s. 1H), 4.26-4.25(m, 2H), 3.24-3.22(m, 4H), 3.03-3.02(m, 4H), 1,55(s, 6H). 530.9 31 1.07 A099 o nA nV^n-^nV A H H < N N l-((2-(4-aminopiperidin-l-yl)pyrimidin-5-yl)methyl)-3-(4-(2 -(4-bromophenyl)propan-2-yl)thiazol-2-yi)urea NMR (400MHz, DMSO-sfc) 3 10.94 - 10.50 (m, 1H), 8.34 (s, 2H), 8.25 -7.95 (m, 3H), 7.42 (d, J = 8.5 Hz, 2H), 7.19 6.92 (m, 3H), 6.74 (s, 1H), 4.71 -4.54 (m, 2H),4.19-4.05 (m, 2H), 3.38 - 3.24 (m, 1H), 3.04 - 2.87 (m, 2H), 2.03 - 1.90 (m, 2H), 1.57 (s, 6H), 1.49 ■ 1.35 (m, 2H). 532.0 13 0.45 WO 2022 / 063152                                                 PCT / CN2021 / 119801 v© V© A100 _ i n no o o 4-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)methyi)-N-(1 -methylpiperidin-4-yl) cyclohexane -1 -carboxamide 576.0 72 1.37 AIOI -4-4 V"Br HO-          / \= / >  0  N-^ 1 U JI > JI ^,1 H H h0 1-(4-(2-(4- bromophenyl)propan-2-yl)thiazol-2-yl)-3-(2-hydroxy-1 -(4-(piperazin-1 -yl)phenyl) ethyl)urea 544.1 50 1.65 A102 A<yBr o n-A I JI 7 C                      'S hnJ    h h 1-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-3 -(3 -(piperazin-1-yl)propyl)urea 466.1 90 0.71 A103 / \=z 0 A J H H rv N J HO-'Xx *x / 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl) ■ 3 -((2-( 4 ■ (2-hydroxyethyl)piperazm-1 -yl)pyrimi din-5 -yl)methyi)urea 560.1 97 6.2 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A104 H J H H N 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(pyrimidin-5-ylmetbyl)urea 384.1 223 1.69 A105 ___L-^^-OMe 0  N-{ A A > N S HO       J]       H H H I l-((5-fluoro-6-((2-hydroxy ethyl) amino)pyr idin-3 -yl)methyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol -2-yl)urea 460.1 144 1.02 A106 '-y'-O'”8' O N-% A Ji ) N / Y^N'^NZ^S 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6-(3-(dimethylamino)pyrrolid in-1 -yl)pyridin-3 ■■ yl)methyl)urea 543.1 48 6.72 A107 y-o-* o n-& A Ji J J H H MeO'^y^ F 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3-(3-fluoro-4-methoxybenzyl)nrea 478.1 216 A108 i<7* o N-A A A / A^r^'N s ho^nA> H ” H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-((2-hydroxyethyl)amino)ben zyl)urea 489.1 244 0.82 WO 2022 / 063152                                                 PCT / CN2021 / 119801 0.94 1.24 146 193 127 126 441.0 350.0 364.0 547.1 530.1 377.0 1-(4-((2-hydroxyethyl)amino)ben zyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yI)urea 1 -(2 -methoxyethvl)-3 -(4-(2-(4- ’ ' methoxyphenyl)propan-2-yl)thiazol-2-yI)urea 1-(4-(2-(4-methoxyphenyl)propan-2 -y l)thi azol-2 -y 1)-3-(3-methoxypropyl)urea 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((5-fluoro-6-(3-oxopiperazin-1 -yl)pyridin-3-yl)methyl)urea 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3-((2-(3-oxopiperazin-1 -yl)pyrimi din-5 -yl)methyl)urea 4-(3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)butanami de 0.. 0 0 P H .J O N-\ H H t-O'0"' I N N s H H 03 Ary ZT / pVu. C>-° —z 3: $ 0 zx °=< ZI / / / ’A <z z z=( z—x X H H      9 S- -N        .-x 11 , II                 N H _ Vn o A109 AllO Alli Al 12 Al 13 Al 14 o to Al 15 \ / V o s-^ / R „ A ARC N ''V N N N J x r'YyM 0 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyi)-N-(1 -propylpiperidin-4-yl)picolinamide 551.0 19 0.83 Al 16 ( o > z z ZJ 7 r 1 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yI)thiazol-2-yl)ureido)methyl)-2-(4-propylpiperazin-1 -yl)benzamide 551.0 72 0.72 Al 17 q N- / UJy H H F 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(3,5-difluoro-4-((4-methylpiperazin-1 -yl)methyl)benzyl)urea 578.1 67 5.03 Al 18 $ $ / Ry M ZI ZI / M \ / z—z ( > Z—' / 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(1 -(4-((4-methylpiperazin-l -yl)methyl)phenyl)ethyl) urea 556.1 2^7 4.38 Al 19 Br / R . x xvtC N' N > H0—nV " H H 1-(4-(2-(4-bromophenyl)propan-2 -vlHhiazol-2-yl)-3-((2-((2-h ydroxy ethyl) amino)pyr imidin-5 -yl)methyl)urea 491.1 36 4.43 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A120 OMe o 0 A A H A" n ( / vNy^ H H A-A o 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-N-(l -methylpiperidin-4-yl)picolinamide 523.0 53 0.99 A121 o nA JI ll } n'xA-^x'n'A'n'A's F d l-((5-fluoro-6-(3-oxopiperazin-1-yl)pyri din-3 -yl)methyl) -3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 499.0 209 2.02 Al 22 JV3 T A o nA 11 A AJ N N S H H 1-(4-hydroxycyclohexyl)-3 ■■ (4-(2-(4-methoxyphenyl)propan-2-yl)thiazol -2-yl)urea 390.0 219 1.70 A123 HO '^ N N S H H 1-(3-hydroxycyclohexyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 390.0 354 2.40 A124 a Ay-pfe o nA aA,- a a> N N S H H 1-(4-(2-(4-methoxyphenyl)propan-2-yi)thiazol-2-yl)-3-(2-(pyridin-4-yl) ethyljur ea 397.0 165 1.05 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A125 I O N-A ZA 'N' 'S H H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-isopropylurea lH NMR (400 MHz, CDCU) <5 8.57 (br s, 1H), 7.39 (d, J =8.8 Hz, 2H), 7.13 (d, J= 8.4 Hz, 2H), 6.43 (s, 1H), 3.96-3.82 (m, 1H), 1.64 (s,6H), 1.10 (d, J = 6.4 Hz, 6H). 382.1 28 2.80 A126 / / $ V"Br HN-< > HN'-4 J O HO-^ 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3 -(3-hydroxypropyl)urea ‘H NMR (400 MHz, CDCh) 3 7.30 -7.26 (m, 2H), 7.15-7.10 (m, 2H), 6.47 (s, 1H), 3.60-3.55 (m, 2H), 3.45-3.30 (m, 2H), 1.63 (s, 6H), 1.40- 1.30 (m, 2H). 398.1 88 2.96 Al 27 & 1] O=<' ZI o o 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(3-morphoiinopropyl)urea 'H NMR (400 MHz, DMSO-Je) 3 10.50 (br s, 1 H), 7.40 (d, 1===8.56 Hz, 2 H), 7.12(d, J=8.56Hz,2 H), 6.68 (s, 1 H), 6.29 (br s, 1 H), 3.53 (1. J 4.52 Hz, 4 H), 3.09 (q, 1=6.60 Hz, 2 H), 2.27 (br s, 4 H), 2.22 (t, 1=6.97 Hz, 2 H) 1.54 (s, 6 H), 1.53 - 1.47 (m, 2 H). 467.1 113 0.94 A128 O nA 1 -(4-hydroxybutyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 364.1 146 0.53 WO 2022 / 063152                                                 PCT / CN2021 / 119801 o Uh A129 -4-O"Br O N- / A J > "°-O      « 8 1-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-3-(3-(3 ■■ hydroxypyrrolidin-1 -yl)propyl)urea lH NMR (400 MHz, CDCh) 4 7.40 - 7.34 (m, 2H), 7.40 - 7.34 (m, 2H), 7.08 (d, 1=8.78 Hz, 2 H), 6.56 (br s, 1 H), 5.00 ■■ 4.84 (m, 1H), 4.12 - 4.00 (m, 1H), 3.46 - 3.19 (m. 3H), 3.01 - 2.74 (m, 3H), 2.40 -2.21 (m, 1H), 2.00-1.82 (m, 2H), 1.64 - 1,51 (m, 6H), 1.36 -- 1.20 (m, 2H). 467.2 40 0.51 ABO -^L / VBr 0  N-\ 0. ,x\ / x JL JL / X^NN'S 0      H H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(3-(methylsulfonyl)propyl) urea ’H NMR (400 MHz, CDCh) 8 7.38 (d, .1=8.07 Hz, 2 H), 7.10 (d, J 8.31 Hz, 2 H), 6.47 (s, 1 H), 3.38 (q, 1=6.11 Hz, 211),2.99 (br t, 1=7.58 Hz, 2 H), 2.86 (s, 3 H), 2.03 - 1.95 (m, 2 11),1.62 (s, 6 H). 462.1 293 1.10 Al 31 „ 0     0 N-A °<A A a) h n ^ N hsS h2n      h h 2-(3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)ureido)ethanesulfona mide ’H NMR (400 MHz, CD3OD) d 7.38 (d, 1=8.31 Hz, 2 H), 7.16 (d, 1=8.56 Hz, 2 H), 6.66 (s, 1 H), 3.67 (t, 1=6.48 Hz, 2 H), 3.26 (t, J 6.36 Hz, 2 Hl, 1.63 (s. 6 H). 447.0 219 0.94 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A132 O o                      !j       i; ° NH2   h h 3-(3-(4-(2-(4-bromophenyl)propan-2-yi)thiazol-2-yl)ureido)propane-1 ■■ sulfonamide lI-I NMR (400 MHz, CDCh) 6 7.43 - 7.35 (m, 2 H), 7.13-7.03 (m, 2 H), 6.53 (s, 1 H) 5.56 - 5.31 (m, 1 H), 3.34 (d, 7=5.77 Hz, 2 H), 3.03 (s, 2 H), 1.99 ■ 1.89 (m, 2 H), 1.61 (s, 6 H). 463.1 80 4.56 A133 ~AO"o / 0 H H 1 -(3 -hydroxvpr opyl)-3 ■ ' (4-(2-(4- methoxyphenyl)propan-2-yl)thiazol -2-yl)urea 350.2 57 0.60 Al 34 -J-O o nO NN N-^S H H 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(3-morpholinopropyl)urea 'H NMR (400 MHz, DMSO-t / e) d 10.46 (br s, 1 H), 7.11 - 7.05 (m, 2 H), 6.77 (d, 1=9.05 Hz, 2 H), 6.59 (s, 1 H), 6.32. (br s, 1 H), 3.66 (s, 3 H), 3.53 (brt, 1=4.52 Hz, 4 H), 3.12- 3.06 (m, 2 H), 2.27 (br s, 4 H), 2.22 (t, .1=6.97 Hz, 2 H), 1.59 - 1.49 (m, 8 H), 419.2 152 5.11 Al 35 i^Q / z zs / x A D H0Xo H S 1-(3-(3-hydroxypyrro lidin-1 -yl)propyl)-3-(4-(2 -(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea Al NMR (400 MHz, CDCh) d 7.08 (d, 7=8.8 Hz, 2H), 6.77 (d, 7=8.8 Hz, 2H), 6.69 (s, 1H), 6.60 (s, 1H), 5.40 (s, 1H), 4.34 (s, 1H), 3.66 (s, 3H), 3.11 (s, 3H), 3.03 (s, 3H), 1.77 (s, 2H), 1.53(s, 6H), 1.35--1.15 (m, 2H), 0.95 - 0.85 (m, 2H). 419.2 112 1.24 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A136 0  N-< Ov     A A / '         N N s 6      H H 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol -2 -y 1)-3 -(3 -(methyisulfonyl)propyl) urea lI-I NMR (400 MHz, CD3OD) <5 7.17 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8Hz, 2H), 6.43(s, 3H), 3.78(s, 3H), 3.42-3.38(m, 2H), 3.00-2.97(m, 2H), 2.86(s, 3H), 2.05-1.98(m, 2H), 1,64(s, 3H) 412.2 209 0.64 A137 ACA „ n     O N-& A A A h2n      N h 2-(3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)ethanesulfona mide M NMR (400 MHz, CD3OD)d7.18(d,. / -8.8 Hz, 2H), 7.25 (4.. / 8.4 Hz, 2H), 6.61 (s, 1H), 3.77 (s, 3H), 3.72-3.66 (m, 2H), 3.30-3.25 (m, 2H), 1.65 (s, 6H). 399.2 42 1.96 Al 38 j ry l 7 \= / o n-n A A / ° nh2 h h 3-(3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)propane-1 -sulfonamide lH NMR (400 MHz, CD3OD) <5 7.17 (d, J - 8.8 Hz, 2H), 6.83 (d.. / 8.0 Hz, 2H), 6.63 (s, HI), 3.77 (s, 3H), 3.39-3.35 (m, 2H), 3.15-3.02 (m, 2H), 2.12-2.00 (m, 2H), 1.65 (s, 6H). 413.2 97 2.38 WO 2022 / 063152                                                 PCT / CN2021 / 119801 o 00 A139 ^‘0 \ zx 0=< zx b Z—\ / \ 0 X 1-(4-(4-hydroxypiperidin-1 -yl)benzyl)-3-(4-(2-(4-methoxyphenyl)propan-2 -yl) thiazo 1-2 -yl)urea lI-I NMR (400 MHz, DMSO-ak) <5 10.48 (s, 1 H), 7.09 (dd, 1=12.59, 8.68 Hz, 4 H), 6.87 (d, 1=8.56 Hz, 2 H), 6.79 (d, J 9.?)5 Hz, 2 H), 6.68 (br s, 1 H), 6.63 (s, 1 H), 4.67 (d, J 4.16 Hz, 1 H), 4.17 (d, .1=5.87 Hz, 2 H), 3.69 (s, 3 H), 3.59 (td, 1=8.80, 4.40 Hz, 1 H), 3.51 - 3.44 (m, 2 H), 2.83 ■■ 2.72 (m, 2 H), 1.82 - 1.73 (m, 2 H), 1.56 (s, 6 H), 1.52 - 1.34 (m, 2 H). 481.2 261 1.35 A140 ±Cr* o n-A f,          N N o 1-(4-(hydroxymethyl)benzyl) -3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 1H NMR (400 MHz, CDC13) 4 7.25 - 7.22 (m, 2H), 7.18-7.10 (m,4H), 6.83-6.73 (m, 2H), 6.45 (s, 1H), 4.57 (s, 2H), 4.31 ■■ 4.29 (m, 2H), 3.76 (s, 3H), 1.59 (s, 6H). 412.2 131 5.52 WO 2022 / 063152                                                 PCT / CN2021 / 119801 e--) 1.33 228 180 53 446.3 432.3 C-xJ lH NMR (400 MHz, DMSO-de) d 10.43 (s, HI) 7.08 (d, 1=8.82 Hz, 2H) 6.77 (d, 1=8.82 Hz, 2H) 6.58 (s, 1H) 6.36 (s, 1H) 3.66 (s, 3H) 3.08 (q, 1=6.39 Hz, 2H) 2.57-2.70 (m, 2H) 2.50-2.56 (m, 1H) 2.232.40 (m, 3H) 2.19 (t, 1=7.06 Hz,lH) 2.05 (s, 6H) 1.73-1.84 (m, 1H) 1.44-1.60 (m, 9H). lH NMR (400 MHz, DMSO-O 3 10.49(br, 1H), 7.14-7.12(m, 2H), 6.83-6.80(m, 2H), 6.63(s, HI), 6.34(br, U B. 3.73(s, 3H), 3.14-3.09(m, 2H), 2.53(s, 3H), 2.40-2.29(m, 9H), 2.21(s, 3H), 1.57-1.52(m, 8H). 'H NMR (400 MHz, CD3OD)d7.17(d, J=9.2 Hz, 2H), 7.25 (d, J = 8.8 Hz, 211), 6.60 (s, III), 3.77 (s, 3H), 2.78 (s, 3H), 1.64 (s, 6H). 1-(3-(3-(dimethylamino)pyrrolid in-1 -yl)propyl)-3-(4-(2- (4-methoxyphenyl)propan-2-yl)thiazol -2-yl)urea 1-(4-(2-(4-methoxyphenyl)propan-2 -y l)thi azol-2 -y 1)-3-(3-(4-methylpiperazin-1 -yl)propyl)urea 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-methylurea 0 ZI h h O / °-Ot H H < ¥ Y Vn o A141 A142 A143 A144 7-0-°' o n-A HO A JLz N N S H H 1 -hydroxy-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea lH NMR (400 MHz, DMSO-cfc) 6 9.26 - 8.43 (m, 2H), 7.12 - 7.04 (m, 2H), 6.80 - 6.74 (m, 2H), 6.67 (s, 1H), 3.66 (s, 3H), 1.54 (s, 6H). 308.1 154 1.75 A145 / O' o n-A |          H H 1-(3-(dimethylamino)propyl) -3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 'H NMR (400 MHz, CD3OD) d 7.14 (d, J S 82 Hz, 2 H), 6.80 (d, J 9.0- / Hz, 2 H), 6.59 (s, 1 H), 3.74 (s, 3 H), 3.22 (t, .1=6.84 Hz, 2 H), 2.35 - 2.30 (m, 2 H), 2.21 (s,6H), 1.71 - 1.64 (m, 2 H), 1.62 (s, 6 H). 377.2 216 4.49 A146 IZ A° TZ ® ,AJ 0 1 o 1-(3- (diethvlamino)propvD-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea H NMR (400MHz, CD3OD) d 7.14 (d, J= 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.59 (s, HI), 3.74 (s, 311),3.21 (brt, J=6.7 Hz, 2H), 2.68 - 2.24 (m, 6H), 1.97 - 1.39 (m, 8H), 1.03 (t, J =7.2 Hz, 6H). 405.2 124 3.07 A147 yA u         o n-4 H                        ii        ! n       w A w .A „ / if          — N   N   b [|      1                      H H 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(phenylamino)butyl)ure a 'H NMR (400 MHz, CD3OD) d 7.13 (d, .1=8.82 Hz, 2 H), 7.09 - 7.04 (m, 3 H), 6.79 (d, J 8.82 Hz, 2 H), 6.62 - 6.55 (m, 4 H), 3.72 (s, 3 H), 3.25 - 3.19 (m, 2 H), 3.06 (br t, .1=6.50 Hz, 2 H), 1.61 (s, 6H), 1.59 - 1.54 (m, 4 H). 439.3 235 1.91 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A148 °' —A A3 ,              N N S HN 'V      h H I 3-(3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)-N-methylpropane-1 -sulfonamide ‘H NMR (400MHz, CI)Ch) <5 7.16 - 7.14 (m, 2H), 6.84 -6.82 (m, 2H), 6.46 (s, 1H), 3.78 (s, 3H), 3.38 - 3.34 (m, 2H), 2.97 ■■ 2.93 (rn. 2H), 2.68 - 2.67 (m, 3H), 1.96 -1.89 (m, 2H), 1.63 (s, 6H). 427.0 45 0.85 A149 b y=o TZ O-oLS u 4 O \ rac-(ls,3s)-3-((3-(4-(2-fo" methoxyphenyl)propan-2-yl)thiazol-2-yl)urei do)methyl)-N-methylcyclobutane-1 -sulfonamide M NMR (400MHz, CDCh) 4 8.67 (brs, HI), 7.13 -7.11 (m, 2H), 6.82 - 6.80 (m, 2H), 6.41 (s, 1H), 4.85 (brs, 1H), 3.77 (s, 3H), 3.67 - 3.60 (m, 1H), 3.27 - 3.24 (m, 2H), 2.64 - 2.63 (m, 3H). 2.41 - 2.37 (m, 1H). 2.25-2.17 (m,2H), 2.10-2.05 (m, 2H), 1.61 (s, 6H). 453.2 155 9.40 A150 \ o 4. w .□ < ZT C-----(, / v 4 \\ fl \ rac-(1 r. 3 r) ■ 3 -((3 -(4 ■ (2 -(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urei do)methyl)-N-methylcycl o butane-1 -sulfonamide ‘H NMR (400MHz, 6 i X i 0 4 9.06 (brs, 1H), 7.12 -7.09 (m, 2H), 6.82 - 6.79 (m, 2H), 6.44 (s, 1H), 4.94 (brs, 1H), 3.77 (s, 3H), 3.75 ■ 3.64 (m, 1H), 3.31 - 3.28 (m, 2H), 2.68 - 2.67 (m, 311),2.51 -2.47 (m, HI), 2.43 - 2.36 (m, 2H), 1.99 -1.91 (m, 2H), 1.60 (s, 6H). 453.2 25 1.41 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Al 51 X z—^ o , Q 'A / / zz / =O        | IZ         O 1-(3,5-difluoro-4-(piperidin-4-yl)benzyl) -3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea hydrochloride 11 NMR (400MHz, DMSO-cfc) 6 10.72 (br, 1H), 9.10-8.70 (m, 2H), 7.09 -7.07(m, 2H), 6.95 - 6.93 (m, 2H), 6.78-6.76 (m, 2H), 6.62 (s, 1H), 4.22 - 4.20 (m, 2H), 3.66 (s, 3H), 3.30 -3.25 (m, 4H), 3.20-3.14 (m, 4H), 1.53 (s, 6H). 502.1 43 0.95 Al 52 b fX 1 ? s'^ _ / i || H H ^N'y HN.^ F 1 -(1 -(3,5-difluoro-4-(piperazin-1-yl)phen vl)ethyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea !H NMR (400MHz, DMSO-a6n 10.74 (br s, 2H), 7.27 (s, 1H), 7.13 -7.10 (m, 2H), 6.99 - 6.9 / (m, 2H), 6.82 - 6.79 (m, 2H), 6.68 (s, 1H), 4.26 -4.24 (m, 2H), 3.70 (s, 3H), 3.47 - 3.40 (m, 4H), 3.28 -3.25 (m, 2H), 3.16 - 3.08 (m, 2H), 2.80 - 2.79 (m, 3H),1.57 (s, 6H). 516.1 55 0.35 A153 X o b? )^o xz N-(4-(2-(4-bromoph eny l)but-3 -yn-2-yl)thiazol-2-yl)-3-hydroxyazetidine-1 -carboxamide !H NMR (400MHz, CDCh) 8 7.84(br, 1H), 7.44(d, J = 8.4Hz, 2H), 7.34(d, J === 8.8Hz, 2H), 7.28(s, III), 6.80(s, 1H), 4.72-4.68(m, 1H), 4.29-4.25(m, 2H), 3.95-3.91 (m, 2H), 2.58(s, 1H), 1.93(s, 3H). 408.0 76 0.37 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A154 A H H Br 1-(4-(2-(4-bromophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3 -(3-hydroxypropyl)urea 1H NMR. (400MHz, CDCI3) 8 7.46(d, J = 7.6Hz, 2H), 7.37(d, J = 8.4Hz, 2H), 6.76(s, 1H), 3.64(1, J = 5.2Hz, 2H), 3.43(1, J -6.0Hz, 2H), 2.58(s, 1H), 1.95(s, 3H), 1.70-1.69(m, 2H). 408.0 21 0.38 A155 H H Br 1-(4-(2-(4-bromophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-morpholinoethyl)urea si NMR (400MHz, CI)Ch) 8 TAK-1 Al (m, 4H), 7.00(s, iH), 4.11-4.08 (m, 2H), 3.82-3.67(m, 2H), 3.66-3.63(m, 4H), 3.35(s, 2H), 3.33-3.21(m, 2H), 3.00(s, HI), 1.94(s, 3H). 463.1 30 0.90 Al 56 0 s A \ / ' "V"X~A" < A" - A Br 1-(4-(2-(4-bromophenyl)but-3 -yn-2-yl)thiazol-2-vl)-3-(2,3-dihydroxypropyl)urea H NMR (400MHz, CD3OD) 7.44 (s, 4H), 6.91 (d, >1.0 Hz, HI), 3.66-3.75 (m, HI), 3.51 (d, J 5.3 Hz, 2H), 3.38-3.47 (m, 1H), 3.21 (ddd, 1=13.8, 6.9, 2.6 Hz, 1H), 2.95 (s, 1H), 1.92 ppm (s, 3H) 424.0 22 0.38 A157 H H N-HO'^ / if V / gr-^\sA 1-(4-(3-(4-bromophenyl)pent-1 -yn-3-yl)thiazol-2-yl)-3-(2-hydroxyethyl)urea 1H NMR R (400 MHz, CDCh) 8 7.44 - 7.42 (m, 2 H), 7.37 - 7.35 (m, 2 H), 6.81 (s, 1 11),3.53-3.50 (m, 2 H), 3.38- 3.35 (m, 2 H), 2.59 (s, 1 H), 2.38- 2.29 (m, 1 H), 2.21 - 2.12 (m, 1 H), 0.94 (t, J = 7.6 Hz, 3 H) 408.0 22 1.36 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A158 HO     0    A H S Br 1-(4-(1-(4-bromophenyl)cyclobutyl )thiazol-2-yl)-3-(2-hydroxyethyl)urea lH NMR (400 MHz, DMSO-O 4 10.50 (s, 1 H), 7.47 (br d, J = 8.28 Hz, 2 H), 7.19 (br d, J = 8.28 Hz, 2 H), 6.66 (s, 1 H), 6.47 (br s, 1 H), 4.76 (br s, 1 H), 3.41 (br d, J = 5.27 Hz, 2 H), 3.16 (br d, J = 5.77 Hz, 2 H), 2.65 (br d, J - 13.30 Hz, 2 H), 2.33 (br s, 2 H), 1.91 ■ 2.03 (m, 1 H), 1.83 (br s, 1 H) 398.0 67 2.86 A159 / / o N-A L 1 ho        11 IL / N S H H 1-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(2-hy droxyethyl) urea UAMR(400MHz,CDC13) d 7.46 (d, J=8.5 Hz, 2H), 7.36 (d, >8.5 Hz, 2H), 6.72 (s, HI), 3.62 (br d, J 4.3 Hz, 2H), 3.36 (br d, .1=3.9 Hz, 2H), 2.67 (s, 1H), 1.96 (s, 3H) 394.0 48 0.49 A160 / ""•Z ~. 0 N"A E h HO^x 1mA /   Br 'x N N b H H (8)-1-(4-(2-(4- bromophenyl)but-3-yn-2-yI)thiazol-2-yl)-3 -(2-hydroxyethyl)urea lH NMR (400MHz, CDC13) 4 7.41-7.39(111, 2H), 7.31-7.29(m, 2H), 7.24(s, HI), 3.45-3.43(m, 2H), 3.32-3.29(m, 2H), 2.52(s, 1H), 1.89(s, 3H). 394.0 10 0.17 A161 / 0 N A jl An'V Br H H (R)-l-(4-(2-(4-bromophenyl)but-3-yn-2-yI)thiazol-2-yl)-3 -(2-hydroxyethyl)urea lH NMR (400MHz, CDC13) 4 7.37-7.35(m, 2H), 7.26-7.24(m, 2H), 7.19(s, 1H), 6.69(s, 1H), 3.38-3.37(m, 2H), 3.25-3.24(m, 2H), 2.47(s, 1H), 1,84(s, 3H). 394.0 68 0.55 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A162 o nA L L 117 H,N N S H 1-(4-(2-(4-bromoph eny l)but-3 -yn-2-yl)thiazol-2-yl)urea 41NMR (400MHz, DMSOA) 8 10.60(s, 1H), 7.53-7.50(m, 2H), 7.39-7.37(m, 2H), 6.90(s, 1H), 3.50(s, 1H), 1.85(s, 3H). 352.0 38 0.18 A163 / o nA L 1 117 H2N N S H (8)-1-(4-(2-(4- bromophenyl)but-3-yn-2-yl)thiazol-2-yl)urea H NMR (400MHz, DMSOA) 8 10.61 (s, 1H), 7.53-7.51(m, 2H), 7.39-7.34(m, 2H), 5.76(s, 3H), 3.50(s, HI), 1.85(s, 3H). 349.9 4 0.35 A164 / 1 f i j . / o nA L !l A A / H2N N S H (R). 1-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol -2-yl)urea !H NMR (400MHz, DMSO-4) 8 10.64(s, 1H), 7.53-7.50(m, 2H), 7.39-7.37(m, 2H), 6.89(s, 1H), 3.50(s, 1H), 1.85(s,3H). 350.0 17 0.59 A165 / 9 H UL 11 A /       Br / "N N s h N-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl) azetidin e-1-carboxamide ‘H NMR (400MHz, CDCh) 8 7.79(br, 1H), 7.41-7.39(m, 2H), 7.31-7.29(m, 2H), 7.24(s, 1H), 6.75(8, 1H), 4.07(t, J = 8.0Hz, 2H), 3.83-3.80(m, 2H), 3.72-3.71(m, 2H), 2.81-2.77(m, 1H), 2.54(8, HI), 1.89(s, 3H). 420.0 138 0.73 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A166 o        1 A A / / -N^N^S HOs^AJ h (RAN-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl) azetidin e-1 -carboxamide 1H NMR. (400MHz, CI)Ch) <5 7.85(br, 1H), 7.46 -7.43 (m, 2H), 7.36-7.33 (m, 2H), 6.79 (s, 1H), 4.11 -4.08 (m, 2H), 3.88-3.85 (m, 2H), 3.76 -3.75 (m, 2H), 2.8? / 2.80 (m, 1H), 2.58 (s, 1H), 1.94 (s, 3H). 420.0 25 5.71 A167 T o Q >o IZ ». A? 5 (S)-N-(4-(2-(4-bromophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(hydroxymetbyl)azetidin e-1 -carboxamide si NMR (400MHz, CDCI3) d 7.85(br, HI), 7.45 -7.43 (m, 2H), 7.36-7.33 (m, 2H), 6.79 (s, 1H), 4.11 -4.09 (m, 2H), 3.87-3.85 (m, 2H), 3.77 -3.75 (m, 2H), 2.85-2.81 (m, HI), 2.58 (s, 1H). 1.93(s, 3H). 420.0 / 0.74 Al 68 -A o AA ho.^--nAnA-s      i H H 1 -(2-hvdroxyethyi)-3 - 0-(2-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2-yl)urea *H NMR (400MHz, CDC13) d 7.38(d, J - 8.8Hz, 2H), 6.87-6.84(m, 2H), 6.73(s, 1H), 3.80(s, 3H), 3.45(s, 2H), 3.35-3.33(m, 2H), 2.54(s, 1H), 1.94(s, 3H). 346.1 27 0.40 A169 / o ~ N S             ! H H (R) -142-hvdroxy ethyl) -3-(402-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2-yljurea lH NMR (400MHz, CDCh) d 7.36 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 3.78 (s, 3H), 3.46 (br d, J - 4.8 Hz, 2H), 3.32 (br d, J = 4.8 Hz, 2H), 2.52 (s, 1H), 1.92 (s, 3H) 346.1 23 1.67 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A170 ° ri H H (S)-1 -(2-hydroxyethyl)-3-(4-(2-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2 -yl)urea 1H NMR (400MHz, CI)Ch) 6 7.37 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 3.78 (s, 3H), 3.49 (br d, J === 5.3 Hz, 2H), 3.34 (br d, J === 5.3 Hz, 2H), 2.52 (s, 1H), 1.92 (s, 3H) 346.1 8 0.46 A171 / o n"C l 11 I A / H?N N S 2     H 1-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2 -yl)urea H NMR (400MHz, DMSO-A) 8 10.58 (s, HI), 7.33 (d, J === 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.22 (br s, 2H), 3.72 (s, 3H), 3.40 (s, 1H), 1.83 (s, 3H) 302.0 16 0.73 A172 / 0 AO-0 h2nAn s       1 (R)-1-(4-(2-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2-yl)urea H NMR (400MHz, DMSO-4) 8 10.58 (br s, 1H), 7.33 (d, J === 8.8 Hz, 2H), 6.86 (d, J === 8.8 Hz, 2H), 6.81 (s, 1H), 6.24 (br s, HI), 3.72 (s, 3H), 3.41 (s, 1H), 1.83 (s, 3H) 302.0 36 1.28 A173 / n nA IL x A / hAn (8)-1-(4-(2-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2-yl)urea !H NMR (400MHz, DMSO-4) 8 10.60 (br s, HI), 7.33 (d, J === 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 6.23 (br s, 1H), 3.72(s, 3H), 3.40 (s, 1H), 1.83 (s, 3H) 302.0 8 0.58 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A174 o N'A L 1 HO^ I   ^01 - N N a H H 1-(4-(2-(4-chiorophenyl)but-3 -yn-2-yl)thiazol-2 -yl)-3-(2-hydroxyethyl)urea lH NMR (400 MHz, DMSO-^6) 4 1 0.64 (s, 1 H), 7,33 - 7.46 (m, 4 H), 6.90 (s, 1 H),6.34 (br s, 1 H), 4.75 (t, J === 5.14 Hz, 1 H), 3.50 (s, 1 H), 3.41 (q, J === 5.52 Hz, 2 H),3.16 (q, J = 5.52 Hz, 2 H), 1,85 (s, 3 H) 350.0 34 0.31 A175 / H H (R)-l-(4-(2-(4-chiorophenyl)but-3 -yn-2-yi)thiazol-2-yl)-3-(2-hydroxyethyl)urea i 1 NMR (400 MHz, DMSO-t / e) 8 10.63 (br s, 1 H), 7.33 - 7.48 (m, 4 H), 6,90 (s, 1H), 6.35 (br s, 1 H), 4.75 (t, J = 5.27 Hz, 1 H), 3.50 (s, 1 H), 3.41 (q, J === 5.35 Hz, 2H), 3.16 (q, J ==== 5.52 Hz, 2 H), 1.85 (s, 3 H) 350.0 32 1.31 A176 / o nA L Jl HO      JL JL.eS H H (S)-l -(4-(2-(4-chlorophenyl)but-3 -yn -2-yi)thiazol-2-yl)-3-(2-hydroxyethyl)urea 4-1 NMR (400 MHz, DMSO-Je) 8 10.64 (br s, 1 H), 7.34 - 7.49 (m, 4 H), 6.90 (s, 1H), 6.35 (brs, 1 H), 4.76 (t, J = 5.14 Hz, 1 H), 3.51 (s, 1 H), 3.42 (q, J === 5.52 Hz, 2H), 3.16 (q, J ==== 5.35 Hz, 2 H), 1.85 (s, 3 H) 350.0 5.4 0.28 A177 A-^Ar-Br o nA X X / An n s 1 H H H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3 -(2-(piperazin-1 ■ yl)ethyl)urea 452.0 249 1.66 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Al 78 I A J H H HN^J 1-(4-(2-(4-iodophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)urea 564.0 42 0.92 A179 0  N-\\     \ x Az N V^N N S X J H  H [^N N' l-(4-(2-(4-chloro-3-fluorophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)urea 490.0 95 1.36 A180 0 N"A L 1 A A> N       N N s l| J H H HN^^J 1-(4.