ERK2 degraders and antagonists

Abstract

The present disclosure relates to compounds according to Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, as well as compositions including such compounds and uses thereof, where R1 is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; R2 is H, alkyl, halo, amino, amide, hydroxyl, or O-R5; R3 is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R4 is H or alkyl; R5 is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; Z1 is CH, N, or C-R6; Z2 is CH, N, or C-R7; Z3 is CH, N, or C-R8; R6, R7, and R8 are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy; and X1 is NH or O. As evidenced by this application, these compounds and compositions are suitable for, among other things, treating cancer.

Description

MSK-20525ERK2 DEGRADERS AND ANTAGONISTSRELATED APPLICATIONSThis application claims the benefit of to U. S. Provisional Application Nos.63 / 755,034, filed February 6, 2025 and 63 / 943,132, filed December 17, 2025, the contents of each of which are fully incorporated by reference herein.FIELD

[0001] The present technology is directed to compounds, compositions, and methods related to degraders and antagonists of extracellular signal-regulated kinase and uses thereof.SUMMARY

[0002] In an aspect, the present technology provides a compound or a pharmaceutically acceptable salt thereof according to Formula I / S^ N\ II HZ3'Z2(I)whereinR1is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;R2is H, alkyl, halo, amino, amide, hydroxyl, or O-R5;R3is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;R4is H or alkyl;R5is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;Z1is CH, N, or C-R6;Z2is CH, N, or C-R7;Z3is CH, N, or C-R8;R6, R7, and R8are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy; andX1is either NH or O.

[0003] In an aspect, a composition is provided that includes a compound of any embodiment disclosed herein, a pharmaceutically acceptable carrier or one or moreMSK-20525excipients, fillers, or agents (collectively referred to hereafter as “pharmaceutically acceptable carrier” unless otherwise indicated and / or specified).

[0004] In a related aspect, a medicament for treating a cancer, such as colon cancer, in a subject is provided that includes a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier.

[0005] In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective to treat a cancer; and (ii) a pharmaceutically acceptable carrier.

[0006] In further related aspects, the present technology provides methods including a compound of any aspect or embodiment disclosed herein and / or a composition of any embodiment disclosed herein and / or a medicament of any embodiment disclosed herein. Such methods include a method of treating a subj ect suffering from a cancer, where the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 shows the pharmacokinetics of Compound 54 in mice, where the graph displays the plasma concentrations of the indicated compounds following a single intravenous (IV, 1 mg / kg) or oral (PO, 25 mg / kg) dose in male CD-I mice for 24 hours. Data is shown as the mean ± standard deviation.

[0008] FIG. 2 shows the pharmacokinetics of Compound 61 in mice, where the graph displays the plasma concentrations of the indicated compounds following a single intravenous (IV, 1 mg / kg) or oral (PO, 25 mg / kg) dose in male CD-I mice for 8 and 24 hours, respectively. Data is shown as the mean ± standard deviation.

[0009] FIG. 3 shows the pharmacokinetics of Compound 72 in mice, where the graph displays the plasma concentrations of the indicated compounds following a single intravenous (IV, 1 mg / kg) or oral (PO, 25 mg / kg) dose in male CD-I mice for 8 and 24 hours, respectively. Data is shown as the mean ± standard deviation.MSK-20525

[0010] FIG. 4 shows the pharmacokinetics of Compound 162 in mice, where the graph displays the plasma concentrations of the indicated compounds following a single intravenous (IV, 1 mg / kg) or oral (PO, 25 mg / kg) dose in male CD-I mice for 4 and 8 hours, respectively. Data is shown as the mean ± standard deviation.DETAILED DESCRIPTION

[0011] The following terms are used throughout as defined below.

[0012] For ease of reference, the compounds included in any aspect or embodiment herein may be referred to anywhere in this disclosure as “a compound of the present technology,” “compounds of the present technology,” or the like. The compounds of the present technology are also referred to herein as “ERK degraders,” “ERKds,” “ERK inhibitors,” “ERKis” and the like. Similarly for ease of reference, the compositions, medicaments, and pharmaceutical compositions of the present technology may collectively be referred to herein as “compositions,” “compositions of the present technology,” or the like.

[0013] As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0014] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term - for example, “about 10 wt.%” would be understood to mean “9 wt.% to 11 wt.%.” It is to beMSK-20525understood that when “about” precedes a term, the term is to be construed as disclosing “about” the term as well as the term without modification by “about” - for example, “about 10 wt.%” discloses “9 wt.% to 11 wt.%” as well as disclosing “10 wt.%.”

[0015] The phrase “and / or” as used in the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof -for example, “A, B, and / or C” would mean “A, B, C, A and B, A and C, B and C, or the combination of A, B, and C.”

[0016] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C14, P32and S35are thus within the scope of the present technology.Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0017] In general, “substituted” refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group is substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (z.e., F, Cl, Br, and I); hydroxyls; alkyl; amino; hydroxyl; carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl); thiocarbonyl (such as a thioester, a thioacetate, or a thioformate); phosphoryl; phosphate; phosphonate; phosphinate; imine; sulfhydryl; alkylthio; sulfate; sulfonate; sulfamoyl; sulfonamido; sulfonyl; aralkyl; aryl; heteroaryl; alkoxy; alkenoxy; aryloxy; aralkyloxy; heterocyclyl; heterocyclylalkyl; heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (z.e., SFs), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (z.e., CN); and the like.MSK-20525

[0018] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0019] Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, secbutyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0020] Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with, non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.

[0021] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above.MSK-20525In some embodiments, cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. Cycloalkylalkyl groups may be substituted or unsubstituted. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri -substituted with substituents such as those listed above.

[0022] Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, among others. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.

[0023] Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms. In some embodiments the cycloalkenyl group may have one, two or three double bonds but does not include aromatic compounds.Cycloalkenyl groups have from 4 to 14 carbon atoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl. Cycloalkenyl groups may be substituted or unsubstituted.

[0024] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0025] Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments,MSK-20525from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to -C=CH, -C=CCH3, -CH2C≡CCH3, -C=CCH2CH(CH2CH3)2, among others. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or trisubstituted with substituents such as those listed above.

[0026] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. In some embodiments, the aryl groups are phenyl or naphthyl. Although the phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[0027] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Aralkyl groups may be substituted or unsubstituted. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.

[0028] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and nonaromatic ring compounds containing 3 or more ring members, of which one or more is aMSK-20525heteroatom such as, but not limited to, N, O, and S. Heterocyclyl groups may be substituted or unsubstituted. The heterocyclyl group may contain 1, 2, 3 or 4 heteroatoms. Heterocyclyl groups may include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase “heterocyclyl group” includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotri azolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadi azolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadi azolyl, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), tri azol opyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.

[0029] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.MSK-20525Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrol opyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotri azolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3-dihydro indolyl groups. The phrase “heteroaryl groups” includes fused ring compounds. Heteroaryl groups may be substituted or unsubstituted. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.

[0030] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-m ethyl, pyri din-3 -yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0031] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.

[0032] Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the present technology are designated by use of the suffix, “ene.” For example, divalent alkyl groups are alkylene groups, divalent aryl groups are arylene groups, divalent heteroaryl groups are divalent heteroarylene groups, andMSK-20525so forth. Substituted groups having a single point of attachment to the compound of the present technology are not referred to using the “ene” designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene.

[0033] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[0034] The terms “alkanoyl” and “alkanoyloxy” as used herein can refer, respectively, to -C(O)-alkyl groups and -O-C(O)-alkyl groups, each containing 2-5 carbon atoms.Similarly, “aryloyl” and “aryloyloxy” refer to -C(O)-aryl groups and -O-C(O)-aryl groups.

[0035] The terms "aryloxy" and “arylalkoxy” refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Aryloxy and arylalkoxy groups may each be substituted or unsubstituted. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

[0036] The term “carboxylate” as used herein refers to a -COOH group.

[0037] The term “ester” as used herein refers to -COOR70and -C(O)O-G groups. R70is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may be found in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein and which is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein.MSK-20525

[0038] The term “amide” (or “amido”) includes C- and N-amide groups,i.e., -C(O)NR71R72, and -NR71C(O)R72groups, respectively. R71and R72are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is -NR71C(O)-(CI-5 alkyl) and the group is termed "carbonylamino," and in others the amide is -NHC(O)-alkyl and the group is termed "alkanoylamino."

[0039] The term “nitrile” or “cyano” as used herein refers to the -CN group.

[0040] Urethane groups include N- and O-urethane groups, i.e., -NR73C(O)OR74and -OC(O)NR73R74groups, respectively. R73and R74are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R73may also be H.

[0041] The term “amine” (or “amino”) as used herein refers to -NR75R76groups, wherein R75and R76are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0042] The term “sulfonamido” includes S- and N-sulfonamide groups, i.e., -SO2NR78R79and -NR78SO2R79groups, respectively. R78and R79are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO2NH2). In some embodiments herein, the sulfonamido is –NHSO2-alkyl and is referred to as the "alkylsulfonylamino" group.

[0043] The term “thiol” refers to -SH groups, while “sulfides” include -SR80groups, “sulfoxides” include -S(O)R81groups, “sulfones” include -SO2R82groups, and “sulfonyls” include -SO2OR83. R80, R81, R82, and R83are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. In some embodiments the sulfide is an alkylthio group, -S-alkyl.MSK-20525

[0044] The term “urea” refers to -NR84-C(O)-NR85R86groups. R84, R85, and R86groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0045] The term “amidine” refers to -C(NR87)NR88R89and -NR87C(NR88)R89, wherein R87, R88, and R89are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0046] The term “guanidine” refers to -NR90C(NR91)NR92R93, wherein R90, R91, R92and R93are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0047] The term “enamine” refers to -C(R94)=C(R95)NR96R97and -NR94C(R95)=C(R96)R97, wherein R94, R95, R96and R97are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0048] The term “halogen” or “halo” as used herein refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0049] The term “hydroxyl” as used herein can refer to -OH or its ionized form, -O. A “hydroxyalkyl” group is a hydroxyl-substituted alkyl group, such as HO-CH2-.