(1-(4. bromophenyl)cyclopent yl)thiazol-2-yl)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)methyl)urea 542.0 45 Al 81 A'D"'8' 115 N N "’s O H H 0 N H 1-(4-(2-(4- bromophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1 -yl)pyridin-4-yl)methyl)urea 515.0 131 1.52 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Al 82 40 5 A II ' H H 0 N H 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2 -yl)-3 -((6-(piperazin-1 -yl)pyridin-2-yI)methyI)urea 515.0 163 4.30 Al 83 nA HN S H 1-(4-((2-aminoethyl)amino)benz y 1)-.)-(4-(2-^4-m eth oxyphenyl )propan -2-yl)thiazol-2-yl)urea 440.0 52 2.31 A184 4Cr0Me J J H H HjN-Z N 1-(4-(3- aminopyrro lidin-1 -yl)benzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 466.0 242 Al 85 xL / ~VoMe / \= / 0 NA - / v A a} f 4 n s J H H hM 0Anx 1 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methy I) -N,N -dimetbyl-2-(piperazin-1 -yl) benzamide 537.0 56 Al 86 ^.OMe o s-% ll      >—< n'<':yx"'n''n‘'n   1 x Ji ^1 H H 1-((6-(3- aminopyrrolidin-1 -yl)pyr i din-3 -yl)methyf) -3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 467.0 19 1.55 WO 2022 / 063152                                                 PCT / CN2021 / 119801 0.7 c<j iN 3.02 6.91 4.34 r- O, ■-n 458 08 106 OO jo 362.0 515.0 375.0 554.0 576.0 1-((2-(3-aminopyrro lidin-1 -yl)pyrimidin-5-yl)methyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 1 -(4-aminobutyl)-3-(4-(2-(4- '    " methoxyphenyl)propan-2-yl)thiophen-2-yl)urea 1-((6-(3-aminopyrro lidin-1 -yl)pyri din-3 -yl)methyl) -' 3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea 1-((3-aminocvclobutyl)methvl 0(4-(2-(4-   “ methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 1 -(4-(4-aminopiperidin-1 -yl)benzyl)-3-(4-( 1 -(4-bromophenyl)cyclopent yl)thiazol-2-yl)urea 1-(4-(1-(4-bromophenyl)cyclopent yl)thiazol-2-yl)-3-(3,5-difl uoro-4-(piperazin-1 -yl)benzyl)urea AlA %—OMe / \=Z o $ v N^Y^N N S jid H H / "'N Y / V h2n c N N           , & r AO „ 1 A> JN y^N' N S OMe o n-A jo r~Y N N s H H H2N q an jg                           NZH Br HN        F                 \ |     1 H H o s~# Ay QO Al 88 Al 89 A190 A191 A192 A193 Br^ O 6 s~# Ly 1 -(4-(4-aminopiperidin-1 -yl)benzyl)-3-(4-( 1 -(4-bromophenyl)cyclopent yl)thiazol-2-yl)urea 556.0 15 6.93 A194 O    \ / V.      hn-< HN N—C y—' HN-y II t J-v_y X=Z           S'          Br 1-(4-(2-(4-bromophenyl)propan-2.-yl)thiazol -2-yl)-3 -(4-(3 -methylpiperazin-1 -yl)benzyl)urea 528.0 172 3.71 A195 KH 0 n-A ji jJ y A / AA'n'S ‘V-n'V " H 'Y HN^ 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-(4-(3 ■■ oxopiperazin-1-yl)benzyl)urea 528.0 132 9.94 A196 ^■O^Br n^W'^n'^'n'^'S JL J H H N l-(4-(2-(4-bromo-3-fluorophenyl)propan-2-yl)thiazol-2-yl)-3-((2-(piperazin-1-yi)pyriimdin-5-yl)methyi)urea 534.0 76 3.34 A197 O N"4   ~’ u A z 1          H H HN     1 X V. / 1 -(4-(1,4-diazepan-1 -yl)-3 -fluorobenzyl)-3 -(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea 546.0 67 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Al 98 Br d 0   3--¾ UM       11 J H H H 1 r 1-(4-((2-amino ethyl) amino) ■■ 3 ■■ fluorobenzyl)-3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol -2-yl)urea 506.0 18 1.32 A199 u.dd-°M® TAJ ° j $ AZAA'dd'S il j H H 1-((6-(3-aminopyrro lidin-1 -yl)pyridin-3 -yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yr)thiazol-2-yl)urea 467.0 34 0.46 A200 -A_^jV“0M® O N0 / NsY^N^N^ / fi A N N is ||     1 H H vj / h2n 1-((5-(3-aminopyrro lidin-1 -yl)pyridin-2-yl)methyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 467.0 43 0.52 A201 -J A A-OMe 0 j 1 H H y-J f H2N 1-(4-(3-aminopyrro lidin-1 -yl)-3,5-difluorobenzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 502.0 25 0.53 A202 \ o S-A 0° _     U L >-< N              n N ' h2n.^_^.nA0 H 1-((6-((2-aminoethyl)amino)pyrid in-3-yl)methyl)-3-(4-(2-(^4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 441.0 34 5.71 WO 2022 / 063152                                                 PCT / CN2021 / 119801 oo 1—1 94 Ox 00 xO o O 469. oo r-4 in 00 oo Ox m n -(2-aminoethyl)-5-((3- (4-(2-(4-,ethoxyphenyl)propan-2-yl)thiazol-2-)ureido)methyl)picolin amide r§ s ’cl o .9 8 -yl)benzyl)-3-(4-(2-(4-*omophenyl)propan-2-yl)thiazol-2-yl)urea 1-(4-((2-mnoethyl)amino)benz E9jn([A7-|0ZRHp(jA - £-ut;dojd( । Xus qdouio; 1-(4.(2-(4- *omophenyl)propan-2-4)thiazol-2-yl)-3-((2-((2-(piperazin-l - ) ethyl)amino)pyrimi di cc ¢0 -S'* to s 05 >> xx T A ( J 1 , 03- / ( O=( Z ( o=( ZI 0:::=( ZX / xx> z=\ zz ZI ( b )=o xz ? Q Z—V Q \ z CM X b < / CM 32 vX / X 0 32 A203 A205 A206 Uh A207 o nA A A z (-¼ n n s iH h h Y F d N H 1-(4.(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3-((3 -fl uoro-2-(piperazin-1 -yl)pyridin-4-yl)methyl)urea 533.0 99 2.18 A208 - I / / V-OMe / \=z _ I J > A n' A l y h h 1-((2-(4-(2-hydroxyethyl)piperazin-l-yl)pwmidin-5-yl)methyl)-3 -(4-(2 -(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 512.0 78 0.76 A209 y.. / AA Ji J H H H&L J yL O' NH2 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)-2-(piperazin-1-yljnicotmamide 510.0 43 A210 H2N HN-4 S"J         Br O 1 ■ (2-aminoethyl)-3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea 383.0 95 4.16 A211 ''"'CUMx* v T Vx, Bf 1-(4-(4- (aminomethyl)piperidin-1 -yl)benzyl)-3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)urea 542.0 94 2.59 WO 2022 / 063152                                                 PCT / CN2021 / 119801 6.38 1.56 2.21 cn 289 Ch A 150 489.0 542.0 546.0 510.0 529.0 1-(4-(2-aminoethoxy)benzyl)-3- (4-(2-(4- ' bromophenyl)propan-2-yl)thiazol-2-yl)urea 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-y 1)-3 -(4(3,5 -dimethylpiperazm-1 -yl)benzyl)urea 1-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3 -(3-fluoro-4-(piperazin-1 -ylmethyl)benzyl)urea 1-(5-((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)pyrimi din-2 -yl)piperidine-4-carboxamide Se l-((5-fluoro-6-(4-(2-hydroxyethyl)piperazin-l-yl)pyridin-3-yl)methyl)-3 -(4-(2 -(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea o O 0'0'^ fl J ov <S y—co ^=O IZ yy -O X \ 0 N'4   ” 0 ii || J H H ''N'" H 2 O zx o=\ ZI b 0 40'“ 0 n-4 z\ vN. J F HO A212 A213 A214 A215 A216 A217 ~y_^'A-oM0 / ~~~i N' Y ''N'^N'^S H2N     O h h b 1-((6-(3-aminopyrrolidine-1 -carbonyl)pyridin-3 -yl)methyl)-3 -(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 495.0 56 32.58 A218 4<y°"e 9 H H 0 N-(2-aminoethyl)-4-((3 ■ (4-(2-(4-' methoxyphenyl)propan-2-yl)thiazoI-2-yl)ureido)methyl)benza mide 468.0 29 6.71 A219 40 04 if          bi N S IO  H H hn^y a 1-(4-(2-(4- bromophenyl)propan-2-yl)thiazol-2-yl)-3-(3-chloro-4-(piperazin-l -yl)benzyl)urea 1H NMR (400 MHz, OMSOYa) 4 10.76 (br s, 1 H), 9.25 (br s, 2 H), 7.43 (d, J =8.56 Hz, 2 H), 7.34 (d, 1==4.96 Hz, 1 H), 7.24-7.20 (m, 1 H), 7.15 (d, J=8.56 Hz, 4 H), 6.74 (s, 1 H), 4.25 (brd, .1=5.62 Hz, 2 H), 3.27 - 3.08 (m, 8 H), 1.57 (s, 6 H). 550.0 46 2.73 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 A220 -rO"Br II : H H HN^ / J 6X 1-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-3 ■■( 3 methoxy-4-(piperazin-1 -yl)benzyl)urea lH NMR (400 MHz, DMSO-Je) <5 10.67 (br s, 1 H) 9.14 (br s, 2 H), 7.43 (d, 1=8.56 Hz, 2 H), 7.15 (d, J=8.56 Hz, 2 H), 7.12 (br s, 1 H), 6.93 ■■ 6.88 (m, 2 H), 6.80 (br d, .1=8.07 Hz, 1 H), 6.74 (s, i H), 4.25 (br d, 1=5.38 Hz, 2 H), 3.77 (s, 3 H), 3.18 (br d, 1=14.18 Hz, 8 H), 1.57 (s, 6 H). 544.2 44 1.32 A221 fYV\AS II 1 H H pN y 1-(4-(2-(4-bromophenyl)propan-2 ■ yl)thiazol-2-yl)-3-(3-isopropoxy-4-(piperazin-1 -yl)benzyl)urea ’H NMR (400 MHz, DMSOY) 8 10.79 (br s, 1 H), 9.48 (br s, 2 H), 7.49 (br d, J 8.80 Hz, 1 H), 7.43 (d, .1=8.56 Hz, 2 H), 7.15 (d, .1=8.56 Hz, 2 H), 7.03 (br d, 1=8.07 Hz, 1 H), 6.94 (s, 1 H), 6.81 (brd, J 7.S3 Hz, 1 H), 6.77 (s, 1 H), 6.01 (br s, 8 H), 4.61 (dt, .1=11.98, 5.99 Hz, 1 H), 4.24 (br d, J 4.40 Hz, 2H), 1.58 (s, 6 H), 1.28 (d, .1=6.11 Hz, 6H). 574.1 144 2.38 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A222 0 N-Z X ji ) B J H H HN^X F 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3-(3-fluoro-4-(piperidin-4-yl)benzyl)urea lH NMR (400 MHz, DMSO-Je) 3 10.76 (br s, 1 H), 9.06 (brs, 1 H), 8.88 (br d, J=9.78 Hz, 1 H), 7.43 (d, J 8.56 Hz, 2 H), 7.29 ■■ 7.19 (m, 2 H), 7.15 (d, .1=8.56 Hz, 2 H), 7.10-7.04 (m, 2 H), 6.74 (s, 1 H), 4.28 (br d, .1=5.62 Hz, 2 H),3.33 (br d, 1=12.47 Hz, 2 H), 3.14 - 2.93 (m, 2 H), 1.93 - 1.81 (m, 3 H), 1.57 (s, 6 II), 1.23 (brs, 2 H). 532.2 56 0.93 A223 OX I -X / \ XX O^Z ZI w o 1-(4-(2-(4-m eth oxyphenyl )pr op an -2-yl)thiazol-2-yl)-3-((4-methyl-2-(piperazin-1 -yl)pyrimidin-5-yl)methyl)urea Hl NMR (400 MHz, DMSO-O S 9.50 (br s, 2 H), 8.23 (s, 1 H), 7.76 -7.57 (m, 1 H), 7.17 - 7.06 (m, 2 H), 6.86 - 6.79 (m, 2 H), 6.72 (s, 1 H), 4.26 ■ 4.18 (m, 2 H), 4.0-3.92 (m, 4 H), 3.70 (s, 3 H), 3.13 ( s, 4 H), 2.40 (s, 3 H), 1.57 (s, 6 H). 482.4 49 0.76 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A224 70 A 13 < V N N S JI 1 H H HN.^J F 1 -(3 -fluoro-4-(piperidin-4-yl)benzyl)-3-(4-(2-(4-m eth oxyphenyl )pr op an -2-yl)thiazol-2-yl)urea lH NMR (400 MHz, DMSO-Je) <5 10.73 (br s, 1 H), 8.93 (br s, 1 H), 8.72 (br s, 1 H), 7.26 - 7.20 (m, 1 H), 7.16 - 7.02 (m, 5 H), 6.81 (d, J 8.80 Hz, 2 H), 6.66 (s, 1 H), 4.29 (br d, J=5.87 Hz, 2 H), 3.70 (s, 3 H), 3.34 (br d, J=12.23Hz, 2 H), 3.15-3.07 (m, 1 H), 3.07-2.94 (m, 2 H), 1.87 (br s, 4 H), 1.57 (s, 6 H). 483.2 21 0.73 A225 rt ff o s ryV HNO 1 -(3-isopropoxy-4-(piperazin-l-yDbenzyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea lH NMR (400 MHz, CD30D) d 7.23 - 7.16 (m, 3 in, 7.11 (s, 1 H), 7.07(s, 1 H), 6.97 - 6.87 (m, 3 II), 4.75 (dt, 1=11.49, 5.75 Hz, 1 H), 4.40 (s, 2 H), 3.76 (s, 3 H), 3.51 (s, 8 H), 1.69 (s, 6 H). 1.38 Id. J=5.87 Hz, 6 H). 524.3 108 1.05 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A226 O N-^ 1-(3-(3-aminopyrro lidin-1 -yl)propyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yI)urea lH NMR (400 MHz, DMSO-l,) 3 11.30 (s, 1H) 10.94 (s, 1H) 8.64 (s, 1H) 8.55 (s, 1H) 7.09 (d, 1=8.82 Hz, 2H) 6.95 (s, 1H) 6.78 (d, J 8.82 Hz, 2H) 6.64 (s, 1H) 4.00 (d, J=13.89Hz, 1H) 3.67 (s, 3H) 3.37-3.49 (m, 1H) 3.35 (s,2H) 3.01-3.23 (m, 5H) 2.06-2.28 (m, 1H) 1.92-2.06 (m, 1H) 1.75-1.86 (m, 2H) 1.54 (s, 6H) 418.3 100 4.82 A227 1-0-^ x 15 H H 1-(2-(3- x aminopyrrolidin-1- yl) ethyl) ■ 3 -(4-(2 -(4- methoxyphenyl)propan-2-yl)thiazol-2-yl)urea M NMR (400 MHz, D2O) 3 7.20 - 7.13 (m, 2H), 6.95 (s, HI), 6.89 - 6.83 (m, 2H), 4.20 - 3.74 (m, 3H), 3.71 (s, 3H), 3.68 - 3.47 (m, 4H), 3.46 - 3.32 (m, 2H), 2.65 -2.48 (m, 1H), 2.24 - 2.07 (m, 1H), 1.56 (s, 6H). 404.3 138 3.12 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A 228 hq-o » TA HSJ     H H f 1-(4-(2-(4-methoxyphenyl)propan-2 -y l)thi azol-2 -y 1)-3-(3-(3 -methy Ipiperazin-1 -yl)propyl)urea 11 NMR (400MHz, DMSO-0) d 11.79 (br s, 1H), 10.68 (br s, 1H), 9.97 (br s,2H),7.12(d,J=8.6 Hz, 2H), 6.88 (s, 1H), 6.81 (d.. / 8.8 IN. 2H), 6.67 (s, 1H), 3.75 - 3.62 (m, 6H), 3.58 - 3.49 (m, 1H), 3.48 -3.36 (m, 1H), 3.29 - 3.16 (m, 3H), 3.15 - 2.99 (m, 3H), 1.96 - 1.82 (m, 2H), 1.57 (s, 6H), 1.30 (d, J-6.4 Hz, 2H). 432.3 100 3.86 A229 yc^0 o H / -A. H H 0 1-(3-((3-aminopyrroHdin-1 -yi)sulfonyI)propyl)-3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 01 NMR (400 MHz, DMSO-0) S 8.47 (br s, 3 H), 7.24 (br s, 1 H), 7.12 (d, J-8.82 Hz, 2 H), 6.82 (d, >8.60 Hz, 2 H), 6.70 (s, 1 H), 3.83 (br d, 1 5.07 Hz, 1 H), 3.70 (s, 3 H), 3.58 (br dd, >10.80, 6.62 Hz, 1 H), 3.52 - 3.43 (m, 1 H), 3.41 -3.28 (m, 3 H), 3.26 - 3.13 (m, 4 H), 2.22 (dq, >13.70, 6.90 Hz, 1 H), 2.05 - 1.92 (m, 1 H), 1.84 (dt, J = 14.55, 7.06 Hz, 2 H), 1.57 (s, 6 H). 482.2 169 2.27 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A230 o— q 1 (^N'%   H HN A 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol -2 -yl)-3 -(3 -(piperazin-1-ylsulfonyl)propyl)urea lH NMR (400 MHz, DMSO-Y) d 7.10 - 7.07 (m, 2 H), 6.78 - 6.75 (m, 2 H), 6.59 (s, 1 H), 3.67 (s, 3 H), 3.30 - 3.15 (m, 2 H), 3.02 -2.95 (m, 6 H), 2.68 ■ 2.66 (m, 4H), 1.79- 1.72 (m, 2 H), 1.52 (s, 6 H). 482.2 197 3.01 A231 rj 1 H H HN^^J 5 l-(2,5-difluoro-4-(piperazin-1 -yl)benzyl)-3-(4-(2-(4- methoxyphenyl)propan-2-yl)thiazol-2-yl)urea hydrochloride i 1 NMR (400 MHz, DMSO-Je) d 10.75 (br s, 1 H), 9.33 (br s, 2 H), 7.39 (br s, 1 H), 7.16 - 7.10 (m, 3 H), 6.98 (dd, 1=11.36, 7.39 Hz, 1 H), 6.80 (d, 1=8.82 Hz, 2 H), 6.68 (s, 1 II), 4.27 (br d, 1=5.51 Hz, 2 H), 3.70 (s, 3 H), 3.23 (br s, 8 H), 1.57 (s, 6 H), 502.2 2 / 3.36 A232 fO wAA JI J H H A Y HN^ f 1-(4-(3,6- , diazabicyclo[3.1.1 ]hepta n-3-yl)-3,5- difluorobenzyl)-3-(4-(2-A methoxyphenyl)propan-2-yI)thiazol-2-yl)urea H NMR (400MHz, DMSO-Je) d 10.85 - 10.72 (m, 1H), 9.80 - 9.68 (m, 1H), 8.16 - 8.08 (m, 1H), 7.12 (br d, J= 8.8 Hz, 2H), 7.05 - 6.93 (m, 2H), 6.86 -6.76 (m, 2H), 6.71 - 6.64 (m, 1H), 4.27 (br d, J= 6.1 Hz, 4H), 3.88 (s, 2H), 3.70 (s, 3H), 3.54 - 3.49 (m, 2H), 2.86 -2.76 (m, 1H), 2.14-2.06 (m, HI), 1.57 (s, 6H). 514.3 88 0.59 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A233 o z >=o ZZ in          I 6 1 N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)phenyl)azetidine-l -carboxamide 11 NMR (400MHz, DM.SO-^6) 3 9.25 (br s, 2H), 7.33 (s, 0.4H), 7.25 -7.2.3 (m, 2H), 7.20 - 7.18 (m, 2H), 7.14 - 7.12 (m, 0.4 H), 6.98 ■ 6.96 (m, 2H),6.82 - 6.80 (m, 2H), 6.66 (s, 1H), 4.38 - 4.36 (m, 2H), 3.94 -3.91 (m, 2H), 3.76 - 3.72 (m, 1H), 3.72 (s, 3H), 3.39 -3.38 (m, 4H), 3.37 - 3.20 (m, 4H), 1.60 (s, 611). 492.2 43 0.33 A234 0 IZ IZ 1-(4-(2-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2-yl)-3 - (l-(4-(piperazin-l- _ yl)phenyl)ethyl)urea 1H NMR (400 MHz, DMSO-4) 4 10.50 (br s, 1 H), 9.22 (br s, 2 H), 7.31 (d, J - 8.8 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 3 H), 6.95 (d, J = 8.4 Hz, 2. H), 6.85 (dd, J 8.4. 1.2 Hz, 2 H), 6.81 -6.79 (m, 1 H), 4.76 - 4.73 (m, 1 H), 3.71 (s, 3 H), 3.39 (s, 1 H), 3.35 - 3.32(m, 4 H) 3.24 - 3.16 (m, 4 H), 1.82 (d, J = 2.4 Hz, 3 H), 1.33 (d, J=6.8 Hz, 3 H) [M+Na]+^51 2.3 36 2.67 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A235 n        \ 9H i O s A \ _ 1 1 aV-V N^N \ 1 -(4-( 1 -hydroxy-2-(4-methoxyphenyl)propan-2-yl)thiazol-2 -yl)-3 -(1-(4-(piperazin-l-yl)pheny]) ethyl)urea 1H NMR (400 MHz, DMSO-Je) 4' 10.47 (br s, 1 H), 9.11 (br s, 2 H), 7.36 -7.23 (m, 1 H), 7.19 (d, J = 8.8 Hz, 2 H), 7.10 (d, J === 8.8 Hz, 2 H), 6.95 (d, J === 8.8 Hz, 2 H), 6.75 (d, J = 8.0 Hz, 2 H), 6.69 (s, 1 H), 4.77 - 4.73 (m, 1 H), 3.80 -3.76 (m, 1 H), 3.70 (s, 3 H) 3.34 ■■ 3.31 (m, 4 H), 3.24 ■ 3.16 (m, 4 H), 2.07 (s, 1 H), 1.55 (s, 3 H), 1.33 (d, 1===6.8 Hz, 3 H) 496.2 61 27.01 A2.36 0 zz °A M 0 Z -X / \ \ 7 \~.z T N-(4-( 1-(4-bromophenyl)cyclopent yl)thiazol-2-yl)-3 -(3-fluoro-4-(piperazin-1 -yl)phenyl)azetidine-l -carboxamide 'H NMR (400 MHz, CD3OD) 8 7.34 (d, 1===8.56 Hz, 2 H) 7.21 (d, 1=8.56 Hz, 2 H) 7 08 - 7.00 (m, 3 H) 6.68 (s, 1H) 4.59 (br d, 1=16.63 Hz, 1 H) 4.40 (t, 1=8.56 Hz, 2 H) 3.98 (dd, .1=8.31,6.11 Hz, 2 H) 3.77 -3.87 (m, 1 H) 3.02 (br d, 1=6.11Hz, 8 H) 2.43 - 2.53 (m, 2 H) 2.01 - 2.13 (m, 2 H) 1.62 ■ 1.77 (m, 4 H) 584.3 13 4.50 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A237 0 b o z X? CO 6 i N-(4-(2-(4-bromophenyl)bul-3-yn-2-yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)phenyl)azetidine-1 -carboxamide ’ll NMR (400 MHz, DM SOX j ¢5 10.93 (s, 1 H) 9.22 (s, 2 H) 7.47 (d, J = 8.4 Hz, 2 H) 7.30 (d, J = 8.4 Hz, 2 H) 7.21 (d, J === 8.4Hz, 2 H), 6.90 - 6.98 (m, 3 H), 4.30 (brs, 1 H), 3.87-3.84 (m, 2 H), 3.66 - 3.74 (m, 1 H), 3.46 (s. 1 H), 3.31 -3.30 (m, 4 H),3.22 - 3.10 (m, 4 H), 1.82 (s, 3 H) 550.1 / 0.61 A238 HO_ x xv / I 1 H H      / A H                      Br 1-(4-(2-(4-bromophenyi)but-3-yn-2-yl)thiazol-2-yl)-3-((4-hydroxypiperidin-4-yl)methyl)urea ’H NMR (400 MHz, CD3OD) ¢5 7.53 -7.20 (m, 2 H), 7.44 - 7.42 (m, 2 H), 7.14 (s, 1 H), 3.33 - 3.27 (m, 2 H), 3.26 - 3.25 (m, 4 H), 3.16(8, 1 H), 1.95 (s, 3 H), 1.79 -1.77 (m, 4 H) 465.1 19 27.00 A239 z 0 Z—7 IZ 0O xz >0 □3 1-(4-(2-(4-bromophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(2-(piperazin-1 ■■ yl)ethyl)urea 111 NMR (400MHz, CD3OD) d’ 7.47-7.54 (m, 2H), 7.38-7.46 (m, 2H), 7.14 (s, 1H), 3.62-3.82 (m, 8H), 3.47 (brt, 4 5 6 Hz, 2H), 3.14 (s, 1H), 1.95 (s, 3H) 462.0 20 0.85 A240 0L^ V'OMe ^-7  0 N0 z0 11 / |XX N N S Jl J H H hn0 1-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3 -(1 -(4-(piperazin-l -yl)phenyl)cyclopropyi)u rea 492.0 97 1.88 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A241 H H 1-(4-(2-(4-bromophenyl)propan-2 ■■ yl)thiazol-2-yl)-3-ethylurea 368.1 98 3.41 A242 o— / S H H     V- / \vZ N 0 1 -ethyl-3 -(4-(2 -(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea 320.1 42 0.98 A243 III A-CA” o o          || hZ^B b s 2-(3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)ureido)ethane-l -sulfonamide H NMR (400 MHz, CDCh) d 7.44-7.26 (m, 4 H), 6.75 ( s, 2 H), 5.82 (s, 2 H), 3.80 - 3.65 (m, 2 H), 3.25 - 3.13 (m, 2 H), 2.63 (s, 1 H), 1.92 (s, 3 H). 413.1 23 0.59 A244 4-O“a H H ho^nAnAs^ / H H HO' 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-vl)-3-(2,3-dihydroxypropyl)urea 'H NMR (400 MHz, CDCh) d 9.63 (br. s, 1 II), 7.39 - 7.35 (m, 2 H), 7.25 -7.19 (m, 2 H), 6.65 ( s, 2 H), 3.72 - 3.62 (m, 1 H), 3.52 - 3.33 (m, 2 H), 3.29 -3.09 (m, 2 H), 2.56 (s, 1 H), 1.86 (s, 3 H). 380.1 72 1.03 WO 2022 / 063152                                                 PCT / CN2021 / 119801 0.68 o. in in 00 "° Ox r-1 408 524.1 524.1 429.7 ‘H NMR (400 MHz, DMSO-J6) 4’ 10.95 (s, 1 H), 8.97 (br s, 2 H), 7.35 - 7.42 (m, 4 H), 7.20 - 7.30 (m, 1 H), 7.11 - 7.18 (m, 1 H), 7.04 - 7.09 (m, 1 H), 6.97 (s, 1 H), 4.33 (brt, 7 =8.11 Hz, 2 H), 3.91 (brt, 7 = 7.03 Hz, 2 H), 3.75 - 3.81 (m, 1 H), 3.48 (s, 1 H), 3.21 (br d, 7 = 8.94 Hz, 8 H), 1.85 (s, 3 H) U NMR (400 MHz, DMSO-4) 4 10.95 (s, 1 H), 8.95 (br s, 2 H), 7.35 - 7.42 (m, 4 H), 7.18 - 7.30 (m, 1 H), 7.10 - 7.17 (m, 1 H), 7.02 - 7.09 (m, 1 H), 6.97 (s, 1 H), 4.33 (brt, 7= 8.17 Hz, 2 H), 3.86 - 3.97 (m, 2 H), 3.75-3.81 (m, 1 H), 3.48 (s, 1 H), 3.23 (br s, 4 H), 3.20 (br s, 4 H), 1.86 (s, 3H) 'H NMR (400 MHz, DM S( )-7.)4 10.92(1, 1H), 7.38 - 7.36 (m, 4H), 6.49 (s, 1H), 4.80 (s, 1H), 3.58 (s, 1H), 3.45 -3.35 (m, 2H), 3.22 -3.18 (m, 2H), 1.85 (s, 3H) S)-N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(3-fluoro-4-(piperazin-1 -yl)phenyl)azetidine-l -carboxamide (R)-N-(4-(2-(4-chlorophenyl)but-3 -yn -I 2-yi)thiazol-2-yl)-3-(3-fluoro-4-(piperazin-1 ■■ yl)phenyl)azetidine-l ■■ carboxamide (S)-1 -(5-chloro-4-(2-(4-ch!orophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-hydroxy ethyl) urea o n-4 I L r-N^N s F>^,Jx H o xP zx o=( LL    Z"™\ Q / OH Cl^ A245 A246 A247 A248 OH J        Q jo (R)-1 -(5-chloro-4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-hydroxyethyl)urea NMR (400 MHz, DMSO-^) 8 10.92 (1, 1H), 7.40 - 7.30 (m, 4H), €).50 (s, 1H), 4.77 (s, 1H), 3.55(s, 1H), 3.43 -3.35 (m, 2H), 3.20 -3.15 (m, 2H), 1.87 (s, 3H) 429.9 1294 2.73 A249 / , o        L l ■> / X Xz HO ^ N N S ri (8)-1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3 -(3-hydroxy-3-methylbutyl) urea H NMR (400 MHz, DMSO-O 8 10.66 (s, 1H), 7.40-7.46 (m, 2H), 7.33-7.39 (m, 2H), 6.88 (s, 1H), 6.27 ( s, 1H), 4.32 (s, 1H), 3.48 (s, 1H), 3.13-3.23 (m, 2H), 1.85 (s, 3H), 1.45-1.57 (m, 2H), 1.09 (s, 611) 392.0 128 0.67 A250 / ,      o n-X L jl \ /   X X / HO          N S (R)-l-(4-(2-(4-chiorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3 -(3-hydroxy-3-methylbutyl)urea H NMR (400 MHz, DMSO-4) 8 10.65 (s, 1H), 7.41-7.46 (m, 2H), 7.34-7.40 (m, 2H), 6.88 (s, 1H), 6.26 ( s, 1H), 4.31 (s, 1H), 3.49 (s, 1H), 3.13-3.22 (m, 2H), 1.85 (s, 3H), 1.46-1.56 (m, 2H), 1.09 (s, 6H) 392.0 417 1.18 A251 O S & % X XVk H2N N N \__ H zx Cl (R)-l-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)urea H NMR (400 MHz, DMSCM0 8 10.59 (1, 1H), 7.44 - 7.42 (m, 2H), 7.38 -7.36 (m, 2H), 6.89 (s, 1H), 6.22 (s, 1H), 3.49 (s, Hit 1.85 (s, 3H) 305.9 81 1.67 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A252 0 s-a 4 A AzX H,N N N H    / A Ci (S)-1-(4-(2-(4-chiorophenyl)but-3 -yn-2-yl)thiazol-2-yl)urea U NMR (400 MHz, DMSO-4) 3 10.60 (1, 1H), 7.44 .. 7.42 (m, 2H), 7.39 ■■ 7.36 (m, 2H), 6.90 (s, 1H), 6.22 (s, 1H), 3.49 (s, 1H), 1.85 (s, 3H) 305.9 30 0.53 A253 / 9 Zss, / ll —N "N S' H N"X-OH r OH 3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-l, 1 -bis(2-hydroxyethyl)urea 'H NMR (400 MHz, DMSO-AM 7.36 (4H, J = 19.6 Hz, t), 6.91 (1H, s), 3.51 (411, s), 3.45 (HI, s), 3.40 (4H, s), 1.83 (3H, s) 394.0 172 3.05 A254 Xz Ai r „N   p ft Z"~n"Z C!         S H N^X—OH 3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-l -(2-hydroxyethyl)-] - methylurea 'H NMR (400 MHz, DMSO-^) ¢5 7.38-7.33 (4H, m), 6.90 (1H, s), 3.47 (2H, 1==40.4 Hz, t), 3.44 (1H, s), 3.37 (2H, .1 =10.4 Hz, t), 2.91 (3H, s), 1.82 (3H, s) 364.0 548 2.07 A255 OH     0  S-% t k A A>A N^N \ H / A OMe (R)-3 -(hydroxymethyl) -N-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)azeddine-l -carboxamide 'H NMR (400 MHz, DMSO-^) ¢5 10.83 (s, 1 H), 7.29 (d,. / 8.78 Hz, 2 H), 6.87 (s, 1 H), 6.85 (s, 2 H), 4.78 (t, J === 5.27 Hz, 1 H), 3.94 (br s, 2 H), 3.71 (s, 3 H), 3.68 (br s, 2 H), 3.48 (t, . / 5.65 Hz, 2 H), 3.38 (s, 1 H), 2.56 - 2.70 (m, 1 H), 1.83 (s, 3H). 372.0 688 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A256 QH H Q OMe (S)-3-(hydroxymethyl)-N-(4-(2-(4-methoxyphenyl)but-3 ■■ yn-2-yl)thiazol-2-yl)azetidine-l-carboxamide ‘H NMR (400 MHz, DMSO-J6) 3 10.85 (s, 1 H), 7.30 (br d, J = 8.78 Hz, 2 H), 6.87 (s, 1 H), 6.86 (s, 2 H), 4.79(1.. / 5.14 Hz, 1 H), 3.86 ■■ 4.07 (m, 2 H), 3.72 (s, 3 H), 3.69 (br s, 2 H), 3.49 (br t, J = 5.52 Hz, 2 H), 3.39 (s, 1 H), 2.56 -2.72 (m, 1 H), 1.84 (s, 3 H). 372.1 273 14.3 A257 OH o s-n t A AjA n n \__ H    / ¾ Cl (R)-N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl) azetidin e-1-carboxamide i 1 NMR (400 MHz, CDC13) 6 7.79 (s, 1 H), 7.45-7.40 ( m, 2 H), 7.30-7.20 (m, 2 H), 6.78 (s, 1 H), 4.20 - 4.08 (m, 2 IT), 3.90 -3.84 (m, 2 H), 3.80 - 3.75 (m, 2 H), 2.88 -2.75 (m, 1 H), 2.57 (s, 1 H), 2.10 -2.00 (m, 1 H), 1.92 (s, 3 H). 376.1 1554 2.01 A258 OH . ixA >r'N N \ H O Cl (S)-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazoI-2-yI)-3-(hydroxymethyl)azetidin e-1 -carboxamide 'H NMR (400 MHz, CDCh) d 7.78 (s, 1 H), 7.45 - 7.36 ( m, 2 H), 7.30 - 7.20 (m, 2 H), 6.78 (s, 1 H), 4.20 - 4.08 (m, 2 H), 3.90 - 3.84 (m, 2 H), 3.80 - 3.75 (m, 2 H), 2.90 -2.80 (m, 1 H), 2.57 (s, 1 H), 2.05 - 1.95 (m, 1 H), 1.93 (s, 3 H). 376.1 357 1.33 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A259 / Ci U H  y r / 0   S-»#  \ % N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(piperazin-1-ylmethyl)azetidine-1 -carboxamide 444.2 48 0.44 A260 h / X® 0 nX rAXj H (S)-N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-6-(piperazin-1 -yl)-3,4-dihydroisoquinoline-2( 1 II)-carboxamide U NMR (400 MHz, DMSO-4) 8 8.23 (s, 1H), 7.41 -7.35 (m, 4H), 6.99 -6.91 (m, 2H), 6.75 (d, J = 7.7 Hz, 1H), 6.67 (s, 1H), 4.47 (s, 2H), 3.63 (s, 2H), 3.05(s, 4H), 2.90 (s, 4H), 2.70 (s, 2H), 1.81 (s, 3H). 506.2 74 1.08 A261 HO          Ci X^-N             / = / o s / \~ % N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(piperazin-1-yl)azetidine-l -carboxamide 430.1 83 0.51 A262 p        N  N x^N o s-y \---x / Cl 1-(4-(2-(4-chlorophenyl)but-3 -yn-2 -y l)thi azol-2 -y 1)-3-(3-fl uoro-4-(piperazin-1 -yl)benzyl)urea 498.1 13 0.67 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A263 z )—\ ) £j 'A z ?-( % z 3 -((4-aminopiperidin-1 -yl)methyl)-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)azetidine-l-carboxamide 458.1 39 1.44 A264 _ 5 jy / A Cl N-(4-(2-(4-chlorophenyl) but-3 -yn-2-yl)thiazol-2-yl)-4-(hydroxymethyl)piperidi ne-1 -carboxamide 404.1 1374 2.81 A265 Q Cl 4-amino-N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)piperidine-l-carboxamide 389.1 4974 2.90 A266 \^n   0 AJ I AA C!         S H N'A-OH 3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-1 -(2-hydroxy ethyl) -1 -methylurea i! NMR (400 MHz, DMSO-d6) 8 7.34 (t,J = 20.0 Hz, 4H), 6.87 (s, 1H), 3.44-3.40 (m, J= 16.0, 5H), 2.88 (s, 3H), 1.79 (s, 3H). 364.0 546 2.07 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A267 / 9 af-X-OH 3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-1,1 -bis(2-hydroxyethyl)urea ‘H NMR (400 MHz, DMSO-4) 5 7.34 (t, J = 20.0 Hz, 4H), 6.86 (s, 1H), 3.46-3.40 (m, J = 16.0, 9H), 1.78 (s,3H). 394.0 171 3.05 A268 . / . AO. x i H H 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-hydroxy-2-methylpropyl)urea U NMR (400 MHz, DMSO-A) 8 7.43-7.34 (dd, J === 27.8, 7.5 Hz, 4H), 6.87 (s, III), 6.38 (s, 111), 4.56 (s, 1H), 3.02 (d, .7=== 4.0 Hz, 2H), 1.83 (s, 3H), 1.03 (s, 6H). 378.1 218 1.31 A269 g ry\ / H°-O N N 0 Cl N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-hydroxypyirolidine-1 -carboxamide i! NMR (400 MHz, DMSO-J6) 8 7.36 (s, 4H), 6.90 (s, 1H), 4.93 (s, 1H), 4.22 (s, 1H), 3.44 (s, 4H), 1.83 (s, 3H), 1.74 (s, 2H). 376.0 881 1.26 A270 0  s-^ \ / HO'         Q Cl N-(4-(2-(4-chiorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(hydroxymethyl)pyrroli dine-1 -carboxamide ‘H NMR (400 MHz, DMSO-4) 6 7.36 (s, 4H), 6.90 (s, 1H), 4.68 (s, 1H), 3.44 (s,4H), 3.11 (s, 2H), 2.24 (s, 1H), 1.83 (s, 3H), 1.60 (s, 2H). 390.1 904 1.97 WO 2022 / 063152                                                 PCT / CN2021 / 119801 0.73 0.89 2.68 2.55 493 C’’) 09 46 / 322.0 494.1 465.1 417.1 'H NMR. (400 MHz, DMSO-^) 5 7.40-7.36 (m, J = 16.0 Hz, 4H), 6.94 (s, 1H), 3.47 (s, 1H), 1.84 (s, 3H). lH NMR (400 MHz, DMSO-de) 8 7.31 (s, 4H), 7.13-7.09 (m, 4H), 6.83 (d, J == 8.0 Hz, 1H), 3.54 (s, , 2H), 3.50 (m, 4H), 2.78 (s, 4H), 1.84 (s,3H). 'H NMR (400 MHz, DMSCWe) 8 7.41-7.34 (m, 4H), 6.86 (s, 1H), 3.16 (s, 4H), 2.67 (s, 1H), 1.82 (s, 3H), 1.66(s, 2H), 1.49 (s,lH), 1.25 (s, 2ID, 1.01 (s, 3H). 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-hydroxyurea 1-(4-(2-(4-chlorophenyl) but-3 -yn-2-yl)thiazol-2 -yl)-3 -(4-(piperazin-1-yl)phenethyl)urea N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-2-(4-(piperazin-1-yl)phenyl) acetamide 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yi)thiazol-2-yl)-3 -(1 -(piperidin-4-yl)ethyl)urea H Q Cl H H      / -¾ \=Z Ci Cl 6 o 5^^ / —\ H H |     । X jl 7 N ° ! A271 A272 A273 A274 A275 / o l il A A / / -~N N S Aj h h2n 3-amino-N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)azetidine-l -carboxamide 361.0 503 1.59 A276 Ji i T Anh a / U L-g Anh2 U            HN 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)guanidine 305.0 475 1.58 A272 III Ab       II —MH cr\> ks ANH O CN [M+H]+=331 .0 666 NA A273 III Z" °a H__r> A     Anh   A- ci-^A A /      / A N o X—j. 1-(4-(2-(4-chlorophenyl)but-3 -yn -2-yl)thiazol-2-yl)-3-( 1 - (4-(piperazin-l-yl)phenyl)cyclopropyl)u rea i !H NMR (400 MHz, DMSOAt? 10.77-11.73 (m, 1 H), 8.01 (br s, 1 H), 7.39 - 7.44 (m, 2 H), 7.34 -7.39 (m, 2 H), 7.02 {d.. / 8.70 Hz, 2 H), 6.86 (s. 1 H), 6.80 (br d,. / -8.82 Hz, 2 H), 3.48 (s, 1 H), 2.92 -2.99 (m, 4 H), 2.75 - 2.83 (m, 4 H), 1.84 (s, 3 H), 1.06 (br d, J - 9.06 Hz, 4 H). 506.1 237 3.20 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A274 xz cr z z^co Q o 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(1 -(4-(piperazin-l -yl)phenyl)cyclopropyl)u rea A 1 NMR (400 MHz, DMSO-dy 4’ 10.50 (br s, 1 H), 7.40 - 7.47 (m, 2 H), 7.34 - 7.40 (m, 2 H), 7.02 (br d, J ------ 8.70 Hz, 3 H), 6.91 (s, 1 H), 6.82 (bi d, J = 8.82 Hz, 2 H), 3.50 (s, 1 H), 2.92 - 3.04 (m, 4 H), 2.75 -2.88 (m, 4 H), 1.84 (s, 3 H), 1.09 (br d, J = 3.58 Hz, 4 H). 506.1 327 3.8 A275 A iW N                        \ II          F H N-(4-(2-(4-fluorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(piperazin-1-ylmethyl)azetidine-1 -carboxamide 1H NMR (400 MHz, DMSO-A. ) a 12.00 (br s, 1 H), 11.01 (brs, 1 H), 9.79 (br s, 2 H), 7.40 (dd, J 8.66, 5.40 Hz, 2 11),7.13 (t, . / 8.66 Hz, 2 H), 6.93 (s, 1 H), 4.09 (br s, 2 H), 3.76 -3.85 (m, 2 H), 3.57 (br d, J == 4.77 Hz, 2 H), 3.39 ■ 3.53 (m, 7 H), 3.26 (br s, 2 H), 3.11 (br d, J - 6.53 Hz, 1 H), 1.85 (s, 3 H). 428.0 246 3.38 WO 2022 / 063152                                                 PCT / CN2021 / 119801 0.56 cn r-1 — 345 2667 428.1 424.0 ‘H NMR (400 MHz,      1 DMSO-dy 4' 12.01 (br s, 1 H), 11.01 (brs, 1 H), 9.79 (br s, 2 H), 7.40 (dd, J= 8.41, 5.40 Hz, 2 H), 7.13(1, . / 8.78 Hz. 2 H), 6.93 (s, 1 H), 4.01 - 4.12 (m, 2 H), 3.75 - 3.85 (m, 2 H), 3.58 (br s, 2 H), 3.37 - 3.52 (m, 7 H), 3.27 (br s, 2 H), 3.10 (br s, 1 H), 1.85 (s, 3 H). ’H NMR (400 MHz,      j DMSO-r / .) 8 10.60 (br s, 1 E^H^8 / -’P) 14’4 (H H), 7.37 (d, .) 8.53 Hz, 2 H), 6.90 (s, 1 H), 6.33 (br s, 1 H), 4.86 (br d, J = 4.77 Hz, 1 H), 4.59 (t, J = 5.65 Hz, 1 H), 3.50 (s, 1 H), 3.42 ■■ 3.49 (m, 1 H), 3.34 ■■ 3.37 (m, 0.5 H), 3.20 - 3.31 (m, 2.5 H), 2.90 - 3.04 (m, 1 H), 1.85 (s, 3 H).                    | N-(4-(2-(4-fiuorophenyl)but-3 -yn-2-yl)thiazoI-2-yI)-3-(piperazin-1-ylmethyl)azetidine-1 -carboxamide 1-(4-(2-(4-bromophenyl)but-3 -yn-2-yl)thiazol-2-yr)-3- (2,3- ' ' dihydroxypropyl)urea 1          / / & Jj OT— ZI O=^ 2q „ ( / S 6 X M3 5 A278 / un     JL 'Q"~A N N S !    H H ^OH 1-(4-(2-(4-bromophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(z,3-dihydroxypropyl)urea ‘H NMR (400 MHz, DMSO-dy 3 10.62 (br s, 1 H), 7.51 (d, / = 8.53 Hz, 2 H), 7.37 (d, / = 8.53 Hz, 2 H), 6.89 (s, 1 H), 6.34 (br s, 1 H), 4.86 (br d. / 4.52 Hz, 1 H), 4.60(1, / =5.40 Hz, 1 H), 3.50 (s, 1 H), 3.47 (br d, J = 4.77 Hz, 1 H), 3.35 (br s, 0.5 H), 3.20 -3.31 (m, 2.5 H), 2.90 ■ 3.03 (m, 1 H), 1.84 (s, 3 H). 424.0 624 0.52 A279 W            OH L o / --7 iO / VN >-NH fIsH» 1-(4-(2-(4-chiorophenyl)but-3 -yn-2-yI)-5 -fluorothiazol-2-yl)-3-(2-hydroxyethyl)urea U NMR (400 MHz, DMSO-4) 3 10.65 (s, 1 H), 7.50 - 7.35 (m, 4H), 6.34 (br. s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 3.53 (s, 1 H), 3.41 (q, J = 4.0 Hz, 1H), 3.15 (q, J = 4.0 Hz, 1H), 1.86 (s, 3 H). 368.0 222 4.23 A280 X _ / v "“"T X J A jrt / y^NANASZ H HN'^ N-(4-(2-(4-chlorophenyI)but-3 -yn -2-yl)thiazol-2-yl)-6-(piperazin-1 -yl)-3,4-dihydroisoquinoline-2( 1 H)-carboxamide U NMR (400 MHz, DMSO- / 5) <5 7.44 - 7.35 (m, 4 H), 7.01 ■■ 6.94 (m, 2 H), 6.81 - 6.75 (m, 1 H), 6.72 -6.68 (m, 1 H), 4.53 (s, 2H), 3.66 (1, J =8 Hz, 2H), 3.50 (s, 1H), 3,05 - 2.99 (m, 4H), 2.88 2.82 (m, 411), 2.75 (t, J 8 Hz, 2H), 1.87 (s, 3H). 506.5 21 2,18 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A281 O Al 7 < V N N s JI J    j    H HN^J ..       N-(4-(2-(4- chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-6-(piperazin-1 -yl)-3,4-dihydroisoquinoline-2(1 H) -carboxamide ‘H NMR (400 MHz, DMSO-dy b 7.44 - 7.36 (m, 4 H), 7.01 - 6.94 (m, 2 H), 6.80 - 6.75 (m, 1 H), 6.71 -6.68 (m, 1 H), 4.53 (s, 2H), 3.66 (t, J 8 Hz, 2H ), 3.50 (s, 1H), 3.04 - 2.98 (m, 4H), 2.86 - 2.80 (m, 4H), 2.75 (t, J K Hz, 2H), 1.87 (s, 3H). 506.5 38 0.86 A282 o     C 1 h°-—F H H 1-(4-(2-(4-fluorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(2-hydroxyethyl)urea 1H NMR (400 MHz, DMSO-X 3 10.63 (s, 1 H), 7.44 (dd, 7=8.78, 5.52 Hz, 2 H), 7.13 (t, J = 8.91 Hz, 2 H), 6.87 (s, 1 H), 6.34 (br s, 1 H), 4.75 (t, J =5.02 Hz, 1 H), 3.48 (s, 1 H), 3.41 (q, 7=5.52 Hz, 2 H), 3.16 (q, 7= 5.60 Hz, 2 H), 1.85 (s, 3 H). 334.1 2.153 7.72 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A283 ho^nAnA /   F H H 1-(4-(2-(4- fluorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(2-hydroxyethyl)urea ‘H NMR (400 MHz, DMSO4) J 10.63 (s, 1 H), 7.44 (dd, J =8.78, 5.52 Hz, 2 H), 7.13 (t, / =8.91 Hz, 2 H), 6.88 (s, 1 H), 6.33 (br s, 1 H), 4.75 (t, / = 5.14 Hz, 1 H), 3.48 (s, 1 H), 3.41 (q, / = 5.35 Hz, 2 H), 3.16 (q, / = 5.52 Hz, 2 H), 1.85 (s, 3H). 334.1 550 1.70 A284 CM X ,o K o A O z , ^= / LL 2-(3-(4-(2-(4-fluorophenyl)but-3-yn-2-yl)thiazol-2-yl)ureido)ethanesuifona mide 41 NMR (400 MHz, DMSO- / 6) S 10.94 (br s, 1 H), 7.44 (dd, / = 8.78, 5.52 Hz, 2 H), 7.13 (t, / = 8.91 Hz, 2 H), 6.92 (s, 2 H), 6.90 (s, 1 H), 6.48 (br t, J = 5.65 Hz, 1 H), 3.49 - 3.56 (m, 2 H), 3.48 (s, 1 H), 3.13 (t, / = 6.65 Hz, 2 H), 1.85 (s, 3 H). 397.0 666 2.60 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh A285 CM X O N Ax 0 LL 2-(3-(4-(2-(4-fluorophenyl)but-3 -yn-2-yl)thiazol-2-yl)ureido)ethanesulfona mide ‘H NMR (400 MHz, DMSO-t / e) d 10.95 (br s, 1 H), 7.37 - 7.50 (m, 2 H), 7.13 (t, J = 8.78 Hz, 2 H), 6.92 (s, 2 H), 6.90 (s, 1 H), 6.48 (br 1,7=5.90 Hz, 1 H), 3.49 - 3.56 (m, 2 H), 3.48 (s, 1 H), 3.14 (t, J =6.65 Hz, 2 H), 1.85 (s, 3 H). 397.1 350 1.36 A286 111           Hh K % H 7-OH N y-N— / aAJ I A«h w 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3 -((3-hydroxyazetidin-3 -yl)methyl)urea i 1 NMR (400 MHz, DMSO-76) S 10.75 (br s, 1 H), 9J7(brs. 1 H), 8.99 (br s, 1 H), 7.46 -7.41 (m, 2 H), 7.40 -7.36 (m, 2 H), 6.93 (s, 1 H), 6.82 (br s, 1 H), 3.75 -3.90 (m, 5 H), 3.52 (s, 1 H), 3.43 (d..7 6.0 Hz. 2 H), 1.85 (s, 3 H) 391.1 495 15.40 A287 ill               HN"7 > V / 0H fl A-X \,--N r~N---' a-V 0 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2 -yl)-3 -((3 -hydroxyazetidin-3 -yl)methyl)urea 'H NMR (400 MHz, DMSO-t / 6) d 10.75 (br s, 1 H), 9.10 (brs, 1 H), 8.95 (br s, 1 H), 7.45 -7.41 (m, 2 H), 7.40- 7.35 (m, 2 H), 6.93 (s, 1 H), 6.77 (br s, 1 H), 3.86 (br s, 5 H), 3.51 (s, 1 H) 3.43 (br d, J =6.0 Hz, 2 H), 1.85 (s, 3 H) 391.1 130 4.40 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A288 nh2 A. ls>~nh 2-(3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)ureido)ethanesulfona mide IINMR (400 MHz, Ci KA) <59.48 (br s, 1 H), 7.30 (s, 4 H), 6.76 (s, 1 H), 6.05 (br s, 3 H), 3.75-3.65 (m, 2 H). 3.09 - 2.99 (m, 2 H), 2.53 (s, 1 H), 1.87 (s, 3 H) 413.1 270 1.21 A289 nh2 ill O / --o >-NH a-v v* 2-(3-(4-(2-(4-chlorophenyl)but-3 -yn-2-yI)thiazol-2-yl)ureido)ethanesul fona mide H NMR (400 MHz, CDCh) <59.48 (br s, 1 H), 7.30 (s, 4 H), 6.76 (s, I H), 6.06 (br s, 3 H), 3.75 - 3.65 (m, 2 H), 3.10 - 2.98 (m, 2 H), 2.53 (s, 1 H) 1.87 (s, 3 H) 413.1 54 0.47 A290 W            OH f, °\ / J T V-NH Cr'XA / . / F b 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)-5-fluorothiazol-2-yb-3-(2-hydroxyethyl)urea ‘H NMR (400 MHz, DMSO-Je) <5 10.65 (s, 1 II), 7.50 - 7.35 (m, 4H), 6.34 (br. s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 3.53 (s, 1 H), 3.41 (q, J === 4.0 Hz, 1H), 3.15 (q, J === 4.0 Hz, 1H), 1.86 (s, 3 H). 368.0 222 4.23 A291 / ~\ HN   N—\ ^--- / V U ~N / —NH          C| 0   2=N (f ill u> N-(4-(2-(4-chlorophenyl) but-3 -yn-2-yl)thiazoi-2-yi)-3-(piperazin-1-ylmethyl)azetidine-1 -carboxamide ’H NMR (400 MHz, DMSO-<4) d 7.46 - 7.34 (m, 4 H), 6.94 (s, 1H), 4.10 - 3.95 (m, 2 H), 4.0 (br. s, 2H), 3.58 (br. s. 2H), 3.49 (br. s, 1 H), 2.81 - 2.70 (m, 1H), 2.64 (br. s, 4 H), 2.46 -2.40 (m, 3H), 2.24 (br. s, 4 H), 1.85 (s, 3 H). 444.0 109 1.65 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A292 HN / N Cl tii 11! N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(piperazin-1-yimethyl)azetidine-l -carboxamide ‘H NMR (400 MHz, DMSO-dk) 4 10.91 (br. s, 1H), 8.78 (br. s, 1H), 7.42 -7.35 (m, 4 H), 6.95 (s, 1H), 4.09 - 3.96 (m, 2 H), 3.65 -3.55 (br. s, 2H), 3.50 (br. s, 1 H), 3.08 - 2.99 (m, 4H), 2.87 - 2.70 (m, 1H), 2.60 -2.52 (m, 4 H), 1.85 (s, 3 H). 444.1 43 0.65 A293 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(1 -hydroxy-2-methylpropan-2-yl)urea 'H NMR (400 MHz, DMSO-^) ¢5 10.47 (s, 1 H), 7.29 - 7.49 (m, 4 H), 6.88 (s, 1 H), 6.15 (br. s, 1 H), 4.93 (t, J === 5.40 Hz, 1 H), 3.49 (s, 1 H), 3.33 (br s, 2 H), 1.84 (s, 3 H), 1.19 (s, 6 H). 378.1 9361 8.11 A294 ho K p W_Z"A ^—ri VV-V 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(l-hydroxy-2-methylpropan-2-yl)urea H NMR (400 MHz, DMSO-^) ¢5 10.47 (s, 1 H), 7.31 - 7.50 (m, 4 H), 6.88 (s, 1 H), 6.15 (brs, 1 H), 4.94 (t, J = 5.52 Hz, 1 H), 3.49 (s, 1 H), 3.33 (br s, 2 H), 1.84 (s, 3 H), 1.19 (s, 6 H). 378.1 285 3.04 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A295 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-( 1 -(hydroxymethyl) cyclopr opyl)urea i! NMR (400 MHz, DMSO-dy 4 10.46 (br s, 1 H), 7.33 - 7.47 (m, 4 H), 6.91 (s, 1 H), 6.57 (br s, 1 H), 4.58 - 4.99 (m, 1 H), 3.49 (s, 1 H), 3.37 (br s, 2 H), 1.84 (s, 3 H), 0.54 -0.75 (m, 4 H). 376.1 522 1.79 A296 SI 1-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-(1 -(hydroxymethyl)cyclopr opyl)urea ‘H NMR (400 MHz, DMSO-4) 6 10.45 (br s, 1 H), 7.31 - 7.45 (m, 4 H), 6.92 (s, 1 H), 6.55 (br s, 1 H), 4.77 (br s, 1 H), 3.49 (s, 1 H), 3.36 - 3.37 (m, 2 H), 1.84 (s, 3 H), 0.53 - 0.77 (m, 4 H). 376.1 114 4.79 A297 s-va / M N M Cl 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(1,3-dihydroxypropan-2-yl)urea ‘H NMR (400MHz, CDCh) 8 7.42 (d, J= 8.3 Hz, 2H), 7.31 - 7.27 (m, 2H), 6.76 (s, 1H), 3.87 (s, 1H), 3.71 -3.52 (m, 4H), 2.60 (s, 1H), 1.93 (s, 3H) 380.1 935 4.39 A298 1-(4-(2-(4-chlorophenyl)bat-3 -yn-2-yl)thiazol-2-yl)-3-(1,3 -dihydroxypropan-2-yl)urea U NMR (400MHz, CDCh) <5 7.41 (d.. / 8.3 Hz. 2H), 7.32 - 7.26 (m, 2H), 6.75 (s, HI), 3.86 (s, HI), 3.69 -3.52 (m, 4H), 2.60 (s, 1H), 1.92 (s, 3H) 380.1 246 1.15 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh A299 D    . p     f h<k^^nAnAn H H     { / ¾ Ci 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-hydroxyetbyl)urea U NMR (400MHz, CDCh) 8 7.44 - 7.36 (m, 2H), 7.31 ■ 7.27 (m, 2H), 6.77 (s, 1H), 3.52 - 3.41 (m, 2H), 3.39 -3.27 (m, 2H), 2.56 (s, 1H), 1.93 (s, 3H) 351.1 58 0.46 A3 00 D     , p s"A_Aa a. H H Q Cl 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-hydroxyethyl)urea H NMR. (400MHz, CDCh) 8 7.43 - 7.36 (m, 2H), 7.29 (d. J-7.3 Hz, 2H), 6.77 (s, 1H), 3.53 - 3.41 (m, 2H), 3.38 - 3.27 (m, 2H), 2.56 (s, 1H), 1.93 (s, 3H) 351.1 341 3.01 A3 01 O S-A \ $ hoz           \=Z 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-vl)-3-((R)-2,3; dihydroxypropyl)urea H NMR (400MHz, DMSO-O S 10.64 (br s, 1H), 7.47 - 7.40 (m, 2H), 7.40 - 7.34 (m, 2H), 6.89 (s, 1H), 6.41 (s, 1H), 3.54 -3.42 (m, 2H), 3.37 - 3.20 (m, 3H), 3.04 - 2.91 (m, 1H), 1.85 (s, 3H) 380.0 354 2.22 A3 02 ? rM / ho'           vJ 1-(4-(2-(4-chiorophenyl)but-3 -yn-2-yl)thiazol-2-vl)-3- ((8)-2,3^ dihydroxypropyl)urea U NMR (400MHz, DMSO-tsk) 3 10.64 (br s, 1H), 7.46 - 7.40 (m, 2H), 7.40 - 7.34 (m, 2H), 6.89 (s, HP. 6.43 (s, 1H), 3.54 -3.43 (m, 2H), 3.37-3.20 (m, 3H), 3.03 - 2.91 (m, 1H), 1.85 (s, 3H) 379.9 417 2.04 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A3 03 O S"V. / \ / N N N   \__ :    H                Ar HO^           V_ / Cl 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-((R)-2,3-dihydroxypropyl)urea i! NMR (400MHz, DMSO-dy d 10.64 (br s, 1H), 7.48 - 7.40 (m, 2H), 7.40 - 7.33 (m, 2H), 6.89 (s, 1H), 6.43 (s, 1H), 3.56 ■■ 3.41 (m, 2H), 3.37-3.19 (m, 3H), 3.04 - 2.88 (m, 1H), 1.85 (s, 3H) 380.0 101 0.66 A3 04 o s"\3 $ HO.    Jk )  M N / "A HCj                ^= / Cl 1-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-((S)-2,3-' ' dihydroxypropyl)urea ‘H NMR (400MHz, DMSO-4) 6 10.67 (br s, 1H), 7.48 - 7.40 (m, 2H), 7.40 - 7.33 (m, 2H), 6.90 (s, 1H), 6.54 (s, 1H), 3.57 -3.42 (m, 2H), 3.38 - 3.20 (m, 3H), 3.07 - 2.90 (m, III), 1.85 (s, 3H) 380.0 90 0.52 A3 05 HO^ _ ? ry / / , l-[4-[l-(4-bromophenyl) ■■ 1 -methyl ■ prop-2-ynyl]thiazol-2-yl]-3 -(2-hydroxy-2-methyl-propyl)urea ‘H NMR (400MHz, DMSO-4) d 10.57 (br. s, 1H), 7.51 (d, 7=8.5 Hz, 2H), 7.38 (d, 7=8.6 Hz, 2H), 6.89 (s, 1H), 6.37 (br. s, 1H), 4.54 (s, 1H), 3.50 (s, 1H), 3.04 id.. / 5.7 !   2H). 1.85 (s, 3H), 1.05 (s, 6H). 422.0 167 2.69 A306 HO^ O^ kW' y l-[4-[l-(4-bromophenyl)-l -methyl-prop-2-ynyl]thiazol-2 ■ y 1] -3 -(2-hydroxy-2-methyl-propyl)urea H NMR (400MHz, DMSO-y) d 10.57 (br. s, III), 7.51 (d, 7=8.6 Hz, 2H), 7.38 (d, 7=8.6 Hz, 2H), 6.89 (s, 1H), 6.37 (br. s, 1H), 4.54 (s, 1H), 3.50 (s, 1H), 3.04 (d, 7=5.7 Hz, 2H), 1.85 (s, 3H), 1.05 (s, 6H). 422.1 56 0.83 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh 00 A307 P fv / jo H A \ Cl N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-4-hydroxypiperidine-1 -carboxamide 390.1 2058 3.15 A308 ! N   N   N V- O H Q Cl N-(4-(2-(4-chlorophenyl) but-3 -yn-2-yl)thiazol-2-yl)piperazine-l-carboxamide 375.1 1535 5.33 A3 09 / --I   0   s-^. \ 0 rN A 1 X W 0 H H 0 '                                          Cl 1-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2 -yl)-3 ■( 1 ■■ (4-methylbenzyl)pyrrolidin -3-yl)urea 1H NMR (400 MHz, DMSO-rfc) S 10.44 (br s, 1H), 7.48 - 7.33 (m, 4H), 7.23 - 7.06 (m, 4H), 6.90 (s, 1H),6.51 (brs, 1H), 4.10 (brs, 1H), 3.60-3.43 (m, 3H), 2.74 - 2.59 (m, 1H), 2.56 - 2.51 (m, 1H), 2.38 - 2.21 (m, 5H), 2.20-2.08 (m, 1H), 1.84 (s, 3H), 1.54 - 1.40 (m, 1H). 479.1 1414 4.12 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh AO A310 In / / / o „    o n-A Ip   jf ji A H H 2-(3-(4-(2-(4-methoxyphenyl)but-3 ■ yn-2-yl)thiazol-2-yl)ureido)ethanesulfona mide ‘H NMR (400 MHz, CDCh) 3 7.32 - 7.27 (m, 2H), 6.89 - 6.79 (m, 2H), 6.74 (s, 1H), 6.02 (br s, 3H), 3.80 (s, 3H), 3.74 -3.59 (m, 2H), 3.15-2.95 (m, 2H), 2.54 (s, 1H), 1.87 (s, 3H). 409.0 223 0.98 A311 III K S X5 HjN"     'N" "N S H H 2-(3-(4-(2-(4-methoxyphenyl)but-3 -yn-2-yl)thiazol-2-yl)ureido)ethanesuifona mide 41 NMR (400 MHz, CDCh) J 7.27 - 7.23 (m, 2H), 6.88 - 6.80 (m, 2H), 6.75 (s, 1H), 6.07 (br s, 3H), 3.80 (s, 3H), 3.74 -3.62 (m, 2H), 3.10 - 2.93 (m, 2H), 2.51 (s, 1H), 1.86 (s,3H). 409.0 95 0.66 A312 / S O           L ]i hoxAaA / & N N ° H H 1-(4.(2-(4-chlorophenyl)but-3 -yn -2-yl) thi azol-2 -yl) -3 -(1 -hydroxypropan- 2-yl)urea 41 NMR (400 MHz, CD3OD) <5 7.54 - 7.46 (m, 2H), 7.32 - 7.25 (m, 2H), 6.91 (s, 1H), 3.93-3.76 (m, 1H), 3.60 - 3.41 (m, 2H), 2.96 (s, Hl). 1.92 (s, 3H), 1.16 (d, J 6.4 Hz, 3H). 365.6 545 2.12 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A313 / 1 0        L 1 H H 1-(4-(2-(4-chloropheny l)but-3 -yn-2~yl)thiazol~2-yl)-3-(1 -hydroxypropan- 2-yl)urea ‘H NMR (400 MHz, CD3OD) 3 7.55 - 7.43 (m, 2H), 7.37- 7.24 (m, 2H), 6.90 (s, 1H), 3.91 - 3.76 (m, 1H), 3.56 - 3.44 (m, 2H), 2.96 (s, 1H), 1.92 (s, 3H), 1.16 (d, J =6.4 Hz, 3H). 365.5 614 2.82 A314 / । o nA L 1 ho^X A As / Ci NN* H H 1-(4.(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(1 -hydroxypropan- 2-yl)urea 41 NMR (400 MHz, CD3OD) ¢5 7.58 - 7.39 (m, 2H), 7.36 - 7.18 (m, 2H), 6.90 (s, 1H), 3.97 - 3.75 (m, 1H), 3.62 - 3.37 (m, 2H), 2.96 (s, 1H), 1.92 (s, 3H), 1.16 (d, J =6.4 Hz, 3H). 365.5 261 0.80 A315 / i o n"( l 1 h°xJ^n^na^ a H H 1-(4-(2-(4-chlorophenyl)but-3 -yn -2-yl) thi azol-2 -yl) -3 -(1 -hydroxypropan- 2-yl)urea 41 NMR (400 MHz, CD3OD) d 7.57 - 7.46 (m, 2H), 7.35 - 7.21 (m, 2H), 6.91 (s, 1H), 4.00 -3.73 (m, 1H), 3.56 - 3.41 (m, 2H), 2.96 (m, 1H), 1.92 (s, 3H), 1.16 (d, . / = 6.4 Hz, 3H). 365.6 81 0.65 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A316 o n-4 l n HO    A ,A / | H H 1-(4-(2-(4-chloropheny l)but-3 -yn-2~yl)thiazol~2-yl)-3-(2-hydroxypropyl)urea ‘H NMR (400 MHz, CD3OD) 3 7.54 - 7.44 (m, 2H), 7.32 - 7.25 (m, 2H), 6.91 (s, 1H), 3.90 - 3.76 (m, 1H), 3.28 (s, 1H), 3.16-3.04 (m, 1H), 2.95 (s, 1H), 1.92 (s, 3H), 1.15 (d, J-6.4 Hz, 3H). 365.6 421 1.81 A317 / o n-X L Ji | H H 1-(4.(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-3-(2-hydroxypropyl)urea 41 NMR (400 MHz, CD3OD) ¢5 7.52 - 7.44 (m, 2H), 7.32 - 7.26 (m, 2H), 6.91 (s, 11-1),3.89-3.78 (m, 1H), 3.30 - 3.25 (m, 1H), 3.15-3.06 (m, 1H), 2.95 (s, 1H), 1.92 (s, 3H), 1.15 (d,J= 6.4 Hz, 3H). 365.6 85 0.97 A318 / ° n \TC. x hoV^nANAs>    C! | H H 1-(4-(2-(4-chlorophenyl)but-3 -yn -2-yl) thi azol-2 -yl) -' 3-(2-hydroxypropyl)urea 41 NMR (400 MHz, CD3OD) J 7.56 - 7.43 (m, 2H), 7.34 - 7.22 (m, 2H), 6.91 (s, 1H), 3.92-3.70 (m, 1H), 3.30-3.25 (m, 1H), 3.15-3.06 (m, 1H), 2.95 (s, 1H), 1.92 (s, 3H), 1.15(d,J=6.4Hz,3H). 365.6 534 2.24 WO 2022 / 063152                                                 PCT / CN2021 / 119801 A319 / o          L II HO   A A AzVV s | H H 1-(4-(2-(4-chloropheny l)but-3 -yn-2~yl)thiazol~2-yl)-3-(2-hydroxypropyl)urea ‘H NMR (400 MHz, CD3OD) ci 7.59 - 7.43 (m, 2H), 7.35 - 7.14 (m, 2H), 6.91 (s, 1H), 3.89 - 3.75 (m, 1H), 3.30 - 3.24 (m, 1H), 3.14-3.05 (m, 1H), 2.95 (s, 1H), 1.92 (s, 3H), 1.15 (d.. / 6.4 Hz. 3H). 365.6 156 0.67 A320 / nd 9 fCCL A H H l-[4-[l-(4-chlorophenyl) -1 -methyl-prop-2-ynyl]thiazol-2 ■■ yl]-3 -(2,2.-dideuteri o-2-hydroxy-ethyl)urea NMR (400MHz, CDCh) d 7.34-7.28 (m, 2H), 7.22-7.19 (m, 2H), 6.69 (s, 11-1),3.23 (d, J 5.5 Hz, 2H), 2.48 (s, 1H), 1.84 (s, 3H) 352.1 44 A3 21 / „ o nA l 0 HO   A A / N N S A H H 1-[4-(1-(4-chlorophenyl)-1 -methyl-prop-2-ynyl]thiazol-2-yl] -3 -(2,2 -did euterio-2-hydroxy-ethyl)urea fH NMR (400MHz, CDCh) S 7.43 - 7.35 (m, 2H), 7.31 -121 (m, 2H), 6.76 (s, 1H), 3.31 (d, J= 5.5 Hz, 2H), 2.55 (s, 1H), 1.92 (s, 3H) 352.1 28 0.30 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Example 13: Preparation of tert-butyl 4-(4-((3-(4-(l-(4-bromophenyl)ethyl)thiazoi-2- yl)nreido)methyl)phenyl)piperazine-l-carboxylate [281 ]         To a solution of tert-butyl 4-(4-((3-(4-( 1 -(4-bromophenyl)vinyl)thiazol-2- yl)ureido)methyl)phenyl)piperazine-l-carboxylate (120 mg) in MeOH (5 mL) was added Pd / C (12 mg), the mixture was stirred overnight at RT under hydrogen pressure. After filtration and evaporation, the obtained residue was purified by column chromatography on a silica gel to afford tert-butyl 4-(4-((3-(4-(1 -(4-bromophenyl)ethyl)thiazol-2-yl)ureido)methyl)phenyl)piperazine-1 -carboxylate (73 mg). Example 14: Preparation of tert-bntyl 4-(5-((3-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-vI)nreido)methyl)-3-fluoropyridin-2-yl)piperazine-l-carboxyIate Br

[282] A suspension of 1 -(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-3-((6- chloro-5-fluoropyridin-3-yl)methyl)urea (174 mg, 0.4 mmol), tert-butyl piperazine-1-carboxylate (82 mg, 0.44 mmol), X-phos (39 mg, 0.08 mmol), Pd2 (dba) 3 (36.6 mg, 0.04 mmol) and t-BuONa (46.1 mg, 0.48 mmol) in toluene (5 mL) was stirred at 90 °C under N2 atmosphere o vernight. The reaction mixture was cooled to RT and filtered off the solid, the residue was dissolved in ethyl acetate (100 mL) and washed with brine. The organic phase was dried over MgSO4, filtered, concentrated in vacuum to give the crude product, which was purified by flashed column to give the desired product ( 67 mg, yield 25%). Example 15: Preparation of 5-((3-(4-(2-(4-methoxyphenyl)propan-2-yI)thiazoI-2- yl)nreido)methyi)-2-(3-methylpiperazin-l-yI)benzamide

[283] Step 1 Preparation of 2-(4-( tert-butoxycarbonyl)-3~methylpiperazin-l-yl)-5~ ((3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)ureido)methyl)benzoic acid \

[284] 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-l-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 sat. NH4CI (aq), extracted with EA, washed with brine, dried overNa2SO4, filtered and evaporated to dryness. The resulting residue was purified by Prep-TLC to give the desired compound (215 mg).

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

[286] A mixture of 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-l-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) were dissolved in THF (0.1 M) and stirred for 15 min at RT. NH4CI (36.9 mg, 0.69 mmol, 2 eq) was then added in one portion and the reaction was stirred at RT. Once judged 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 Prep-TLC to give the desired product (201 mg). Example 16: Preparation of l-((6-((2-hydroxyethyl)amino)pyridin-3-yr)methyl)-3-(4-(2- (4-methoxyphenyl)propan-2-yl)thiazol-2-y])ttrea

[287] A mixture of l-((641uoropyridin-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 was cooled down to RT, concentrated to give a residue, which was purified by column chromatography on a silica gel to afford 1 -((6-((2-hydroxyethyl)amino)pyri din-3-yl)methyl)~ 3-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)urea (21 mg). Example 17: Preparation of l-(4-(2-(4-methoxyphenyl)but-3-yH-2-yl)thiazol-2-yl)-3-(l-(4-(piperazm-l-vI)phenyi)ethyl)urea

[289] 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 pL) at 15 °C. The mixture was stirred for 12 h at 85°C. The mixture was diluted with EA (400 mL), washed with sat, NaHCOj aq (100 mL), brine (TO mL), dried over anhydrous Na?SO4, filtered and concentrated in vacuum 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 yellow oil.

[290] NMR (400 MHz, CDCh) 8 7.21 (d, J = 8.8 Hz, 2 H) 6.87 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 3.69 (s, 3 H), 3.58 (s, 2 H)

[291] Step 2. Preparation of compound methyl 2-(4-methoxyphenyl)-3-oxobutanoate b' w / A ^omjhmds^ 7 -78 °C-0 °C, 2 h \= /

[292] 0M®                       OMe

[293] To a solution of compound obtained from step 1 above (23.8 g, 132.2 mmol) in THF (200 mL) was added LiHMDS (1 M, 159 mL) at -78°C. The mixture was stirred for 20 min at -78°C. Acetyl acetate (13.5 g, 132.2 mmol) was added to the solution. Then the mixture was warmed to 0°C and stirred for 2 h at 0°C. The mixture was quenched with sat NH4CI aq. (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified on silica gel chromatography (ethyl acetate in petroleum ether ===0-15%) to give the desired compound (14.23 g, yield: 48.4%) as a yellow oil.

[294] Al NMR (400 MHz, CDCh) 8 12.97 (s, 1 H), 7.25 - 7.23 (m, 1.5 H), 7.07 -7.03 (m, 2 H), 6.87 -6.85 (m, 2 H), 4.63 (s, 0.5 H), 3.80 (s, 3 H), 3.78 (s, 1.5 H), 3.73 (s, 1.5 H), 3.67 (s, 3 H), 2.15 (s, 1.5 H), 1.83 (s, 3 H). MS (ESI) m / z (M + II) 223.1

[295] Step 3, Preparation of compound methyl 2-(4-methoxyphenyl)-2-methyl-3-oxobutanoate Ox /                  % / 0 V-o               0 \ r-o \ X      CH3I / K2CO3       \ \ /    Acetone, 70°C      \— / OMe 12 h             OMe

[296] To a mixture of compound obtained from step 2 above (14.5 g, 65.4 mmol) 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 fi ltrate was concentrated in vacuum to give a residue. The residue was purified by silica column (ethyl acetate in petroleum ether =0-15%). The desired compound (9.76 g, yield: 63.2%) was obtained as a colorless oil.

[297] NMR (400 MHz, CDCh) 8 7.25 - 7.19 (m, 2 H), 6.95 - 6.86 (m, 2 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 2.10 (s, 3 H), 1.77 (s, 3 H)

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

[299] To a solution of compound obtained from step 3 above (1 g, 4,2 mmol) in CHCh (20 mL) was added Br2 (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 vacuum to give a residue. The desired product (1.03 g, crude) was obtained as a colorless oil. The crude product was directly used for the next step without further purification.

[300] MS (ESI) m / z (M • H)' 315.1

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

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

[303] NMR (400 MHz, CDCI3) 8 7.20 -7.18 (m, 2 H), 6.97 - 6.92 (m, 2 H), 6.88 -- 6.86 (m, 2 H), 5.95 (s, 1 H), 3.73 (s, 3 H), 3.61 (s, 3 H), 1.77 (s, 3 H).

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

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

[306] MS (ESI) mh (M • H i' 413.0

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

[308] To a mixture of compound obtained from step 6 above (330 mg, 800 pmol) and tert-butyl 4-[4-(l-aminoethyl)phenyl]piperazine-l-carboxylate (269 mg, 880 pmol) in THF (2 mL) was stirred at 100°C for 1 h under Microwave. The mixture was directly concentrated in vacuum 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.

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

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

[311] To a solution of compound obtained from step 7 above (370 mg, 593 pmol) 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 xa / .NH4Cl (15 mL) and extracted with EA (3x15 mL). The organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica column (ethyl acetate in petroleum ether = 0-100%) to give the desired compound (307 mg, yield: 87.0%) which was obtained as a yellow solid.

[312] Tl NMR (400 MHz, CDCh) <5 7.17 (d, J= 8.4 Hz, 2 H), 7.09 - 7.06 (m, 2 H), 6.86 - 6.80 (m, 4 H), 6.45 (s, 1 H), 4.94 - 4.91(m, 1 H), 4.05 - 4.00 (m, 1 H), 3.81 - 3.77 (m, 4 H), 3.56 - 3.54 (m, 4 H) 3.09 - 3.07 (m, 4 H), 1.56 (d, J- 1.6 Hz, 3 H), 1.49 (s, 9 H), 1.46 (d, J 6.8 Hz, 3 H).

[313] Step 9. Preparation of compound 1-(4-( l-hydroxy-2-(4- methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-( 1 -(4-(piperazin-1 -yl)phenyl)ethyl)urea hydrochloride OH HCI / EtOAc ----------------------- DCM,15°CS 12 h

[314] To a solution of compound obtained from step 8 above (50 mg, 83.93 pmol) in DCM (2 ml,) was added HCI / EtOAc (4 M, 2 ml,) at 15 °C. The mixture was stirred for 12 h at 15°C. The mixture was concentrated in vacuum to give the desired compound (34 mg, yield: 76.1%) was obtained as a yellow solid. 1315]            NMR (400 MHz, DMSO) 5 10.47 (br s, 1 H), 9.11 (br s, 2 H), 7.36 - 7.23 (m, 1 H), 7,19 (d, J 8.8 Hz, 2 H), 7.10 (d.. / 8.8 Hz, 2 H), 6.95 (d, J 8.8 Hz, 2 H), 6.75 (d, J = 8.0 Hz, 2 H), 6.69 (s, 1 H), 4.77 - 4.73 (m, 1 H), 3.80 - 3.76 (m, 1 H), 3.70 (s, 3 H) 3.34 - 3.31 (m, 4 H), 3.24 - 3.16 (m, 4 H), 2.07 (s, 1 H), 1.55 (s, 3 H), 1.33 (d, >6.8 Hz, 3 H). MS (ESI) m / z (M HL 496.2

[316] Step 10. Preparation of compound tert-butyl 4-(4-(1-(3-(4-(2-(4- methoxyphenyl)-l-oxopropan-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-l-carboxylate

[317] To a solution of oxalyl dichloride (68. 2 mg, 537.14 pmo) in DCM (2 mL) was added DMSO (66 mg, 839 pmol) at -78°C. After 10 min, compound obtained from step 9 above (100 mg, 168 pmol) in DCM (2 mL) was added and stirred for 1 h at -78°C. EbN (170 mg, 1.68 mmol) was added and stirred for 10 more min then warmed to 15°C and stirred for another 1 h. The mixture was diluted with H2O (20 mL), extracted with DCM (3 x 20 ml,). The organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The desired product (120 mg, crude) was obtained as a yellow oil. The crude product was directly used for the next step without further purification.

[318] Step 11. Preparation of compound tert-butyl 4-(4-( 1-(3-(4-(2-(4-methoxyphenyl)but-3-yn-2-yl)thiazol-2-yl)ureido)ethyl)phenyl)piperazine-l-carboxylate K2CO3 / MeOH 15°C,12 h mixtrue of compound obtained from step 10 above (100 mg, 168 pmol) , dimethyl (1-diazo-2-oxopropyl)phosphonate (49 mg, 252.6 nmol) and K2CO3 (47 mg, 337 pmol in MeOH (5 mL) was stirred for 1 h at 15°C. The reaction was directly concentrated in vacuum. The residue was purified by prep. HPLC (column: Venusil ASB Phenyl 150*30mm*5um;mobile phase: [water(0.05%HCl)-ACN];B%: 65%-95%,10min) to give the desired compound (50 mg, yield: 50.34%) was obtained as a yellow oil, 1319] MS (ESI) m / z (M H)590.3

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

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

[322] NMR (400 MHz, DMSO-t / 6) 8 10.50 (br s, 1 H), 9.22 (br s, 2 H), 7.31 (d, J = 8.8 Hz, 2 H), 7.19 (d, J 8.4 Hz, 3 H), 6.95 (d, J 8.4 Hz, 2 H), 6.85 (dd, . / 8.4. 1.2 Hz, 2 H), 6.81- 6.79 (m, 1 H), 4.76 - 4.73 (m, 1 H), 3.71 (s, 3 H), 3.39 (s, 1 H), 3.35 - 3.32(m, 4 H) 3.24 - 3.16 (m, 4 H), 1.82 (d, . / 2.4 Hz, 3 H), 1.33 (d, . / 6.8 Hz, 3 H).

[323] MS (HSI) w / c (M Na)' 512.3 Example 18: Preparation of l-(4-(2-(4-cyclopropylpheiiyl)propan-2-vl)thiazoI-2-yl)-3-(4-(piperazm-l-yl)benzyl)iirea

[324] Step 1: Preparation of tert-butyl 4-(4-((3-(4-(2-(4-cyclopropylphenyl)propan- 2-yl)thiazoI-2-yl)ureido)methyl)phenyl)piperazine-l -carboxylate

[325] To a solution of compound obtained from step 1 above (81 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was added cyclopropylboronic acid (14 mg, 0.16 mmol), Pd(dppf)C12 (10 mg, 0.013 mmol), KOAc (25 mg, 0.26 mmol). The reaction mixture was stirred at 115 °C overnight under N2 atmosphere. The reaction progress was monitored by TLC. After the completion of the reaction, the mixture was filtered through a pad of celite, washed with EA .The filtrate was removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE / EA = 2:1) to give the desired compound (45 mg, yield: 60.2%) as a white solid. 1326]         Step 2.Preparation of compound l-(4-(2-(4-cyclopropylphenyl)propan-2- yl)thiazol-2-yl)-3-(4-(piperazin-1 -yl)benzyl)urea

[327] The desired compound was obtained as a white solid (40 mg, HC1 salt, yield: 100%) with the procedure described in example 9. MS (ESI) m / z (M+H)1' = 476.2. Example 19: l-(4-(2-(4-chIorophenyl)but-3-yn~2-yI)thiazoI-2-yl)-3-(2~hydroxyethyl-2,2- d2)urea

[328] Step 1. Preparation of compound tert-butyl A%2,2-dklcutcrio-2-hydroxy- ethyl)carbamate D O^UUD   LiA!D4, THF   HO-J / w.. W NHBoc --------] NHBOC

[329] 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 then the mixture was stirred at 80 °C for 3 h. EA (20 ml) was added dropwise and the H2O (5 mL), and then extracted with EA (100 mL * 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The desired compound (610 mg, yield: 70.7%) was obtained as yellow oil, which was used into the next step without further purification,

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

[331] Step 2. Preparation of compound 2-amino-l,l-dideuterio-ethanol HoJ?^        HCI / MeOH HO P . % NHBoc ------■'K'NHs D                         D

[332] A mixture of compound obtained from step 1 above (610 mg, 3.74 mmol) in HCI / MeOH (4 M, 5 mL) was stirred at 25 °C for 3 h. The reaction mixture was concentrated. The desired compound (520 mg, crude, HC1) was obtained as yellow oil, which was used into the next step without further purification.

[333] NMR (400MHz, DMSO-J6) 5 2.80 (q, J - 5.7 Hz, 2H).

[334] Step 3. Preparation of compound phenyl Af-[4-[l-(4-chlorophenyl)-l-methyl- prop-2-ynyl]thiazol-2-yl]carbamate

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

[336] MS (ESI) m / z ! M 11) 383.0

[337] Step 4, Preparation of compound l-[4-[l-(4-chlorophenyl)-l-methyl-prop-2- ynyl]thiazol-2-yl]-3-(2,2-dideuterio-2-hydroxy-ethyl)urea

[338] A mixture of compound obtained from step 3 above (400 mg, 1.04 mmol), compound obtained from step 2 above (98,9 mg, 1.57 mmol) and DMAP (12.8 mg, 104.48 umol) in DCE (20 mL) was stirred at 80 °C for 5 h. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Xtimate C18 150*40mm*5um; mobile phase: [water (HCl)-ACN]; B%: 28%-58%,10min). The desired compound (90 mg, yield: 24.5%) was obtained as a white solid.

[339] MS (ESI) m / z (M 11) 3 5 2.1.

[340] SFC: Column: ChiralPak IG-3 100><4.6mm I.D., 3um Mobile phase: A: CO2 B:Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.5min and hold 40% for 3 min, then 5% of B for 1.5 min Flow rate: 2.5mL / min Column temperature:40 C, (Pl: Rf = 4.159 min, P2: Rf 4,831 min).

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

[342] The compound obtained from step 4 above ((90 mg, 255.79 umol) was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,I0um); mobile phase: [0.1%NH3H2O ETOH];B%: 40%-40%,min). Chiral isomers 1 (26.85 mg, yield: 29.8%) was obtained as a white solid,

[343] fH NMR (400MHz, CDCI3) 5 7.34-7.28 (m, 2H), 7.22 - 7.19 (m, 2H), 6.69 (s, 1H), 3.23 (d, J % Hz, 2H), 2.48 (s, 1H), 1.84 (s, 3H). MS (ESI) m / z (M IL351.9. SFC Rf = 4.151 min.

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

[345] ]H NMR (400MHz, CDCI3) d 7.43 - 7.35 (m, 2H), 7.31 - 7.27 (m, 2H), 6.76 (s, 1H), 3.31 (d, J= 5.5 Hz, 2H), 2.55 (s, 1H), 1.92 (s, 3H). MS (ESI) m / z (M+H)+=351.9. SFC: Rf === 4.815 min. General Method A

[346] Carboxylic acids (1 equiv), EDCI (2-2.5 equiv), with or without HOBt (2 equiv) and DIEA (3 equiv) / pyridine / DMAP were dissolved in THF / DMF and stirred for 1530 min at RT. Amine (1 equiv) was then added in one portion and the reaction was stirred at RT to 70°C for 2-16 hours. Once the reaction was completed, the resulting suspension was diluted with organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by trituration / Prep -TLC / chromatography / Prep-HPLC to give the product. Example 20: Preparation of compound 4-((2-hydroxyethyI)amino)-N-(4-(2-(4- methoxyphenyI)propan-2-yl)thlazo]-2-vQbenzamide H

[347] To a solution of 4-((2-hydroxyethyl)amino)benzoic acid (200 mg, 1.10 mmol) and 4-[l-(4-methoxyphenyl)-l-methyl-ethyl]thiazol-2-amine (261.98 mg, 919.85 umol, HC1) in Py (8 ml) was added EDO (440.84 mg, 2.30 mmol). The mixture was stirred at 70 °C for 16 hr. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Agela ASB 150 x 25mm x Sum; mobile phase: [water (0.05% HC1)-ACN]; B%: 48%-78%, lOmin). The desired compound (52 mg, yield: 13.57%) was obtained as a pale yellow7 solid.

[348] NMR (400MHz, DMSO-^) 3 12.06 (br s, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.12 (d.. / 8.8 Hz, 2H), 6.86 (s, 1H), 6.82 (d. J 8.8 Hz, 2H), 6.62 (d, .J 8.8 Hz, 2H), 3.70 (s, 3H), 3.54 (t, . / = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H), 1.62 (s, 6H). MS (ESI) m / z fM If) 412.5. General Method B

[349] The acid chloride w7as obtained by using SOCI2 in appropriate solvent like DCM. To the acis chloride solution TEA or pyridine (3 equiv) a and mine (1 equiv) in DCM were added slowly at 0 °C under N2, and further stirred for 0.5-2 h at RT. Once the reaction was completed, it was quenched with H2O, extracted by EA and washed with brine then dried (Na2SO4), filtered and evaporated to dryness. The resulting residue was purified by trituration / Prep-TLC / chromatography / Prep-HPLC to give the product. Example 21

[350] To a solution of 4-(4-tert-butoxycarbonylpiperazin-l -yl)-2,6-difluoro-benzoic acid (150 mg, 438.16 umol) in DCM (6 mL) was added SOCI2 (31.8 uL, 438.16 umol). The mixture was stirred at 25 °C for 1 hr. The Py (176.74 uL, 2.19 mmol) was added and the reaction was stirred at 25 °C for 5 min , then 4-[l-(4-chlorophenyl)-l-methyl-prop-2-ynyl]thiazol-2-amine (115,07 mg, 437.94 umol) was added and the mixture was stirred at 25 °C for 16 hr. 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.

[351] MS (ESI) mh (M • Hi' === 587.1. Example 22:Preparation of compound N-(4-(2-(4-chIorophenyI)but-3-yn-2-yl)-lH-imidazoI-2-yl)-2,6-difluoro-4-(piperazin-l-yl)benzamide

[354] A mixture of pyrimidin-2-amine (1.0 g, 10.5 mmol) and methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxo-butanoate (3.36 g, 10.5 mmol) in EtOH (20 mL) was stirred at 80 °C for 16h. The reaction was concentrated under reduced pressure and diluted with CH2CI2 (40 mL) and sat. aq NaHCOs (20 mL), and the water phase was extracted with CH2CI2 (3 x 30 mL). The combined organic layers were washed with sat. aq NaHCCh (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / 0 to 0 / 1) to afford methyl 2-(4-chlorophenyl)-2-imidazo[l,2-a]pyrimidin-2-yl-propanoate (1.48 g, yield: 40.1%) as a white solid.

[355] MS (ESI) m / z (M ■ H)' 316.0.

[356] Step 2. Preparation of compound methyl 2-(2-amino-lH-imidazol-4-y 1)-2-(4H N N                    H2N_N X >        NH2NH2.H2O M /            —————————————————————\ dioxane H J                      A J O-. chlorophenyl)propanoate Cl

[357] To a solution of methyl 2-(4-chlorophenyl)-2-imidazo[1,2-a]pyrimidin-2-yl-propanoate (600 mg, 1.90 mmol) in dioxane (5 mL) was added NH2NH2TI2O (650 mg, 11.04 mmol, 85% purity). After addition, the reaction mixture was stirred at 80 °C for 16h. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiCh, DCM: MeOH = 100 / 1-10 / 1) to afford methyl 2~(2-amino-lH-imidazol-4-yl)-2-(4-chlorophenyl)propanoate (60 mg, yield: 33.9%) as white solid.

[358] MS (ESI) m / z (M • H)' 280.1.

[359] lH NMR (400MHz, CD3OD) J 7.29 (d, J= 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 3.72 (s, 3H), 1.79 (s, 3H).

[360] Step 3. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-l-methoxy-1 -oxopropan-2-yl)-1 H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1 - P61] SOCI2 (92 mg, 772 umol) was added to a solution of 4-(4-tert- butoxycarbonylpiperazin-l-yl)-2,6-difluoro-benzoic acid (220 mg, 644 umol) in DCM (10 mL), then DMF (13 mg, 172 umol) was added and the reaction mixture was stirred at 25 °C for 1 h, followed by Py (204 mg, 2.57 mmol) was added into the reaction mixture and stirred at 25 °C for 10 min, then methyl 2-(2-amino-lH-imidazol-4-yl)-2-(4-chlorophenyI)propanoate (120 mg, 429 umol) was added into the reaction mixture and stirred at 25 °C for 16 h. The reaction mixture was washed with sat. NaHCOj (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 2 / 1) to afford tert-butyl 4-[4-[[4-[ 1-(4-chlorophenyl)-2 -methoxy- l-methyl-2-oxo-ethyl]-lH-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (120 mg, yield: 38.9% yield, 84% purity) as colorless gum.

[362] MS (ESI) m / z (M ■ HV 604.1.

[363] Step 4. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-l-hydroxypropan-2-yl)-1 H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1 -

[364] To a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-methoxy-l-methyl-2-oxo- ethyl]-lH-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l -carboxylate (120 mg, 199 umol) in THF (8 mL) was added LiBH4 (4 M, 248 uL) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 16h. The reaction mixture was poured into 5 mL of sat. NH4CI and extracted with EtOAc (8 mL x 2), the extracts was washed with water (8 mL x 3), brine (8 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-hydroxy-l-methyl-ethyl]-lH-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l -carboxylate (110 mg, crude) as light brown gum which was used in next step without any purification.

[365] MS (ESI) m / z {MH) 576.1.

[366] Step 5, Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-l-oxopropan-2-yl)-1 H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1 -carboxylate

[367] To a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-hydroxy-l-methyl-ethyl]- lH-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (170 mg, 295 umol) in DCM (10 mL) was added DMP (500 mg, 1.18 mmol), after addition, the reaction mixture was stirred at 25 °C for 4h. The reaction mixture was diluted with DCM (10 mL), washed with sat, NaHCOs / sat. NaiSzOs (10 mL / 10 mL) for 3 times, then washed with brine (10 mL), dried overNa2SO4, filtered and concentrated in vacuum to afford tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-l-methyl-2-oxo-ethyl]-lH-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (150 mg, crude) as light brown gum which was used in next step without any purification.

[368] Step 6, Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)but-3-yn-2-yl)-1 H-imidazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1 -carboxylate K2CO3, MeOH

[369] To a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-l-methyl-2-oxo-ethyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazme-l-carboxylate (150 mg, 261 umol) and l-diazo-l-dimethoxyphosphoryl-propan-2-one (75.3 mg, 392 umol) in MeOH (8 mL) was added K2CO3 (72.2 mg, 522.63 umol). After addition, the reaction mixture was stirred 25 °C for 16h. The reaction mixture was concentrated in vacuum and the residue was diluted with 10 mL of water and extracted with EtOAc (10 mL x 2), the combined extracts was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA condition) to afford tert-butyl 4-[4-[[4-[l-(4- chlorophenyl)-l-methyl-prop-2-ynyl]-1H-imidazol-2-yl]carbamoyl]-3,5-difluoro- phenyl]piperazine-l-carboxylate (12 mg, yield: 8.1%) as off-white solid.

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

[371] To a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-l-methyl-prop-2-ynyl]-lH- imidazol-2-yl]carbamoyl]~3,5-difluoro~phenyl]piperazine-l -carboxylate  (12 mg, 21.05 umol) in MeOH (0.3 mL) was added HCl / dioxane (4 M, 900 uL). After addition, the reaction mixture was stirred at 25°C for Ih. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (TFA condition) to afford N-[4-[l-(4-chlorophenyl)-l-methyl-prop~2-ynyl]-lH-imidazoI-2-yI]-2,6-difluoro-4-piperazin-l-yl-benzamide (5 mg, yield; 40.2% yield, 2HC1 salt) as light brown solid.

[372] MS (ESI) m / z {M Na)' 492.3.

[373] NMR (400MHz, CD3OD) J 7.52 (br d, J = 8.4 Hz, 2H), 7.40 (br d, J = 8.4 Hz, 2H), 7.22 (s, IH), 6.76 (br d, J= 12.4 Hz, 2H), 3.65 - 3.59 (m, 4H), 3.39 - 3.32 (m, 4H), 3.20 (s, IH), 1.97 (s, 3H). Example 23: Preparation of N-(4-(2-(4-chlorophenyl)but-3-vn-2-vI)oxazoI-2-vl)-2,6-difluoro-4-(piperazin"l-yI)benzamide

[375] To a solution of methyl 4-bromo-2-(4-chlorophenyl)-2-methyl-3-oxobutanoate (1.00 g, 3.13 mmol) in EtOH (30 mL) was added urea (282 mg, 4.69 mmol) and the mixture was stirred at 80 °C for 20 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiOv Petroleum ether / Ethyl acetate=l / 0 to 3 / 1) to afford methyl 2-(2-aminooxazol-4-yl)-2-(4-chlorophenyl)propanoate (50.0 mg, yield; 4.2%) as a yellow solid.

[376] MS (ESI) m / z (M 11) 281.1.

[377] %NMR (400MHz, CD3OD) d 7.31 (s, 4H), 6.98 (s, IH), 3.71 (s, 3H), 1.85 - 1.79 (m, 3H).

[378] Step 2. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-l-methoxy- l-oxopropan-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-l-carboxylate

[379] SOCI2 (38.0 mg, 321 umol) was added to a solution of 4-(4-tert-butoxycarbonylpiperazin-l-yl)-2,6-difluoro-benzoic acid (91.0 mg, 267 umol) in DCM (5 mL). DMF (5.0 mg, 71.3 umol) was added and the reaction mixture was stirred at 25 °C for 1 h. Then Py (85.0 mg, 1.07 mmol) was added to the above reaction mixture and stirred at 25 °C for 10 min, then methyl 2-(2-aminooxazol-4-yl)-2-(4-chlorophenyl)propanoate (50,0 mg, 178 umol) was added into the reaction mixture and stirred at 25 °C for 16 h. The reaction mixture was washed with sat.NaHCOs (3 mL), brine (3 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 2 / 1) to afford tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-methoxy-l-methyl-2-oxo-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (42.0 mg, yield: 30%) as colorless gum,

[380] MS (ESI) m / z (M ■ H)' 605.1.

[381] Step 3. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-l-hydroxypropan-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-l-carboxylate

[382] To a solution of LiBH4 (4 M, 83 uL) in THF (3 mL) was added a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-methoxy-l-methyl-2-oxo-ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (40.0 mg) in THF (2 mL) at 0 °C under N2 atmosphere. After addition, the reaction mixture was stirred at 25 °C for 2h. The reaction mixture was poured into 5 mL of sat, NH4CI and extracted with EtOAc (8 ml x 2), the extracts was washed with water (8 mL x 3), brine (8 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-hydroxy-l-methyl-ethyl]oxazol- 2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l~carboxylate (28.0 mg, crude) as white solid which was used in next step without any purification.

[383] Step 4. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)-l- oxopropan-2-yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine~l-carboxylate

[384] To a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-2-hydroxy-l -methyl- ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazme-l -carboxylate (28.0 mg, crude) in DCM (5 mL) was added DMP (41.0 mg, 97.05 umol), after addition, the reaction mixture was stirred at 25 °C for 3h. The reaction mixture was diluted with DCM (10 mL), washed with sat.NaHCCh / Na2S2O3 (10 mL / 10 mL) for 3 times, then brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-l-methyl-2-oxo~ethyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine~ 1-carboxylate (30.0 mg, crude) as light brown solid which was used in next step without any purification.

[385] MS (ESI) m / z (M 11} 5“5.1.

[386] Step 5. Preparation of compound tert-butyl 4-(4-((4-(2-(4-chlorophenyl)but-3-yn-2- yl)oxazol-2-yl)carbamoyl)-3,5-difluorophenyl)piperazine-1 -carboxylate K2CO3, MeOH

[387] To a solution of tert-butyl 4-[4-[[4-[l-(4-chlorophenyl)-l-methyl-2-oxo-ethyl]oxazol- 2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (30.0 mg, crude) and 1-diazo- l-dimethoxyphosphoryl-propan-2-one (15.0 mg, 78.3 umol) in McOH (4 mL) was added K2CO3 (14,0 mg, 104 umol). After addition, the reaction mixture was stirred 25 °C for 16h. The reaction mixture was concentrated in vacuum, the residue was diluted with H2O (5 mL), extracted with EtOAc (5 mL x 3), the combined extracts was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 4-(4-((4-(1-(4-chlorophenyl)-! -methyl -prop-2-ynyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-1-carboxylate (28.0 mg, crude) as light brown gum. [388 j MS (ESI) m / z (M ■ H}' 5 71.1.

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

[390] To a solution of tert-butyl 4-(4-((4-(l-(4-chlorophenyl)-l-methyl-prop-2-ynyl]oxazol-2-yl]carbamoyl]-3,5-difluoro-phenyl]piperazine-l-carboxylate (25,0 mg, crude) in DCM (2 mL) was added TFA (2 mL). After addition, the reaction mixture was stirred at 25 °C for Ih. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA condition) to afford N-[4-[ 1 -(4-chlorophenyl)-1 -methyl-prop-2-ynyl]oxazoL2-yl]-2,6-difluoro-4-piperazin-l-yl-benzamide (7.5 mg, yield: 28.7%, TFA salt) as light brown solid. [391 [ MS (ESI) m / z (M I h 471.3.

[392] TINMR (400MHz, CD3OD) 6 7.64 (s, IH), 7.58 (br d, J = 8.0 Hz, 2H), 7.39 - 7.29 (m, 2H), 6.72 (br d, J= 11.8 Hz, 2H), 3.65 - 3.54 (m, 4H), 3.42 - 3.35 (m, 4H), 2.98 (s, IH), 1.90 (s, 3H). General Method C

[393] Carboxylic acids (1 equiv), HATU (1.2 equiv) or HBTU or PyBOP, and TEA or DIEA (3 equiv.) were dissolved in appropriate organic solvent, like THF or DMF and stirred for 15-30 min at RT. Amine (1-1.5 equiv.) was then added in one portion and the reaction was stirred at RT-100°C for 4-16 hours. Once the reaction was completed, the resulting suspension was diluted with organic solvent and washed with brine and then dried. After filtration and evaporation, the resulting residue was purified by trituration / Prep-TLC / chromatography / Prep-HPLC to give the product. Example 24:Preparation of compound methyl N-(4-(2-(4-bromophenyl)but-3-yn-2- yI)thiazoI-2-vI)-3-((tert-buU7Mipheny]silvI)oxy)£vcIobutane-l-carboxamide

[394] 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 stirred 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) was 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), dired over anhydrous Na2SO4, filtered and concentrated in vacuum. 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 yellow oil. MS (ESI) m / z (M • H) 643 J 00

[395] Table 5. The following examples were synthesized analogous to the procedure of example 20, 21 and 24 using the appropriate intermediates and the corresponding fragment Com. ID Structure Name HNMR LCMS (iV- Hf Kinase assay IC50 nM NFkB assay IC50 nM B001 O' o 7 J H methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(piperazin-l -yl)benzamide 1H NMR (400 MHz. CD3OD) d 8.75 -8.74 (m, 1 H), 8.43 - 8.40 (m, 1 H), 7.44.7.42 (m, 2 H), 7.33 -7.31 (m, 1 H), 7.22 ■■ 7.20 (m, 2 H), 6.98 (s, 1 H), 4.08 - 4.06 (m, 4 H), 3.44 -3.42 (m, 4 H), 1.72 (s, 6 H). 437.0 123 0.75 B002 rr H o n-n A A J S 1 H N-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-l H-indole-5-carboxamide 1H NMR (400 MHz, CDCh) <5 8.42 (s, UH. 8.25 (s, 1H), 7.75 (dd, J = 8.6, 1.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.31 -- 7.27 (m, 1H), 7.15--7.11 (m, 2H), 6.68 (s, 1H), 6.65 (s, UH. 1.67 (d, J - 6.9 Hz, 6H). 442.0 206 2.33 B003 0 T-O"* s n i H \.(4.(2..(4-bromophenyl)propan-2.-yl)thiazol-2-yl) terephth al amide 444.0 192 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 Uh B004 0 H N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-3-(piperazin-l-yl)benzamide 437.0 211 2.84 B005 pW Pn^ HN,P N-(4-(2-(4-methoxyphenyi)propan-2-yl)thiazol-2 -yl)-3 ■ (piper azin-1 ■ ylmethyl)benzamide 451.0 215 1.61 B006 4-O0-o rt f N 4-(4-(2-hydroxyethyl)piperazin-1 -yl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazoi-2-yl)benzamide 481 595 2.71 B007 ■Upp-OM® / ’Vj' o n-4, X f! / pspN^S 0 OH 3-(4-(2-hydroxyethyl)piperazin-1 -yi)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide 481.0 230 1.17 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 B008 1 / ^X rv / C! 0 nA A A ) Aj « s p N hnA 2-chloro-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(piperazin-1 -yl)benzamide 471.0 37 0.37 B009 A-^Y OMe 0 N-Z — J / 1 b s ho-AA'A^' " 4-(3 -hydroxypyrroli din-1 -yl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide 438.0 951 0.78 BO 10 nA-N'^A J J H —N \ 6-(3- (dimethyl amino )pyrro lidin-1 -yl)-N-(4-(2-(4-meth oxyphenyl)propan-2 -yl)thiazol-2-yl)nicotinamide 466.0 187 0.84 B011 1 / =, UN—? ||      X <\ / M w \—™r    Q N-(4-(2-(4-meth oxyphenyl)propan-2 -yl)thiazol-2-yl)-3-(4-(piperazin-1-yl)butoxy)benzamide 509.0 230 1.64 B012 Q o nA x     If 7 V’^v Y^n'A^ h N-(4-(2-(4-meth oxyphenyl)propan-2 -yl)thiazol-2-yl)-4-(3-methylpiperazin -1 -yl)benzamide 451.0 118 0.76 WO 2022 / 063152                                                 PCT / CN2021 / 119801 BO 13 /          l 11 ri ft Y^'Y ——OMe 2-fluoro-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(piperazin-l-ylmethyl) benzamide 469.0 111 1.02 BO 14 riX'" jri tert-butyl 4-(4-((4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl) carbamoyl)phenyl) -3 ■■ methylpiperazine-1 -carboxylate 451.0 300 1.17 BO 15 Pf HNX 0 nX AX N ri y-OMe N-(4-(2-(4- methoxyphenyl)propan-2-yl)thiazol-2-yl)-2-(piperazin-l-yl)pyrimidine-5-carboxamide 439.1 161 4.67 B016 o O N- / A > ft 7 pi 's XX H “X2XBr 5.-(4-(2-(4-bromophenyl)propan-2.-yl)thiazol-2-yl)-4-(piperazin-l -yl)benzamide 485.1 60 BO 17 nX i i P N— / xriw uxy-oMe N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-((4-methylpiperazin-1 -yl)methyl)benzamide 465.1 148 3.76 WO 2022 / 063152                                                 PCT / CN2021 / 119801 3 r- oo r-' 00 oc 08 o en oo 495.1 496.1 440.1 3-((4-(2-hydroxyethyl)piperazin-1 ■ yl)methyl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2 -yl)benzami de N-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-4-( 1 -(piperazin-1-yl)ethyl)benzamide 4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)-N-(4-(2-(4-methoxyphenyl)propan-2 -yl)thiazol-2-yl)benzamide 4-(2-(dimethylamino)ethoxy)-'   M-(4-(2-(4-"      * methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide to OS A ? b 9  N~<(   — HN" X        JI JI > H s "'‘a zx 0.-= / Q cf d T Fl HN-< J ,^\  > S' J i)—1 0 r1 — N \ BO 18 BO 19 B020 B021 00 MO B022 HN p'       o h\ y*7 N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(3-(piperazin-1-yl)propoxy)benzamide 495.0 294 0.55 B023 HN— CM 8 N-(4-(2-(4-methoxyphenyl)propan-2-yl) thiazol-2 -yl)-3-(3-(piperazin-1 -yl)propoxy)benzamide 495.0 150 6.15 B024 4 H »     '1 d-OMs HN—X > UQA N-(4-(2-(4-methoxyphenyl)propan-2 -yl)thiazol-2-yl)-4-(2-(piperazin-1 ■■ yl)ethoxy)benzamide 481.1 116 4.29 B025 0 N^XJ~0Me AvA A > s JI T H ® N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-5-(piperazin-l-yl)pyrazine-2-carb oxami de 439.1 298 3.59 B026 HN’A / —4 / / —OMe o N_v JI z H S V(4.(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-((2-methylpiperazin-1 -yl)methyl)benzamide 465.0 127 0.61 WO 2022 / 063152                                                 PCT / CN2021 / 119801 B027 A / Il s's / -“N \ —OMe 4-(3-(dimethylamino)pyrrolidm-1 -yl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide 465.0 219 3.38 B028 ( ) IZ O )==0 —OMe N-(4-(2-(4-methoxyphenyi)propan-2-yl)thiazol-2-yl)-4-(( 1 -methylpiperidin-4-yl)amino)benzamide 465.0 271 2.36 B029 N ,, " HhlA J \ V_ / '“'0Me 4-(2-(dimethylamino)ethoxy)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide 440.0 83 1.48 B030 N-v n / =<, N~< 'ij X_ / ^o -NvjHN      ° tX I N 1-(4-(2-(4-methoxyphenyl)propan-2-yl)lhiazol-2-yl)-N4-(l -methyip iper i din-4 -yl)terephthalamide 493.0 155 1.98 B031 I J > j Wv r v_ / 4 -(piperazin-1 -yl)-N-(4-(2 -(p-tolyl)propan-2-yl)thiazol-2-yl)benzamide 421.0 37 0.51 B032 -•^.J___ O  N—X J > HO       F J (f S H ^-OMe 4-(( 2 -hydroxyethyl)amino)-N ■■ (4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2 -yl)benzami de 412.0 280 3.81 WO 2022 / 063152                                                 PCT / CN2021 / 119801 B033 H 1 x> J H 4-((2-aminoethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide 411.0 247 6.45 B034 H0— kzV Q y~c '' Ai M l o 4-((4-(2-hydroxyethyl)piperazin-1 -yl)methyi)-N-(4-(2-(4-methoxyphenyi)propan-2-yl)thiazol-2-yl)benzamide 495.0 44 0.95 B035 JI HN^ y-Or O N-i 1 A? -^N S H N-(4-(2-(4-bromophenyl)propan-2-yl)lhiazol-2-yl)-6-(piperazin-l-yl)nicotinamide lH NMR (400 MHz, DMSO-^) 6 12.29 (br s, 1 H), 9.42 (br s, 2 H), 8.02 -8.00 (m, 2 H), 7.13-7.11 (m, 1 H), 7.05 - 7.03 (m, 2 H), 6.90 (s, 1 H), 6.83 -6.80 (m, 2 H), 3.69 (s, 3 H), 3.58 - 3.56 (m, 4 H), 3.17 ■ 3.16 (m, 4 H), 1.63 (s, 6 in. 486.2 75 2.76 B036 HN.^ y-O'8' 0 N-ix \.(4.(2-(4- bromophenyl)propan-2.-yl)thiazol-2-yl)-2-(piperazin-l -yl)pyrimidine-5-carboxamide H NMR (400MHz, DMSO-t / 6H 12.51 (brs, 1H), 9.28 (br s, 2H), 9.00 (s, 2H), 7.49 - 7.41 (m, 2H), 7.19 - 7.12 (m, 2H), 7.04 (s, 1H), 4.13 - 3.99 (m, 4H), 3.21 - 3.15 (m, 4H), 1.64 (s, 6H). 487.1 110 4.79 B037 Jjl 4-O"Br I H " hl H 1-(4-(2-(4-bromophenyl)propan-2-yi)thiazol-2-yl)-3 -(3,5-difluoro-4-(piperazin-l -yl)benzyl)urea 11 NMR (400MHz, CD3OD) ¢5 7.54 - 7.46 (m, 2H), 7.21 (d, J === 8.8 Hz, 2H), 7.12 (s, 1H), 6.97 (d, J= 9.8 Hz, 2H), 4.39 (s, [M+Na]' '==574.1 23 1.68 WO 2022 / 063152                                                 PCT / CN2021 / 119801 SO to 2H), 3.43 - 3.37 (m, 4H), 3.36 - 3.32 (m, 4H), 1.71 (s, 6H). B038 o 2=0 xz 3-fluoro-N-(5-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(piperazin-l-yl)benzamide lH NMR (400 MHz, CD30D) 3 7.86 (br d, J 8.56 Hz, 1 H), 7.78 (dd, J 13.57. 1.83 Hz, 1 H), 7.25 ■■ 7.17 (m, 3 H), 7.07 (s, 1 H), 6.87 (d, J 8.80 Hz, 2 H), 3.76 (s, 3 II), 3.49 (br d, J=5.14 Hz, 4 H), 3.41 (br d, .1=5.14 Hz, 4 H), 1.73 (s, 6H). 455.2 216 4.65 B039 Ah 0 iT^i ti s A'P'^'A' ‘ : ! HNo> 3-methoxy-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(piperazin-l-yl)benzamide 11 NMR (400MHz, DMSO-J6) 3 7.65 (s, 2H), 7.12 (br d, J= 8.8 Hz, 2H), 6.93 - 6.87 (m, 2H), 6.82 (d.. / 8.8 Hz. 2i!;. 3.85 1s. 3H), 3.70 (s, 3H), 2.98 (br s, 4H), 2.82 (br s, 4H), 1.63 (s, 6H). 467.1 123 2.97 B040 0  N-< A? Af N S A J H ,N.. Q H N-(4-(2-(4-methoxyphenyl)propan-2-yI)thiazol-2-yl)-4-(piperazin-l-ylmetbyl)benzamide Hl NMR (400MHz, DMSO-Je) 6 12.67 (br s, 1H), 9.61 (brs, 1H), 8.59 (br d, J= 7.9 Hz, 1H), 8.13 (d, J= 8.2 Hz, 2H), 7.78 (br d, , / = 8.2 Hz, 2H), 7.13 (d, J= 8.6 Hz, 2H), 6.98 (s, 1H), 6.82 (d, J = 8.6 Hz, 2H), 4.59 - 4.34 (m, 2H), 3.95 (br s, 8H), 3.70 (s, 451.2 93 0.71 WO 2022 / 063152                                                 PCT / CN2021 / 119801 3H), 3.49 - 3.43 (m, 2H), 1.64 (s, 6H) B041 HN-< $ S \ r=\_Z s h2n 4-(3 -aminopyrrolidin-1 -yl)-N-(4-(2-(4-methoxyphenyi)propan-2-yl)thiazol-2-yl)benzamide H NMR (400MHz, DMSO-J6)£> 11.79 (brs, III), 8.26 (brs, 3H), 8.01 (d, .i 9.0 Hz, 211),7.20 -7.13 (m, 2H),6.85-6.80 (m, 2H), 6.79 (s, 1H), 6.62 (d, J =8.8 Hz, 2H), 4.05 -3.90 (m, 1H), 3.73 (s, 3H), 3.62 - 3.54 (m, 2H), 3.48 ■■ 3.38 (m, 2H), 2.42 - 2.35 (m, 1H), 2.20 - 2.13 (m, 1H), 1.66 (s, 6H). 437.1 80 3.96 B042 z 0 / ^O XZ 'o ox N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-6-(piperazin-l-yl)ni cotinamide 1H NMR (400 MHz, CD3OD) 6 8.78 (d, .1=1.71 Hz, 1 H), 8.43 (br d, 1=7.82 Hz, 1 H), 7.34 (br d, J 9.29 Hz, 1 H), 7.22 (d, 1=8.80 Hz, 2 H), 7.06 (s, 1 II), 6.87 (d, .1=8.80 Hz, 2 H), 4.09 (br s, 4 H), 3.76 (s, 3 H), 3.43 (brs, 4 H), 1.73 (s, 6 H). 438.2 86 0.663 B043 ya 0 N-X N^A zx A f H S 6-(3 -aminopyrrolidin-1 -yl)-N - (4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yi)nicotinamide H NMR (400MHz, DMSO-^)<512.66 (brs, 1H), 8.75 (s, 1H), 8.63 (br s, 3H), 8.40(d,J = 10.3 Hz, HI), 7.16 - 7.06 (m, 3H), 6.96 (s, HI), 6.82 (d, J = 8.8 Hz, 2H), 4.08 - 3.98 (m, 1H), 3.92. - 3.80 (m, 438.1 140 1.49 WO 2022 / 063152                                                 PCT / CN2021 / 119801 3H), 3.70 (s, 4H), 2.41 -2.19 (ro, 2H), 1.63 (s, 6H) B044 । =< / >—<\ / )—o o ,N>', J 2 0        B s H N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-5-(piperazin-l-yl)picolinamide H NMR (400MHz, DMSO-^) <511.64 (brs, HI), 9.39 (br s, 2H), 8.44 -8.37 (m, 1H), 8.03 (d,. / 8.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.94 (s, 1H), 6.83 (d.. / 8.8 Hz. 2!!). 3.70 (s, 3H), 3.69 ■ 3.63 (m, 4H), 3.28 - 3.16 (m, 4H), 1.63 (s, 6H). 438.1 213 1.86 B045 0  N"4 1   11 7 N'<;V N^S 0     \ H HN^J 6-(piperazin-1 -yI)-N-(4-(2-(p-tolyl)propan-2-yl)thiazol-2-yl)nicotmamide H NMR (400 MHz, DMSO-4) 8 12.37 (br s, 1 H), 9.28 (br s, 2 H), 8.83 (d, 1=1.54 Hz, 1 H), 8.23 (br d, J=9.26 Hz, 1 H), 7.11 ■■ 7.04 (m, 4 H), 6.99 (d, .1=9.04 Hz, 1 H), 6.94 (s, 1 H), 3.89 (brs, 4 11),3.16 (br s, 4 H), 2.23 (s, 3 H), 1.63 (s, 6 H). 422.2 30 0.23 B046 A Ji \ If Y N^S H 1 / 4-((4-methylpiperazin-1 -yi)methylj-N-(4-(2-(p-tolyl)propan-2-yl)thiazoI-2-yl)benzamide 1H NMR (400 MHz, CD3OD) 8 8.12 (d, 1=8.07 Hz, 2 H), 7.83 (d, 1=8.31 Hz, 2 H), 7.20 - 7.16 (m, 2 H), 7.14 - 7.10 (m, 2 H), 7.08 (s, 1 H), 4.57 (s, 2 H), 3.64 (br s, 8 H), 3.01 (s, 3 H), 2.29 (s. 3 H), 1.73 (s, 6 H). 449.3 28 0.21 WO 2022 / 063152                                                 PCT / CN2021 / 119801 Uh B047 HN^ o yV h y N °z N—4   ' A > S N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)-4-(piperidin-4-yl)benzamide hydrochloride lH NMR (400 MHz, CD30D) (5 8.08 - 7.96 (ro, 2 H), 7.48 (br d, 1=6.61 Hz, 2 H), 7.26 - 7.16 (m, 2 H), 7.13 - 7.03 (m, 1 H), 6.86 (br d, >6.84 Hz, 2 H), 3.75 (s, 3 H), 3.56 - 3.45 (m, 2 H), 3.23 - 3.09 (m, 2 H), 3.03 (brt, J 12 J 3 Hz, 1 H), 2.15 - 2.03 (m, 2 H), 1.94 (q, >13.38 Hz, 2 H), 1.72 (s, 6 H). 436.2 128 0.54 B048 HNX o |<Y< JI J H 4-(3,6-diazabicyclo[3.1.1 ]heptan-3-yl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide H NMR (400MHz, DMSO-4) ci‘12.18 (brs, HI), 9.99 (br s, 1H), 8.39 (br s, III), 8.04 (d, J == 8.8 Hz, 2H), 7.15 - 7.07 (m, 2H), 6.87 (s, 1H), 6.80 (dd, J == 1.9, 8.9 Hz, 4H), 4.46 (br s, 2H), 3.89 ■■ 3.72 (m, 4H), 3.68 (s, 3H), 2.95 -2.82 (m, HI), 1.83 (brdd, J = 5.8, 10.0 Hz, HI), 1.61 (s, 6H) 450.0 73 0.77 B049 HNn 0 11 oh / ! \ N' H A > s 4-(4-hydroxypiperidin-4-yl)- N-(4-(2-(4-methoxyphenyDpropan-2 -yl)thiazol-2-yi)benzamide hydrochloride 1H NMR (400 MHz, CD3OD) 3 8.06 (br d, 1=8.38 Hz, 2 H), 7.73 (d, >8.60 Hz, 2 H), 7.23 (d, >8.82 Hz, 2 H), 7.15 ■■ 7.05 (m, 1 H), 6.88 (d, 1=8.82 Hz, 2 H), 3.76 (s, 3 H), 3.51 - 3.42 (m, 2 H). 452.2 459 0.37 WO 2022 / 063152                                                 PCT / CN2021 / 119801 O> 3.40 - 3.33 (m, 2 H), 2.36 -2.23 (ro, 2 H), 1,93 (br d, >13.89 Hz, 2 H), 1.74 (s, 6H). B050 I ==.    z / — / / ° H fX)H 1 2 ■ hydroxy ■ 3,5 ■ diiodo-N -(4 -(2 ■ (4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide H NMR (400 MHz, CDCI3) 3 8.28 (br s, 1 H) 8.13 - 8.18 (m, 1 H) 7.21 (d, 1===8.80 Hz, 2 H) 6.90 (d, >8.80 Hz, 2 H) 6.66 (s, 1 H) 3.82 (s, 3 H) 1.74 (s. 6 H) 620.9 77 0.71 B051 0  N"& »vw uJu " N-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-6-((4-(2-hydroxy ethyl )piperazin-1 -yl)methyl)nicotinamide Tl NMR (400 MHz, CD3OD) 3 9.05 (d, >1.76 Hz, 1 H), 9.08 - 9.00 (m, 1 H), 8.33 (dd, >8.16, 2.43 Hz, 1 H), 7.65 (d, >8.16 Hz, 1 H), 7.39 (d, 1=8.82 Hz, 2 H), 7.19 (d, >8.60 Hz, 2 H), 6.88 (s, 1 H), 3.73 (s, 2 H), 3.67 (t, >6.06 Hz, 2 H), 2.49 -2.67 (m, 10 H), 1.69 (s, 6 H). 546.2 61 0.54 B052 i r\^ 0 N-i H0^>> H 6-((4-(2-hydroxyethyl)piperazin-1 -yl)methyl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yi)nicotinamide H NMR (400MHz, CDCh) 3 11.35 (br s, 1H), 8.69 ■ 8.56 (m, 1H), 8.16 (d, . / 8.1 Hz, 111),7.72-7.62 (m, 1H), 7.30 - 7.25 (m, 2H), 7.23 - 7.18 (m, 2H), 6.88 (d, J =8.8 Hz, 2H), 6.61 (s, 1H), 3.79 (s, 3H), 1.80 (s, 6H). 496.2 in 1.73 WO 2022 / 063152                                                 PCT / CN2021 / 119801 BO53 p T J HO 4OV Jo N S H 6-(4-(2-hydroxyethyl)piperazin-1 -yl)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)nicotinamide lH NMR (400 MHz, CD3OD) 3 8.71 (d, .1 2.45 Hz, 1 H), 8.04 (dd, J=9.17, 2.57 Hz, 1 H), 7.17 (d, J8.S0 Hz, 2 H), 6.85 -6.78 (m, 3 H), 6.74 (s, 1 H), 3.74 (s, 3 H), 3.73 -3.69 (m, 6 H), 2.63 - 2.59 (m, 4 H), 2.57 (t, J=5.87 Hz, 2 H), 1.67 (s, 6 H). 482.2 104 1.97 B054 Q Q ( o >L / ~V-Br 'N S H N-(4-(2-(4-bromophenyl)propan-2-yl)thiazol-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1 -yl)nicotinamide n NMR (400MHz, DMSO-H) 3 12.31 - 12.23 (m, 1H), 8.79 (br s, 1H), 8.21 - 8.05 (m, 2H), 7.45 (br d, .7===8.4 Hz, 2H), 7.16 (br d, >7.9 Hz, 2H), 6.98 (br s. 1H), 6.89 - 6.83 (m, 1H), 4.54 - 4.38 (m, 2H), 3.62 (br s, 5H), 3.57 - 3.47 (m, 3H), 2.44 ■■ 2.39 (m, 2H), 1.63 (br s, 6H) 532.1 269 1.02 B055 o H 70 N-(4-(2-(4-bromophenyl)propan-2 -yl)thiazol-2-yl)-6-((2-(dimethylamino)ethyl)amino)n icotinamide H NMR (400MHz, DMSO-4) 3 12.66 (br s, HI), 8.75 (s, 1H), 8.63 (br s, 3i!;. 8.40(d.J 10.3 Hz, HI), 7.16 - 7.06 (m, 3H), 6.96 (s, 1H), 6.82 (d, J === 8.8 Hz, 2H), 4.08 ■ 3.98 (m, 1H), 3.92 ■ 3.80 (m, 3H), 3.70 (s, 4H), 2.41 -2.19 (m, 2H), 1.63 (s, 6H) 490.2 125 3.06 WO 2022 / 063152                                                 PCT / CN2021 / 119801 00 B056 H 6-((2-(dimethylamino)ethyl)amino)-N-(4-(2-(4-methoxyphenyi)propan-2-yl)thiazol-2-yl)nicotinamide Hl NMR (400MHz, UM'hN 11.35 (brs, 1H), 8.69 - 8.56 (m, 1H), 8.16 (d,J=8.1 Hz, 1H), 7.72-7.62 (m, 1H), 7.30 ■■ 7.25 (m, 2H), 7.23 -7.18 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.61 (s, 1H), 3.79 (s, 3H), 1.80 (s, 6H) 440.2 120 0.70 B057 5-0'°” 0 H       li \\ HN.^ 3-(2-methoxyethoxy)-N-(4-(2-(4-methoxyphenyl)propar!-2-yi)thiazol-2-yl)-4-(piperazin-l-yl)benzamide hydrochloride 1H NMR (400 MHz, DMSO-a6)<5 12.43 (brs, 1 H), 9.42 (br s, 2 H), 7.79 -7.52 (m, 2 H), 7.12 (brd, 1==8.56 Hz, 2 H), 7.00 (br d, 1==8.31 Hz, 1 H), 6.92 (s, 1 H), 6.82 (br d, J 8.56 Hz, 2 H), 4.20 (br s, 1 H), 3.74 - 3.68 (m, 5 H), 3.33 (s, 7 H), 3.19 (br s, 4 H), 1.63 (s, 6 H). 511.2 103 0.91 B058 O J J H S f rb HO 4-((4-(2-hydroxyethyl)piperazin-1 -yl)methyl)-N-(4-(2-(p-tolyl)propan-2-yl)lhiazol-2-yl)benzamide H NMR (400MHz, DMSO-Js) <5 8.14- 8.12 (m, 2H), 7.85 - 7.83 (m, 2H), 7.20 -7.18 (m, 2H), 7.14 -7.12 (m, 2H), 7.08 (s, 1H), 4.59 (s, 2H), 3.85 - 3.55 (m, 8H), 3.50 - 3.43 (m, 2H), 2.30 (s, 3H), 1.74 (s, 6H). 479.6 68 0.61 WO 2022 / 063152                                                 PCT / CN2021 / 119801 v© V© B059 O-\  ,—K \— / W / =o iz $ 6-((4-(2-hydroxyethyl)piperazin-1 -yl)methyi)-N-(4-(2-(p-tolyl)propan-2-yl)thiazol-2-yl)nicotinamide Hl NMR (400MHz, CDCh) ¢5 9.09 - 9.05 (m, 1H), 8.33 - 8.28 (m, 1H), 7.75 (br d, J = 8.8 Hz, 3H), 7.45 ■■ 7.41 (m, 1H), 7.13 -7.08 (m, 3H), 7.06 - 7.02 (m, 1H), 6.61 - 6.57 (m, 1H), 3.83 - 3.77 (m, 3H), 3.64 - 3.55 (m, 1H), 2.45 -2.38 (m, 8H), 2.26 - 2.18 (m, 1H), 1.63 ■ 1.58 (m, 3H), 1.19(8, 6H). 480.3 159 1.18 B060 4-Oo / 9 / A ^v^n^'-s7 ho.^nA^ H H 4-((2-hydroxyethyl)amino)-N-(4-(2-(4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide H NMR (400MHz, DMSO-^) S 12.06 (br s, HI), 7.87 (d, J - 8.8 Hz, 2H), 7.:2(6. J 8.8 Hz. 2H), 6.86(s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 3.70 (s, 3H), 3.54 (t, J === 5.9 Hz, 2H), 3.16 (t, J === 5.9 Hz, 2H), 1.62 (s, 6H) 412.2 280 1.23 B061 o 1 zz °x Q 0 N-(4-(2-(4-chlorophenyl)but ■ 3-yn-2-yl)thiazol-2-yl)-6-(piperazin-1 -yl)nicotinamide lH NMR (400 MHz, DMSO-J6)<512.56 (brs, 1 H), 9.61 (br s, 2 H), 8.83 (d, J = 2.8 Hz, 1 H), 8.28 (dd, J = 9.2, 2.4 Hz, 1 H), 7.45 ■■ 7.38 (m, 4 H), 7.18 (s, 1 H), 7.09 (d, J === 8.8 Hz, 1 H), 3.99 - 3.93 (m, 4 H), 3.55 (s, 1 H), 3.18 (br s, 4 H), 1.91 (s, 3 H) 452.1 167 0.78 WO 2022 / 063152                                                 PCT / CN2021 / 119801 200 B062 1a_CI p n-TW rv-M s s N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-4-(piperazin-1 -yl)benzamide Hl NMR (400MHz, OMSCWa) ¢5 12.36 (s, 1H), 9.25 (br s, 2H), 8.01 (d, 1=8.9 Hz, 2H), 7.45 - 7.37 (m, 4H), 7.14 (s, 1H), 7.04 (d, 1==9.1 Hz, 2H), 3.58 ■■ 3.55 (ro, 4H), 3.18 (br s, 4H), 1.91 (s, 3IB 451.1 12 1.01 B063 nV? HO^oX? H 4-(2-hydroxypropoxy)-N-(4-(2 ■ (4-methoxyphenyl)propan-2-yl)thiazol-2-yl)benzamide 4-1 NMR (400MHz, DMSO-^,) d 12.36 (br s, 1H), 8.05 (d. J 9.0 Hz. 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.91 (s, 1H), 6.82 (d, J == 8.8 Hz, 2H), 3.99-3.93 (m, III), 3.88 (d, J == 4.0 Hz, 2H), 3.70 (s, 3H), 1.63 (s, 6H), 1.14 (d, J = 6.3 Hz, 3H) 427.1 245 2.10 B064 F. OCH3 r o A    y. / \ ci'-x^   <s    F N-(4-(2 -(4-chl orophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluoro-3-methoxybenzamide 54 3.37 B065 Y   %\ / -A V—d #-N NH J J ]| V-NH N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-2-fluoro-4-(piperazin-1 -yl)benzamide 469.1 215 2.46 WO 2022 / 063152                                                 PCT / CN2021 / 119801 B066 Y o, Gi            !--s             OCH3 N-(4-(2-(4-chlorophenyl)but-3 -yn-2 -yl)thiazol-2-yl)-3 -methoxy-4-(piperazin-1 ■■ yl)benzamide lH NMR (400 MHz, DMSO-Jt) ¢5 7.66 (1H, J=8.8 Hz, d), 7.41-7.35 (5H, m), 7.16 (1H, s), 6.91 (HL J 7.2 Hz. d;. 3.83 (3H, s), 3.51 (1H, s), 3.01 (4H, s), 2.87 (4H, S), 1.88(3H, s) 481.1 184 1.20 B067 N-(4-(2 -(4-chlorophenyi)but-3-yn-2-yi)thiazol-2-yl)-4-(piperazin-1 -yl)benzamide H NMR (400 MHz, DMSO-Je) 4' 12.36 (br s, 1 H), 9.31 (br s, 2 H), 8.02 (d, J = 8.78 Hz, 2 H), 7.35 - 7.47 (m, 4 H), 7.14 (s, 1 H), 7.04 (d, J 8.78 Hz, 2 II), 3.49 - 3.65 (m, 5 H), 3.19 (brd, . / =4.77 Hz, 4 H), 1.91 (s, 3 H). 451.0 90 1.43 B068 111 _ JU °* / =\ ^“x X 1>"N“ N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazoi-2-yl)-4-(piperazin-1 -yl)benzamide H NMR (400 MHz, DMSO-cfc) 3 12.36 (s, 1 H), 9.19 (br s,2H), 8.02 (d, J = 8.78 Hz, 2 H), 7.36 - 7.46 (m, 4 H), 7.15(s, 1 11), 7.04 (d, J - 8.78 Hz, 2 H), 3.53 - 3.60 (m, 5 H), 3.19 (br s, 4 H), 1.91 (s, 3 H). 451.0 530 4.16 B069 I O Q.....1 V_ / N-[4-[ 1 -(4-fluorophenyl) ■ 1 -methyl-prop -2-ynyl] thiazol ■ 2-yl]-4-[2-(bydroxymethyl)piperazin-1 -yl]benzamide H NMR (400MHz, C Hl14 ¢5 9.26 (br s, 1H), 7.78 (d, .7=8.9 Hz, 2H), 7.45 (dd, 7=5.2, 8.8 Hz, 2H), 6.99 (t, . / 8.7 Hz, 2H), 6.89 - 6.85 (m, 3H), 465.0 20 0.96 WO 2022 / 063152                                                 PCT / CN2021 / 119801 202 4.04 - 3.98 (m, III), 3.98 -3.89 (m, 2H), 3.66 - 3.54 (m, 1H), 3.53 - 3.46 (m, 1H), 3.43 (br d, 7=11.7 Hz, 1H), 3.20 (br d, J=11.3 Hz, 1H), 3.14 (br d, 7=11.9 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.96 (dt, 7=4.2, 11.7 Hz, 1H), 2.59 (s, 1H), 1.97 (s, 3H), 2.02 - 1.93 (m, 1H). B070 HO-         V H Q HN. J                   V N-[4-[l -(4-fluorophenyl)-l -methyl-prop -2 -ynyl]thiazol-2-yI]-4-[2-(hydroxymethyl)piperazin-1 -yl]benzamide n NMR (400MHz, CDCh) <5 9.23 (br s, 1H), 7.74 (d, 7=8.9 Hz, 2H), 7.43 ■■ 7.39 (m, 2H), 6.95 (t, 7=8.6 Hz, 2H), 6.86 -6.80 (m, 3H), 4.00 - 3.94 (m, 1H), 3.94 - 3.85 (m, 2H), 3.56 - 3.49 (m, 1H), 3.49 ■■ 3.42 (m, 1H), 3.39 (brd, 7=12.2 Hz, 111),3.16 (br d, 7=9.5 Hz, 1H), 3.09 (br d, 7 12.0 Hz, III), 2.91 (dt, 7=4.4, 11.7 Hz, 1H), 2.54 (s, 1H), 1.93 (s, 3H). 465.0 169 2.07 B071 o S'A -. HO       A>A h ' N N \__ A JU H O HN. J                 \ r N- [4-[ 1 -(4 - fluorophenyl) ■■ 1 methvl-prop-2-ynyl]thiazol-2-yl]-4-[2-(hydroxymethyl)piperazin-1 -yl]benzamide H NMR (400MHz, CDCh) d 9.62 (br s, 1H), 7.30 (br s, 2H), 7.07 (br s, 2H), 6.64 ■ 6.58 (m, 2H), 6.50 ■■ 6.34 (m, 1H), 6.50 ■ 6.31 (m, 3H), 4.62 (brs, 1H), 3.78 (br s, 1H), 3.64 (br s, 1H), 3.50 (br s, 1H), 465.0 60 1.30 WO 2022 / 063152                                                 PCT / CN2021 / 119801 203 3.36 (br s, 1H), 3.23 (br s, 3H), 3.00 - 2.56 (m, 2H), 2.27 (br s, 1H), 1.70 (br s, 3H). B072 o s-^. % HO^ / 'nJm H Q HN, J                 \ r N-[4-[ 1 -(4-fluorophenyl) ■ 1 methyl -prop -2 -ynyl] thiazol-2-yl]-4-[2- (bydroxymethyl)piperazin-1 -yl] benzamide H NMR (400MHz, CDCl?) d' 9.26 (br s, 1H), 7.76 (d, , / =8.9 Hz, 2H), 7.45 - 7.40 (m, 2H), 6.97 (t, . / 8,8 Hz, 2H), 6.90 ■ 6.82 (m, 3H), 4.02 ■ 3.96 (m, 1H), 3.96 - 3.85 (m, 2H), 3.57-3.51 (m, 1H), 3.44 - 3.43 (m, 1H), 3.50 -3.43 (m, 1H), 3.40 (br d, . / H.8 Hz. 1H), 3.17 (brd, . / 1 1.4 Hz, 111),3.10 (br d, . / 11.8 Hz. 1H), 2.93 (di, . / =4.3, 11.7 Hz, 1H), 2.56 (s, 1H), 1.95 (s, 3H! 465.0 260 4.13 B073 / —NH r,      O R N-7 Fx>\>W 2,6-difluoro-N-(4-(2-(4-fluorophenyi)but-3 -yn-2-yl)thiazol-2 -yl)-3 ■ (piper azin-1 -yl)benzamide di NMR (400 MHz, DMSO-J6)^ 13.06 (s, 1 H), 9.12 (br s, 2H), 7.49-7.43 (m, 2 H), 7.32 - 7.24 (m, 2 H), 7.16 (t, J= 8.8 Hz, 3 H), 3.55 (s, 1 H) 3.22, (brs, 8 H), 1.92 (s, 3 H) 471.1 851 2.39 WO 2022 / 063152                                                 PCT / CN2021 / 119801 204 B074 / —NH o hl            F.    N—7 i       0 JI J T >~NH <s F 2,6 ■ difluoro-N -(4 ■ (2-(4-fluorophenyl)but-3 -yn-2 -yl)lhiazol-2-yl)-3-(piperazin-l-yl)benzamide !H NMR (400 MHz, DMSO-O 4 13.07 (s, 1 H), 9.23 (br s, 2 H), 7.49 -7.42 (m, 2 H), 7.31 - 7.24 (m, 2 H), 7.14 (t, J === 8.8 Hz, 3 H), 3.55 (s, 1 H), 3.22 (s, 8 IB. 1.92 (s, 3 H) 471.1 96 0.36 B075 / —NH „        < J hl            F. N—7 cr\^ L. / N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluoro-3 -(piperazin-1 -yl)benzamide H NMR (400 MHz, DMSO-de) <5 13.05 (s, 1 H), 9.36 (br s, 2 H), 7.48-7.37 (m, 4 H), 7.31 - 7.23 (m, 2 H), 7.18 - 7.15 (t, J = 8.8 Hz, 3 H), 3.56 (s, 1 H), 3.22 (s, 8 H), 1.90 (s, 3 H) 487.1 308 2.13 B076 / —NH ,,                < 2 ill               F. N-7 CI-^X^7   <s7     F N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazoi-2-yi)-2,6-difluoro-3 -(piperazin-1 ■■ yl)benzamide H NMR (400 MHz, DMSO-O S 13.05 (s, 1 H), 9.33 (br s, 2 H), 7.46 -7.37 (m, 4 H), 7.32 - 7.23 (m, 2 H), 7.12 - 7.18 (m, 1 H), 3.56 (s, 1 H), 3.22 (s, 8 H), 1.90 (s, 3 H) 487.1 85 0.64 B077 a J h ho^n      \2 HN J                    \ Cj N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-4-(3 -(hydroxymethyl)piperazin-1 -yl)benzamide II NMR (400MHz, DMSO-J6) ¢5 7.97 (d, J = 8.9 Hz, 2H), 7.45 - 7.37 (m, 4H), 7.12 (s, 1H), 6.94 (d, J === 9.2 Hz, 2H), 4.70 (br s, 1H), 3.85 - 3.70 (m, 2H), 3.53 (s, 1H), 3.41 -3.36 (m, 1H), 3.01 - 2.95 (m, 1H), 2.76 ■ 2.67 (m, 481.1 90 1.35 WO 2022 / 063152                                                 PCT / CN2021 / 119801 205 3H), 2.47 - 2.38 (m, 1H), 1.91 (s, 3H) B078 ho'YV'^    W bi N-(4-(2-(4-chlorophenyl)but ■ 3 -yn-2 -yl) thiazol-2-yl)-4-(3 ■■ (hydroxymethyl)piperazin-1 -yl)benzamide H NMR (400MHz, DMSO-O 4 7.97 (d, J = 8.9 Hz, 2H), 7.45 - 7.37 (m, 4H), 7.11 (s, 1H), 6.93 (d, J == 8.9 Hz, 2H), 4.69 (br s, 1H), 3.79 (d, J = 11.2 Hz, HI), 3.72 (d, J 8.2 Hz, 1H), 3.52 (s, 1H), 3.40 -3.36 (m, 2H), 3.01 - 2.95 (m, 1H), 2.76 - 2.67 (m, 3H), 2.41 (t, 1==11.0 Hz, HI), 1.91 (s, 3H) 481.1 169 2.13 B079 1 J H \> HN. J                  V r N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-4-(3-(hydroxymethyl)piperazin-1 ■■ yl)benzamide M NMR (400MHz, DMSO-H) 3 7.97 (d, J 8.8 Hz, 2H), 7.51 - 7.40 (m, 2H), 7.15 (t, J - 8.9 Hz, 2H), 7.05 - 6.88 (m, 3H), 4.70 (br s, 1H), 3.82 -3.65 (m, 2H), 3.49 (s, 1H), 3.41 - 3.37 (m, 2H), 3.04 -2.93 (m, 1H), 2.80 ■ 2.63 (m, 3H), 2.44 - 2.32 (m, 1H), 1.91 (s, 3H) "b NMR (376MHz, DMSO-J6)(5 -116.67(s. IF) 465.2 174 2.99 WO 2022 / 063152                                                 PCT / CN2021 / 119801 206 B080 2 r N-(4-(2-(4-chlorophenyl)but-3 -yn-2 -yl) thiazol-2-yl)-4-(3 ■■ (hydroxymethyl)piperazin-1 -yl)benzamide II NMR (400MHz, DMSO-cfc) <5 7.98 (d, 7= 8.8 Hz, 2H), 7.49 - 7.36 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.10 (s, 1H), 6.95 (d,. / NHk 2H), 4.83 (br s, 1H), 3.84 - 3.74 (m, 2H), 3.51 (s, 1H), 3.44 -3.41 (m, 2H), 3.05 - 2.99 (m, 1H), 2.82 - 2.73 (m, 3H), 2.49 ■■ 2.48 (m, 1H), 1.91 (s, 3H) i9F NMR (376MHz, OMSO-cfc) <5 -116.51 (s, IF) 465.2 286 3.30 B081 0    0 S"AA^ H2N           N II 1 H        / ¾. Q HN. J N1 -(4-(2-(4-fluorophenyl)but-3 -yn-2-yl) thiazol-2-yl)-4-(piperazin-1 -yl)isophthalamide II NMR (400MHz, DMSO-cfc) <5 12.59 (br s, 1H), 9.42 (br s, 2H), 8.22 (d.. / 2.0 Hz, 1H), 8.15 8.07 (m, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 7.50 - 7.42 (m, 2H), 7.20 - 7.13 (m, 4H), 3.53 (s, 1H), 3.29 (s, 4H), 3.23 (s, 4H), 1.92 (s, 3H) i9F NMR (376MHz, DMSO-4) 0 -116.46 (s, IF) 478.2 102 0.96 WO 2022 / 063152                                                 PCT / CN2021 / 119801 207 B082 III             \ / —A .7 N. ,NH f-O X>~NH M O           J"                   ) H0Z 2,6-difluoro-N-(4-(2-(4-fluorophenyl)but-3 -yn-2 ■■ yl)thiazol-2-yl)-4-(3-(hydroxymethyl)piperazin-1 -yl)benzamide H NMR (400MHz, DMSO-A) 7 12.77 (s, 1H), 9.81 - 9.64 (m, 1H), 9.61 -9.41 (m, 1H), 7.48 - 7.41 (m, 2H), 7.19- 7.17 (m, 1H), 7.15 ■■ 7.12 (m, 1H), 6.87 (s, 1H), 6.79 (d, . / 12.0 Hz, 2H), 3.98 (t, . / =15.7 Hz, 2H), 3.77 - 3.63 (m, 2H), 3.54 (s, 1H), 3.30 ■ 3.20 (m, 3H), 3.16 ■■ 2.97 (m, 2H), 1.90 (s, 3H) i9F NMR (376MHz, DMSO-J6)^-111.73--111.77 (m,2F).-l 16.39 (s, IF) 501.1 25 0.43 B083 »■                F J 0 Ax / ™\ C,AJ T      H HO N-(4-(2-(4-chlorophenyl)but-3 -yn-2 -yl)thiazol-2-yl) -2,6 -difluoro-4-(3-(hydroxymethyl)piperazin-1 -yl)benzamide H NMR (400MHz, DMSO-A) ¢5 7.52 - 7.36 (m, 4H), 7.16 (s, 1H), 6.63 (d.. / 12.6 Hz, 2H),4.68 (1.. / 5.2 Hz, III), 3.77 -3.63 (m, 2H), 3.54 (s, HI), 3.00 - 2.93 (m, 1H), 2.80 -2.63 (m, 3H), 2.47 - 2.29 (m, 3H), 1.90 (s, 3H) i9F NMR (376MHz, DMSO-ds) <5 -112.15 (s, 2F) 517.1 78 1.27 WO 2022 / 063152                                                 PCT / CN2021 / 119801 208 B084 Hi III                K xl      o   \=x y—4 A—n nh LS>“NH      H. or HO 2,6-difluoro-4-(3-(hydroxymethyl)piperazin-l -yl)-N-(4-(2-(4-methoxyphenyl)but-3 -yn-2 -yl)thiazol-2-yl)benzamide H NMR (400MHz, DMSO-cfc) <5 12.74 (br s, 1H), 9.65 - 9.47 (m, 1H), 9.41 - 9.21 (m, 7=10.0 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.12 (s, 1H), 6.87 (d. 7 8.8 Hz, 2H), 6.79 (d, 7 12.0 Hz. 2H), 3.97 (1.7 = 15.1 Hz, 2H), 3.75 - 3.70 (m, 4H), 3.68 - 3.62. (m, 111),3.46 (s, 1H), 3.32 -3.17 (m, 3H), 3.14-2.99 (m, 2H), 1.88 (s, 3H) !9F NMR (376MHz, DMSOY) ¢5 -111.79 (s, 2F) 513.2 28 0.39 B085 I s xW YY N N  2—> _ A A h Cl 4-(3 -aminopyrro lidin-1 -yl)-N -(4-(2-(4-chlorophenyi)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluorobenzamide H NMR (400 MHz, DMSOY) 4 12.65 (s, 1H), 8.29 (br. s, 3H), 7.46 - 7.37 (m, 4 H), 7.19 (s, 1H), 6.37 - 6.29 (m, 2 H), 3.97 (br. s, HI), 3.62 - 3.55 (m, 1 H), 3.55 (s, 1H), 3.52 - 3.47 (m, 1 H), 3.38 - 3.32. (m, 2 H), 2.37 - 2.26 (m, 1H), 2.16 - 2.05 (m, 1H), 1.90 (s, 3H). 487.4 395 2.58 WO 2022 / 063152                                                 PCT / CN2021 / 119801 209 B086 f o Cl 4-(3 -aminopyrrolidin-1 -yl)-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluorobenzamide !H NMR (400 MHz, DMSO-afe) <512.65 (s, > 1B. 8.29 (br. s, 3H), 7.46 - 7.37 (m, 4 H), 7.19 (s, U B. 6.35 ■■ 6.31 (m, 2 H), 3.96 (br. s, 1H), 3.62 - 3.55 (m, 1 H), 3.55 (s, 1H), 3.52 - 3.47 (m, 1 H), 3.38 - 3.32 (m, 2 H), 2.37-2.26 (m, 1H), 2.16 - 2.05 (m, 1H), 1.90 (s, 3H). 487.1 286 2.57 B087 F Q S-\ X ^jX” ” 6 h2nX J     F      ^=( Cl 4-(3 -aminopyrrolidin-1 -yl)-N -(4-(2-(4 ■ chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-2,6-difluorobenzamide H NMR (400 MHz, DMSO-J6) ¢512.64 (s, 1H), 8.28 (br. s, 3H), 7.46 - 7.37 (m, 4 H), 7.19 (s, III), 6.35 -6.31 (m, 2 II), 3.97 (br. s, 1H), 3.62 - 3.55 (m, 1 H), 3.55 (s, 1H), 3.52 - 3.47 (m, 1 H), 3.38 ■ 3.32 (m, 2 H), 2.37 ■ 2.26 (m, 1H), 2.16 - 2.05 (m, III), 1.90 (s, 31B. 487.4 38 1.18 B088 X z 1 -n IZ z nX o-'x^ 4-(3 -aminopyrrolidin-1 -yl)-N-(4-(2-(4 ■ chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-2,6-difl uorobenzami de H NMR (400 MHz, DMSO-de) 3 12.65 (s, 1H), 8.26 (br. s, 3H), 7.46 - 7.37 (m, 4 H), 7.19 (s, 1H), 6.35 - 6.31 (m, 2 H), 3.96 (br. s, 1H), 3.62 - 3.55 (m, 1 H), 3.55 (s, 1H), 3.52 - 3.47 (m, 1 H), 3.38 - 3.32 (m, 2 H), 2.37 - 2.26 (m, 1H), 487.0 42 0.92 WO 2022 / 063152                                                 PCT / CN2021 / 119801 210 2.16-2.05 (m, Ill), 1.90 (s, 3H). B089 F 0 JI J H     f \ h2n- / ^  ' F 4-( 3 -aminopyrrolidin-1 -yl) -2,6-dif1uoro-N-(4-(2-(4-fiuorophenyl)but-3-yn-2-yl)thiazoI-2-yl)benzamide !H NMR (400 MHz, DMSO-cfc) <512.66 (s, 1H), 8.28 (br. s, 3H), 7.50- 7.40 (m, 2 H), 7.20 - 7.10 (m, 3H), 6.40 ■ 6.30 (m, 2 H), 3.96 (br. s, 1H), 3.61 - 3.55 (m, 1 H), 3.53 (s, III), 3.51 - 3.45 (m, 1 H), 3.41 - 3.33 (m, 2 H), 2.35 - 2.27 (m, 1H), 2.15 - 2.07 (m, 1H), 1.91 (s, 3H). IM+Na1] ==493.0 681 2.77 B090 II xA A' N n \ A A H / K*<J F    V F 4-(3-aminopyrrolidin-1 -yl)- 2,6-difluoro-N-(4-(2-(4-fluorophenyl)but-3 -yn-2 ■■ yl)thiazol-2-yl)benzamide H NMR (400 MHz, DMSO-40 d 12.65 (s, 1H), 8.29 (br. s, 3H), 7.50- 7.40 (m, 2 H), 7.20 - 7.10 (m, 3H), 6.40 - 6.30 (m, 2 H), 3.96 (br. s, 1H), 3.61 - 3.55 (m, 1 H), 3.54 (s, 1H), 3.51 -3.45 (m, 1 H), 3.41 -3.33 (m, 2 H), 2.39 - 2.26 (m, 1H), 2.16 ■■ 2.07 (m, 1H), 1.91 (s, 3H). 471.0 107 1.52 WO 2022 / 063152                                                 PCT / CN2021 / 119801 211 B091 nW m N o h2n- / >         W / 1                                  F 4-( 3 -aminopyrrolidin -1 -yl) -2,6-difluoro-N -(4-(2-(4-fluorophenyl)but-3 -yn-2-yl)thiazol-2-yl)benzamide !H NMR (400 MHz, DMSOX) <512.66 (s, U B. 8.25 (br. s, 3H), 7.50- 7.40 (m, 2 H), 7.20 - 7.10 (m, 3H), 6.40 - 6.30 (m, 2 H), 3.96 (br. s, 1H), 3.61 ■■ 3.55 (m, 1 H), 3.53 (s, U B. 3.51 - 3.45 (ro, 1 H), 3.39 - 3.31 (m, 2 H), 2.35 - 2.26 (m, 1H), 2.24 - 2.05 (m, B B. 1.91 (s, 3H). 471.0 65 1.05 B092 N-(4-(2 -(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-4-(piperazin-1 -yl)benzamide H NMR (400MHz, DMSOX) ¢5 10.57 (br s, 1H), 7.50 (d, / = 8.6 Hz, 2H), 7.36 (d, / ==8.6 Hz, 2H), 6.90 (s, III), 6.28 (br s, 1H), 4.75 (t,.!=5.1 Hz, 2H), 3.60 (br. dd, / =4.8, 8.1 Hz, 1H), 3.50 (s, 1H), 3.42 - 3.35 (m, 4H), 1.84 (s, 3H). 424.1 219 3.44 B093 cij^^y.NVO“NCDNH N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-4-(piperazin-1 -yl)benzamide H NMR (400MHz, DMSO-X) d 10.56 (br s, 1H), 7.50 (d, / ===8.6 Hz, 2H), 7.36 (d, / ==8.6 Hz, 2H), 6.90 (s, 1H), 6.28 (br s, 1H), 4.75 (1, / =5.1 Hz, 2H), 3.63 -3.57 (m, 1H), 3.50 (s, 1H), 3.42 - 3.35 (m, 4H), 1.84 (s, 3H). 424.0 43 0.58 WO 2022 / 063152                                                 PCT / CN2021 / 119801 212 B094 Vo j KJ H JO Cl / / \^NH N-(4-(2-(4-chlorophenyl)but ■ 3-yn-2-yl)thiazol-2-yl)-2-fluoro-4-(piperazin-1 -y])benzamide 469.1 151 2.46 B095 PCH3 o ^-G- 1 a N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-3-methoxy-4-(piperazin-l -yl)benzamide H NMR (400 MHz, DMSCM5) 8 7.66 (d,J = 8.8 Hz, 2H), 7.41-7.36 (m, J 20.0 Hz, 4H), 7.15 (s, 1H), 6.92 (d, J =8.0 Hz, 1H), 3.83 (s, 3H), 3.51 (s, 4H), 3 02 (s, 1H), 2.87 (s, 4H), 1.88 (s, 3H). 481.1 184 1.20 B096 % / Z~\ J 9 a w H D ^NH 2,6-dichloro-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)lhiazol-2-yl)-4-(piperazin-l-yl)benzamide 519.0 312 B097 ill                    F HI        $    X___ r OH N-[4-[l -(4-chlorophenyl)-l ■ methyl -prop -2 -yny 1] thiazol-2-yl]-2,6-difluoro-4-[2-(hydroxymethyl)piperazin-1 -yl] benzamide H NMR (400MHz, DMSO-J6) 3 12.72 (s, 1H), 9.37 (br s, 1H), 8.72 (br s, 1H), 7.44 - 7.37 (m, 4H), 7.20 (s, 1H), 6.71 (d, 7=12.5 Hz, 2H), 4.13 (brs, 1H), 3.75 (br s, 1H), 3.60 (br s, 1H), 3.58 (br s, 1H), 3.57 (br s, 1H), 3.49 (br s, lH).3.46(br s, 111),3.33 -3.23 (m, 2H), 3.15 (br d, 517.0 119 1.14 WO 2022 / 063152                                                 PCT / CN2021 / 119801 213 , / 8.8 Hz, III), 3.03 (br d, 7=12.5 Hz, 1H), 1.90 (s, 3H). B098 111 q \...... a-V LA / OH N-[4-[l -(4-chlorophenyl)-1 -methyl-prop-2 -ynyl]thiazol-2-yl]-2,6-difluoro-4-[2-(hydroxymethyl)piperazin-1 ■■ yl]benzamide H NMR (400MHz, DMSOA) <5 12.72 (s, U B. 9.51 (br s, 1H), 8.85 (br s, 1H), 7.50 - 7.33 (m, 4H), 7.20 (s, 1H), 6.71 (bi d, 7=12.5 Hz, 2H), 4.13 (br s, HI), 3.83 (br d, TH 4.3 Hz, 2H), 3.74 (br dd, 7=7.8, 11.3 Hz, 1H), 3.62 - 3.56 (m, 1H), 3.55 (s, 1H), 3.47 (br d, 7=13.0 Hz, 1H), 3.34 - 3.22 (m, 2H), 3.20 - 3.08 (m, III), 3.02 (br d, 7 10.3 Hz, 1H), 1.90 (s, 3H). 517.0 20 0.26 B099 ill             \ Al TA A ).....' OH 2,6-difluoro-N-[4-[l-(4-fluorophenyl)-1 -methyl -prop-2-ynyl]thiazol-2-yl]-4-[2-(hydroxymethyl)piperazin-1 -yl]benzamide H NMR (400MHz, DMSOA) <5 7.48 - 7.41 (m, 1H), 7.44 (dd, 7=5.5, 8.8 Hz, 2H), 7.20-7.10 (m, 3H), 6.57 (br d, 7=13.1 Hz, 2H), 4.71 (br s, HI), 3.76 - 3.65 (m, 2H), 3.52 (s, HI), 3.48 (brd, 7=10.4 Hz, 1H), 3.12 (brd, 7=12.3 Hz, 1H), 2.96 - 2.90 (m, 1H), 2.89 - 2.81 (m, 1H), 2.68 (br d, 7=3.2 Hz, 1H), 501.0 30 0.64 WO 2022 / 063152                                                 PCT / CN2021 / 119801 214 2.66-2.61 (m, III), 2.61 -2.54 (m, 1H), 1.90 (s, 3H). Bl 00 / / / \ _ °* >=\ < / T I >-NH      W OH 2,6-difluoro-4-[2-(hydroxymethyl)piperazin-1 ■■ yl]-N-[4-[l-(4-methoxyphenyl)-1 -methyl-prop-2-ynyl]thiazol-2-yl]benzamide 11 NMR (400MHz, DMSO-afe) <512.71 (s, iH), 9.53 (br s, 1H), 8.87 (br s, 1H), 7.35 - 7.30 (m, 2H), 7.11 (s, 1H), 6.90-6.85 (m, 2H), 6.71 (br d,. / 12.4 Hz, 2H), 3.72 (s, 4H), 3.61 -3.56(m, 1H), 3.49 - 3.41 (m, 2H), 3.32 - 3.23 (m, 2H),3.13(br s, 1H), 3.01 (brd, 7=10.1 Hz, 1H), 1.88 (s, 3H). 513.0 21 0.38 Bl 01 1           F\ Q / “X 7— / —N NH N-(4-(2-(4-chlorophenyl)but-3 -yn-2 -yl)thiazol-2-yl)-4-(2-ethylpiperazin-1 -y I )-2,6-difluorobenzamide 515.1 70 2.47 Bl 02 I i ty^Z W  Q N5^                      p 4-(5 -amino-1 -methyl- 1H-pyrazol-4-yl)-2,6-difluoro-7V-(4-(2-(4-fluorophenyl)but-3-yn-2-yl)thiazol-2-yl)benzamide NMR (400 MHz, DMSO-O ¢512.98 (br s, 1H), 7.67 (s, 1H), 7.51 -7.40 (m, 2H), 7.33 - 7.09 (m, 5H), 5.80 (s, 2H), 3.59 (s, 3H), 3.54 (s, 1H), 1.92 (s, 3H). 482.1 1269 2.25 WO 2022 / 063152                                                 PCT / CN2021 / 119801 215 Bl 03 / n ^:O rvx 2,6-difluorodV-(4-(2-(4-fluorophenyl)but-3 -yn-2 ■■ yl)thiazoI-2-yl)-4-(2-methyl-3-oxo-2,3-dihydro-lff-pyrazol-4-yl)benzamide {H NMR (400 MHz, CD3OD): 3 7.97 (br s, 1H), 7.60 - 7.51 (m,4H), 7.11 (s, 1H),7.O1 (brt, / ==8.6 Hz, 2H), 3.53 (s, 3H), 2.97 (s, HD. 1.97 (s, 3H). 483.0 5139 5.21 Bl 04 F 0 S"\\ \ X anaH AaH o % 4-(5-(ammomethyl)pyrazin-2-yl)-2,6-difluoro-AT-(4-(2-(4-fluorophenyl)but-3 -yn-2 -yl)thiazol-2-yl)benzamide 1H NMR (400 MHz, CD3OD) J 9.28 (s, 1H), 8.81 (s, HR. 7.94 (d.J 8.8 Hz, 2H), 7.64 - 7.48 (m, 2H), 7.16 (s, 1H), 7.06 - 6.95 (m, 2H), 4.45 (s, 2H), 2.99 (s, 1H), 2.04 - 1.92 (m, 3H). 494.0 1474 2.98 Bl 05 HI                    N. XrVXP' “ ? / -[4-[l-(4-chlorophenyl)-l-methyl-prop-2-ynyl]thiazol-2-yl]-l H-benzimidazole-5-carboxamide !H NMR (400MHz, DMSO-J6) 3 12.61 (br s, 2H), 8.50 - 8.30 (m, 2H), 7.94 (br s, 1H), 7.62 (br s, 1H), 7.47 - 7.44 (m, 2H), 7.42 - 7.38 (m, 2H), 7.17(s, 1H), 3.55 (s, 1H), 1.92 (s, 3H) 407.2 Bl 06 ?      / -A ci^ V N- [4-[i -(4-chlorophenyl)-l ■ methyl -prop -2 -yny 1] thiazol-2-y 1] -1 II-benzimidazole-5-carboxamide A NMR (400M Hz, DMSO-rfe) 8 12.90 -12.70 (m, 1H), 12.62 (br d, .7===9.3 Hz, 1H), 8.49-8.39 (m, 1H), 8.37-8.31 407.2 WO 2022 / 063152                                                 PCT / CN2021 / 119801 216 (m, 1H), 7.94 (ddd, . / 1.4. 8.5, 14.6 Hz, 1H), 7.74 - 7.59 (m, 1H), 7.47 - 7.44 (m, 2H), 7.42 -7.38 (m, 2H), 7.18 (d, J=2.0 Hz, 1H), 3.55 (s, 1H), 1.93 (s, 3H) WO 2022 / 063152                                                 PCT / CN2021 / 119801 [3961 Table 6: The following examples were synthesized analogous to the procedure of example 20,21 22,23 and 24 using the 217 appropriate intermediates and the corresponding fragment Corn. ID Structure Name HNMR LCMS (iM ||| +=) Kinase assay IC50 nM NFkB assay IC50 nM C001 III            \.......... N y.-Z       XNH a v /          p / ^-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide il NMR(400 MHz, DMSO4) 3 12.77 (s. 1 H), 9.25 (br s, 2 H), 7.33 - 7.49 (m, 4H), 7.21 (s, 1 H), 6.78 (br d, J = 12.05 Hz, 2 H), 3.52 ■ 3.58 (m, 5 H), 3.16 (br s, 4H), 1.90 (s, 3 H) 487 3.7 0.59 C002 F. 1         O                  \ \ N-N NH yj T y-NH     v~y x-'        ’~S         F 2,6-difhioro-N-(4-(l-phenylethyl)thiazol-2-yl)-4-(piperazin-l -yl)benzamide H NMR (400MHz, DMSO-4) 8 12.62 (br s, 1H), 9.37 (br s, 2H), 7.35 -7.11 (m, 511),6.95 (s, HI), 6.79 (d, 1 12.0 Hz, 2H), 4.16 (br s, 4H), 3.62 - 3.52 (m. 4H), 1.56 (d. J=7.3 Hz, 3H) 429.1 47 0.83 C003 Cl / 0 o \ F N-(4-( 1-(4-chlorophenyl)ethyl)thi azol-2-yl)-2,6-difluoro-4 ■ (piperazin-1 -yl (benzamide lH NMR (400 MHz, DMSO-ds) d 12.62 (br s, 1 H), 9.43 (br s, 2 H), 7.37 ■■ 7.31 (m, 2 H), 7.29-7.22 (m, 2 H), 6.97 (s, 1 H), 6.79 (br d, J = 12.0 Hz, 2 H), 4.19 (q, J = 7.2 Hz, 1 H), 3,64 - 3.54 (m, 4 H), 3.16 (br s, 4 H), 1.55 (d, J 7.2 Hz, 3 H) 463.1 11 1.34 WO 2022 / 063152                                                 PCT / CN2021 / 119801 218 C004 r0'- o F 2,6-difluoro-N-(4-(l-methoxy-2-phenylpropan-2-yI)thiazol-2-yl)-4-(piperazin-1-yl)benzamide 1H NMR (400 MHz, DMSO-dfi) 3 12.64 (br. s,lH), 9.46 (s,lH), 7.28 -7.20 (m. 2H), 7.18 - 7.16 (m. 2H), 6.98 (s,lH), 6.79 -6.76 (m, 2H), 3.84 (s,2H), 3.59 - 3.56 (ro, 4H), 3.26 (s, 3H), 3.16 - 3.14 (m. 4H), 1.67 (s,3H). 473.2 22 0.66 C005 F                   F 2,6-difluoro-N-(4-(2-(4-fluorophenyl)propan-2-yl)thiazo 1-2 -y 1)-4 (piperazin-1 -yl)benzamide lH NMR (400 MHz, DMSO-Je) 3 12.65 (s, 1 H), 9.01 (s. 2 H) , 7.27 - 7.20 (m, 2 H), 7.11 7.04 (m, 2 H), 6.79 (s, 1 II), 6.76 (d, 1 H), 3.58 - 3.52 (m, 4 H), 3.20 - 3.12 (m, 4 H), 1.62 (s, 6H) 461.2 6 0.68 C006 5 CA^Z Z..O 0 N-(4-( 1-(4-bromophenyl)cyclope ntyl)thiazol-2-yl)-2,6-difluoro-4-(piperazin-1 -yl)benzamide i 1 NMR (400 MHz, DMSO-cfc) ¢5 / .42 (d, 2 H),7.22 (d, 2 H), 7.04 (s, 1H), 6.62 (s, 2 H), 3.18(1, 4 H), 2.76 (1, 4 H), 2.45 (1, 4 H), 2.02 (t, 2 H), 1.62 (t, 2 H) 547.1 43 2.53 C007 ill             \ >“4 / >-N NH T >-nh M v~y (R)-N-(4 .(2-(4-chlorophenyl)but-3 -yn -2 -yl)thiazol-2 -y 1)-2,6-difluoro-4-(piperazin-1-yl)benzamide lH NMR (400 MHz, DMSO-4) 3 12.75 (s, 1 H), 9.42 (br. s, 2 H), 7.45 - 7.35 (m, 4 H), 7.20 (s, 1 H), 6.79 (s, 1 H), 6.76 (s, 1 H), 3.60 - 3.55 (m, 4 H), 3.54 (s, 1 H), 2.51 - 2.49 (m, 4H), 1.90(s, 3 H) 487.1 10 2.40 WO 2022 / 063152                                                 PCT / CN2021 / 119801 219 C008 - o y. VX V-N NH a AJ j        •sZ-'                 g               pi (S)-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide 1H NMR (400 MHz, DMSO-<4) <5 12.75 (s, 1 H), 9.47 (br. s, 2 H), 7.46 - 7.36 (m, 4 H), 7.20 (s, 1 H), 6.79 (s, 1 H), 6.76 (s, 1 H), 3.61 ■ 3.55 (m, 4 H), 3.54 (s, 1 H), 3.19-3.11 (m, 4H), 1.89 (s, 3 H) 487.1 5 0.32 C009 III                  F\ K     )=\ -N   / ——N  N— [j —NH / —'   X'— Cl                          p N-(4-(2-(4-chlorophenyl)but-3 -yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(4 -methylpiperazin-1 ■ yl)benzamide 1H NMR (400 MHz, DMSO-de) <5 2.76 (s, III), 7.34-7.47 (m, 4H), 7.20 (s, 1H), 6.75 (br d, 1=12.2 Hz, 2H), 3.56-3.66 (m, 2H), 3.54 (s, 1H), 3.42-3.52 (m, 2H), 2.99-3.16 (m, 4H), 2.74 (s, 3H), 1.90 (s, 3H). 501.1 7 0.70 CO 10 111             \.......... >y y / y J J T >-NH Cl x>      --s      F (R)-N-(4-(2-(4-chl orophenyl)but-3 -yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(4-methylpiperazin-1 ■■ yl)benzamide ‘H NMR (400 MHz, DMSO-^,) a 12.79 (s, 1 H), 10.96 (br. s, 1 H), 7.45 -7.35 (m, 4 H), 7.21 (s, 1 H), 6.82 (s, 1 H), 6.79 (s, 1 H), 4.09 - 4.00 (m, 2 H), 3.58 (s, 1 H), 3.49- 3.40 (m, 2 II), 3.30 - 3.20 (m, 2 H), 3.13 - 3.01 (m, 2H), 2.82 -2.76 (m, 3 H), 1.90 (s, 3 H) 501.1 56 1.49 WO 2022 / 063152                                                 PCT / CN2021 / 119801 220 con III             \ _          / =\ r~\ 4              / / 7—N   N— J J i| ^NH cr                     p (S)-N-(4-(2-(4-chlorophenyI)but-3 -yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(4-methylpiperazin-1 -yl)benzamide 1H NMR (400 MHz, DMSO-J6) d 12.19 (s, 1 H), 11,02 (br. s, 1 H), 7.47 -7.35 (m, 4 H), 7.21 (s, 1 H), 6.82 (s, 1 H), 6.79 (s, 1 H), 4.09 - 4.00 (m, 2 H), 3.56 (s. 1 H), 3.49- 3.40 (m, 2 H), 3.32 - 3.20 (m, 2 H), 3.13 - 3.01 (m, 2H), 2.82 -2.76 (m, 3 H), 1.90 (s, 3 H) 501.1 18 0.44 COM o / =( 0 «1 .Z ( Y ? z o z N-(4-(1 -ethoxy-2 -phenylpropan -2 -yl)thiazol-2-yl)-2,6-difluoro-4-(piperazin-1 -yl)benzamide H NMR (400 MHz, DMSO-fi?6) 6 7,22-7.18 (m, 5H), 6,89 (s, 1H), 6.61 (d, J === 12 Hz, 2H), 3.83 (s, 2H), 3.42-3.40 (m, 2H), 3.14 (t, 411), 2.73 (t, 4H), 1.64 (s, 3H), 1,01 (s, 3H). 487.1 78 1.45 CO 13 F. I           O ^1““—^,      / \ —C / )—N  N— L || g          —v   \—f N-(4-(1 -ethoxy-2-phenylpropan-2 -yl)thiazol-2-yl)-2,6-difluoro-4-(4-metbylpiperazin-1 -yl)benzamide i 1 NMR (400 MHz, DMSO-fifc) <5 7.24-7.15 (m, 5H), 6.89 (s, 1H), 6.66 (d, J = 12 Hz, 2H), 3,80 (s, 2H), 3.25 (s, 4H), 3.22 (s, 3H), 2.35 (s, 4H), 2.17 (s, 3H), 1.63 (s, 3H). 487.1 91 1.05 COM F\ a o >=\ / —\ 7—C zb—N N D A J T >-n M Br       <s    F N-(4-(2-(4-bromophenyl)-l -methoxypropan-2-yl)thiazol-2-yl) -2,6-difluoro-4-(piperazin-1 -yl)benzamide lH NMR (400 MHz, DMSO-4) 3 12.80 (s, 1 H), 7.81 (d, 2 H), 7.07 (d, 2 H), 7.03 (s, 2 H), 6.74 (s, 1 H), 3.81 (s, 2 H), 3.23 (s, 3 H), 3,18 (t, 4 H), 2.76 (t, 4 H), 1.72 (s, 3 H) 551.1 13 1.19 WO 2022 / 063152                                                 PCT / CN2021 / 119801 221 CO 15 E CD1 AJIT F N-(4-(l -(4-bromophenyl)cyclope ntyl)thiazoi-2-yi)-2,6-difluoro-4-(4-methylpiperazin-1 ■ yl)benzamide 11 NMR (400 MHz, DMSO-^6) s 1A2 (d, J = 8 Hz, 2H), 7.20 (d, J = 4 Hz, 2H), 7.03 (s, 1H), 6.65 (d, J == 12 Hz, 2H), 3.38 (s, 4H), 2.35 (s, 4H), 2.17 (s, 3H), 2.01 (s, 4H), 1.62 (d, J = 8 Hz, 4H). 561.1 266 17.01 CO 16 0 z 6 LC -f I A Y 0 N-(4-(2-(4-chlorophenyl)-1 -methoxypropan-2-yl)thiazol-2-yl)-2,6-di fluoro-4-(piperazin -1 -yl)benzamide 1H NMR (400 MHz, DMSCW6) d 12.64 (s, 1 H), 9.39 (s, 2 H), 7.34 - 7.29 (m, 2 H) 7.22 - 7.19 (m, 2 H), 6.99 (s, 1 H), 6.78 (d, J ==12.0 Hz, 2 H), 3.80 ■ 3.77 (m, 2 II), 3.60 - 3.55 (m, 4 H) 3.1 (s, 3 H) 3.18 - 3.12 (m, 4 H), 1.65 (s, 3 H) 507.1 16 1.11 CO 17 a%xx> 0 / (R)-2,6-difluoro-N-(4-(1 -methoxy-2-phenylpropan-2 -yl)thiazol-2-yl)-4-(piperazin-1 -yl)benzamide i 1 NMR (400 MHz, DMSO-^6) d 7.30 - 7.20 (m, 5H), 6.96 (s, 1H), 6.70 -6.60 (m, 2H), 3.84 (s, 2H), 3.27 (s, 3H), 3.25 - 3.17 (m, 3H), 2.83 ■■ 2.75 (m, 3H), 1.67 (s, 3H) 473.1 67 1.38 CO 18 o^yY^ryO" 0 r ¥ (S)-2,6 ■ difluoro-N -(4 ■ (1 -methoxy-2-phenylpropan-2-yl)thiazol-2-yl)-4-(piperazin-1-yl)benzamide lH NMR (400 MHz, DMSO-4) S 129 ■■ 7.23 (m, 2H), 7.21 - 7.13 (m, 3H), 6.98 (s, 1H), 6.79 - 6.72 (m, 2H), 3.84 (s, 2H), 3.50 -3.44 (m, 4H), 3.2.6 (s, 3H), 3.12 ■■ 3.06 (m, 4H), 1.67 (s, 3H) 473.1 36 0.97 WO 2022 / 063152                                                 PCT / CN2021 / 119801 222 CO 19 o o o (R)-N-(5-chloro-4-(2-(4-chlorophenyl)but-3-yn-2-yI)thiazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide 1H NMR (400 MHz, DMSO-O ¢513.07 (s, 1 H), 9.16 (s, 2 H), 7.41 (s, 4 H), 6.83 (d, J =12.4 Hz, 2 H), 3.63 (s, 1 H), 3.62 - 3.57 (m, 4 H), 3.19 (br s, 4 H), 1.94 (s, 3 H). 521.0 C020 ? o V cr^c / ^ / (S)-N-(5-chloro-4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(piperazin-1-yl)benzamide dl NMR (400 MHz, DMSO-O d 13.07 (s, 1 H), 9.23 (s, 2 H), 7.41 (s, 4 H), 6.83 (d, J=12.4 Hz, 2 H), 3.63 (s, 1 H), 3.62 - 3.57 (m, 4 H), 3.19 (br s, 4 H), 1.94 (s, 3 H) 521.0 88 C021 2,6-difluoro-N-(4-(l-methoxy-2-(4-methoxyphenyl)propa n-2-yl)thiazol-2-yl)-4-(piperazin-1-yl)benzamide 44 0.95 C022 HI           \ £ o    O / =^   / —\   / —OH (R)-N-(4.(2-(4-chlorophenyl)but-3 ■ yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(4-(2-hydroxyethyl)piperazi n-l-yl)benzamide lH NMR (400 MHz, DMSO-4) 3 12.68 (br., s, 1H), 7.42 -7.39 (m, 4 H), 7.18 (s, 1 H), 6.67 - 6.65 ( m, 2 H), 4.51 - 4.48 (m, 1 H), 3.53 (s, 1 H), 3.30 -3.22 (m, 2 H), 2.44 - 2.39 (m, 2 H), 1.89 (s, 3 H). 531.0 188 WO 2022 / 063152                                                 PCT / CN2021 / 119801 223 C023 Hi y >=\ / —\ / ~on crN^ y / / (S)-N-(4-(2-(4-chlorophenyl)but-3-yn-2-yl)thiazol-2-yl)-2,6-difluoro-4-(4-(2-hydroxyethyl)piperazi n-1 -yl)ben...

Claims

1. A compound of Formula XI, Formula XI-B or Formula XI-C;Formula XIFormula XI-BFormula XI-Cor a pharmaceutically acceptable salt thereof, whereinX is selected from -S-, -O- and -NRa-, whereinRa is H;A is selected from azetidinyl, -N(R6)-, -CH2-N(R6)-, -CHR9-N(R6)-, whereinR6 is selected from H, D, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl and C1-C6 aminoalkyl, wherein the optionally substituted R6 moieties comprise 0-3 substituents independently selected from -D,-OH and -NH2;R9 is optionally substituted C1-C6 alkyl, whereinoptionally substituted R9 moieties comprise 0-2 substituents are -OH;R1 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 hydroxy deuterated alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C1-C6 alkoxyl, optionally substituted saturated or unsaturated C3-C6 cycloalkyl, optionally substituted mono or bicyclic aryl, optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; and optionally2021350916   13 May 2026substituted saturated or unsaturated 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S;wherein optionally substituted R1 moieties comprise 0-4 substituents independently selected from -D, halo, -OH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 hydroxy-deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, -R7a, -X1-R7a, CHR7a R8a, -OR7a, -O-X1-R7a, -X1-O-X1-R7a-O-X1-C(O)(R7a), -C(O)(R7a),-C(O)N(R7aR8a), , - S(O)2R7a, -S(O)2N(R7aR8a), -N(R7aR8a), saturated or unsaturated C3-C6 cycloalkyl,saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, mono or bicyclic aryl, 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; wherein each X1 is independently C1-6 alkylene;each R7a and R8a are independently selected from H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, mono or bicyclic aryl , saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the mono or bicyclic aryl and 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, -OH, -NH2, =O, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl and saturated or unsaturated C3-C6 cycloalkyl,; andin the substituents of substituted R1, the saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 5-10 membered heteroaryl and the saturated or unsaturated 7-8 membered bridged heterocyclyl, are each independently substituted with 0 to 3 moieties selected from halo, -OH, - -NH2, =O, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, -CHR7bR8b, -OR7b, -C(O)N(R7bR8b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H and C1-C6 alkyl; or2021350916   13 May 2026R1 and R6 combine to form a 3-6 membered heterocycloalkyl;R5is selected from H, deuterium, halo, C1-C6 alkyl, C1-C6 deuteroalkyl, and C1-C6 haloalkyl;R2 and R3 are each independently selected from H, OH, C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and the mono or bicyclic aryl, wherein C1-C6 alkyl,C2-C6 alkynyl, C3-C6 cycloalkyl, and the mono or bicyclic aryl are each substituted with 0-3 moieties independently selected from halo, -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl andC1-C6 alkoxyl,;provided that R2 and R3 are not both H; orR2 and R3 combine to form a C3-C6 cycloalkyl ring;each R4 is independently selected from halo, -OH, -NH2, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl,CHR7eR8e and OR7e, whereineach R7e and R8e are independently selected from H, C1-C6 alkyl and C1-C6 haloalkyl, andthe subscript p is 1, 2 or 3;D is CR10 or N;E is CR14 or N;F is CR12 or N;G is CR11 or N;provided that no more than three of D, E, F, and G are N;R10, R11, R12, and R14, when present, are each independently selected from H, halo, -OH, C1-C6 alkoxyl, -O-X1-R7a, -C(O)N(R7aR8a), and saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; whereineach X1 is independently C1-6 alkylene;each R7a and R8a are independently selected from H, C1-C6 alkyl, and C1-C6 alkoxyl; R13 is H, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S and saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, are optionallysubstituted with 0-2 moieties independently selected from -OH, C1-C6 alkyl, C1-C6 aminoalkyl , -NH2, and C1-C6 hydroxyalkyl;m is an integer from 1-6;2021350916   13 May 2026R18 is H.

2. The compound of claim 1, where R6 is selected from H, C1-C6 alkyl, C1-C6hydroxyalkyl and C1-C6 hydroxy-deuterated alkyl.

3. The compound of claim 1, where R9 is selected from CH3 and CH2OH.

4. The compound of claim 1, wherein R1 is selected from H and optionally substitutedC1-C6 alkyl, whereinoptionally substituted C1-C6 alkyl comprises 0-4 substituents independently selected from halo, -OH, -NH2, =O, -CN, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl, -CHR7aR8a, -OR7a, -C(O)(R7a), -C(O)N(R7aR8a), -S(O)2R7a, -S(O)2N(R7aR8a) and -N(R7aR8a), whereineach R7a and R8a are independently selected from H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxyl,or R1 is optionally substituted saturated or unsaturated C3-C6 cycloalkyl, wherein optionally substituted C3-C6 cycloalkyl comprises 0-4 substituents independently selected from halo, -OH, -NH2, =O, -CN, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, and C1-C6 haloalkoxyl,or R1 is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S,the 5-10 membered bicyclic heteroaryl is substituted with 0 to 3 moieties selected from halo, -OH, -NH2, -CN, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated C3-C6 cycloalkyl, -CHR7aR8a, -OR7a, -C(O)N(R7aR8a), -S(O)2N(R7aR8a) and -N(R7aR8a), whereineach R7a and R8a are independently selected from H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl and C1-C6 alkoxyl,or R1 is mono or bicyclic aryl substituted with 0-3 substituents selected from halo, a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S2021350916   13 May 2026and a 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, whereinthe 3-7 membered heterocyclyl and the 7-8 membered bridged heterocyclyl,are substituted with from 0 to 3 moieties selected from halo, -OH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, -CHR7bR8b, -OR7b, -C(O)N(R7bR8b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, and C1-C6 alkyl.

5. The compound of claim 1, wherein R1 is C1-C6 alkyl substituted with 0-4 substituentsindependently selected from -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxyl, -S(O)2N(R7aR8a) and -N(R7aR8a), whereineach R7a and R8a are independently selected from H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, and saturated or unsaturated C3-C6 cycloalkyl.

6. The compound of claim 1, wherein R1 is C1-C6 alkyl substituted with 0-2 substituentsindependently selected from -OH, C1-C6 hydroxyalkyl, and -S(O)2N(R7aR8a), whereineach R7a and R8a are independently selected from H, and C1-C6 alkyl.

7. The compound of claim 1, wherein R1 is pyridiyl substituted with 0 to 3 moietiesselected from halo, -OH, -NH2, -CN, C1-C6 alkyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, whereinthe 3-7 membered heterocyclyl is substituted with 0-3 substituents selected from halo, -OH, - -NH2, -CN, C1-C6 alkyl and C1-C6 haloalkyl.

8. The compound of claim 1, wherein R1 is mono or bicyclic aryl substituted with 0-3moieties selected from halo -OH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, and a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S,the 3-7 membered heterocyclyl is substituted with 0-3 moieties selected from halo, -OH, -NH2, =O, -CN, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, -CHR7bR8b, -OR7b, -C(O)N(R7bR8b), -S(O)2N(R7bR8b) and -N(R7bR8b), wherein each R7b and R8b are independently selected from H, and C1-C6 alkyl.2021350916   13 May 20269.     The compound of claim 1, wherein R1 is mono or bicyclic aryl substituted with 0-3moieties selected from halo and a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, whereinthe 3-7 membered heterocyclyl is further substituted with 0-3 moieties selected from -OH, -NH2, =O, -CN, and -C1-C6 alkyl.

10. The compound of claim 1, wherein D, E, F and G are CR10, CR14, CR12, and CR11, respectively,or, F and G are CR12 and CR11, respectively, E is N or CR14 and D is N or CR10.

11. The compound of claim 1, whereinR12 and R14 are H;R10 and R11 are each independently selected from halo, -OH, C1-C6 alkyl and-C(O)N(R7aR8a), whereinR7a and R8a are each independently selected from H, C1-C6 alkyl and C1-C6 alkoxyl; andR13 is selected from 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S and saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S,, whereinthe 3-7 membered heterocyclyl and the 7-8 membered bridged heterocyclyl are optionally substituted with 0-2 moieties independently selected from -OH, -NH2, C1-C6 alkyl, C1-C6 hydroxyalkyl andC1-C6 aminoalkyl.

12. The compound of claim 1, having Formula XI-B-1 or XI-B-2Formula XI-B-1Formula XI-B-22021350916   13 May 2026or a pharmaceutically acceptable salt thereof, whereinR15 is selected from -OH, C1-C6 alkyl, C1-C6 hydroxyalkyl and C1-C6 aminoalkyl,R16 and R17 are each independently selected from halo.

13. The compound of claim 1, having Formula XI-B-1-a-I or Formula XI-B-2-a-I(XI-B-1-a-I)(XI-B-2-a-I)or a pharmaceutically acceptable salt thereof, wherein R4 is halo.

14. The compound of claim 1, having Formula XI-B-1-a-IIIor Formula XI-B-2-a-IIIR1R15( XI-B-1-a-III)(XI-B-2-a-III)or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, having Formula XI-C-1Formula XI-C-1.2021350916   13 May 202616.    The compound of claim 1 wherein m is 1.

17. The compound of claim 1 , wherein R2 and R3 are both methyl,or R2 is methyl and R3 is ethynyl,or R2 is methyl and R3 is CH2OMe.

18. The compound of claim 1, wherein the subscript p is 1, and R4 is attached to the phenyl ring as shown below:wherein the wavy line represents the point of attachment to the remainder of the formula.

19. The compound of claim 1, wherein the subscript p is 1, and R4 is chloro attached to the phenyl ring as shown below:,wherein the wavy line represents the point of attachment to the remainder of the formula, or the subscript p is 1, and R4 is methoxy attached to the phenyl ring as shown below:,wherein the wavy line represents the point of attachment to the remainder of the formula.

20. The compound of claim 1, wherein R5 is H or methyl,or R5 is deuterium,or R5 is selected from the group consisting of -CH2D, -CHD2, and -CD3.

21. The compound of claim 1, wherein the carbon atom attached to R2 and R3 is the S isomeror the carbon atom attached to R2 and R3 is the R isomer.

22. A compound selected from265266I IN267OMeIO o oo269HsNOMe270272274N"Ha WOjj276™ -¾ j277N'H278279280| VnhQO282OMeQO Lk)284H,NQOUiI 7—nh2862872021350916   13 May 20262892021350916   13 May 2026or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, and a pharmaceutically acceptable carrier or excipient.

24. A method for inhibiting ALPK1 kinase activity in a cell or tissue of a subject in need of such therapy, the method comprising administering to the subject a compound of any one of claims 1 to 22.

25. A method for inhibiting or reducing inflammation in a target tissue of a subject in need of such treatment, the method comprising administering to the subject a compound of any one of claims 1 to 22.

26. A method for treating a disease, disorder, or condition characterized by excessive or inappropriate ALPK1-dependent proinflammatory signaling in a subject in need of such therapy, the method comprising administering to the subject a compound of any one of claims 1 to 22.

27. The method of claim 26, wherein the disease, disorder, or condition is selected from sepsis, cancer, spiradenoma, spiradenocarcinoma, “Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and migraine Headache” (“ROSAH”) syndrome, and “Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis” (“PFAPA”) syndrome.

28. The method of claim 27, wherein the cancer is selected from lung cancer, colon cancer, and oral squamous cancer.

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