[0050] The term “imide” refers to -C(O)NR98C(O)R99, wherein R98and R99are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0051] The term “imine” refers to -CR100(NR101) and -N(CR100R101) groups, wherein R100and R101are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R100and R101are not both simultaneously hydrogen.

[0052] The term “nitro” as used herein refers to an -NO2 group.

[0053] The term “trifluorom ethyl” as used herein refers to -CF3.MSK-20525

[0054] The term “trifluoromethoxy” as used herein refers to -OCF3.

[0055] The term “azido” refers to -N3.

[0056] The term “trialkyl ammonium” refers to a -N(alkyl)3 group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion.

[0057] The term “isocyano” refers to -NC.

[0058] The term “isothiocyano” refers to -NCS.

[0059] The term “pentafluorosulfanyl” refers to -SF5.

[0060] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[0061] Pharmaceutically acceptable salts of compounds described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable). When the compound of the present technology has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g. alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonicMSK-20525acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g. Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g. arginine, lysine and ornithine). Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.

[0062] Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and / or stereoisomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms, it should be understood that the present technology encompasses any tautomeric, conformational isomeric, stereochemical and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. The phrase “and / or” as used in this paragraph and the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof - for example, “A, B, and / or C” would mean “A, B, C, A and B, A and C, or B and C ”

[0063] Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0064] As another example, guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other:MSK-20525

[0065] Because of the limits of representing compounds by structural formulas, it is to be understood that all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology.

[0066] Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0067] The compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[0068] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by an identifying citation. Also within this disclosure are Arabic numerals referring to referenced citations, the full bibliographic details of which are provided preceding the claims. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure.Compounds

[0069] In certain aspects, disclosed herein are compounds or pharmaceutically acceptable salts thereof according to Formula IMSK-20525R2O R3(I)whereinR1is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;R2is H, alkyl, halo, amino, amide, hydroxyl, or O-R5;R3is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;R4is H or alkyl;R5is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;Z1is CH, N, or C-R6;Z2is CH, N, or C-R7;Z3is CH, N, or C-R8;R6, R7, and R8are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy; andX1isNH or O.

[0070] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof according to Formula I is a compound or a pharmaceutically acceptable salt thereof according to Formula IAO R3H NX AR4(IA).

[0071] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof according to Formula IMSK-20525is a compound or a pharmaceutically acceptable salt thereof according to Formula IB

[0072] In some embodiments, the compound or pharmaceutically acceptable salt thereof,

[0073] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein R2is methyl or Cl.

[0074] In some embodiments, the compound or pharmaceutically acceptable salt thereof,MSK-20525

[0075] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein R4is H or methyl.

[0076] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein Z1is CH or N.

[0077] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein Z2is CH or N.

[0078] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein Z3is CH or N.

[0079] In some embodiments, the compound or pharmaceutically acceptable salt thereof,acceptable salt thereof of any one thereof.MSK-20525

[0080] In some embodiments, the compound or pharmaceutically acceptable salt thereof,MSK-20525thereof.

[0081] A composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0082] In any embodiment herein, the compound or a pharmaceutically acceptable salt thereof according to Formula I may be a compound or a pharmaceutically acceptable salt thereof according to Formula IA

[0083] In any embodiment herein, the compound or a pharmaceutically acceptable salt thereof according to Formula I may be a compound or a pharmaceutically acceptable salt thereof according to Formula IBMSK-20525

[0084] In any embodiment herein, R1may be

[0085] In any embodiment herein, R2may be methyl or Cl.In any embodiment herein, R3may be methyl,

[0086] In any embodiment herein, R4may be H or methyl.

[0087] In any embodiment herein, Z1may be CH or N.MSK-20525

[0088] In any embodiment herein, Z2may be CH or N. In any embodiment herein, Z3may be CH or N.

[0089] In certain embodiments, the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula IAIn certain embodiments, the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula IBIn certain embodiments, R1is alkyl or heterocyclyl. In certain embodiments, R1is unsubstituted heterocyclyl. In certain embodiments, R1is substituted heterocyclyl. In certain embodiments, the heterocyclyl is a four to six-membered heterocyclyl. In certain embodiments, the heterocyclyl is an oxygen or nitrogen-containing heterocyclyl.In certain embodiments, R1is alkyl. In certain embodiments, R1is C1-C4 alkyl.MSK-20525In certain embodiments, R1is selected fromIn certain embodiments, R2is alkyl or halo. In certain embodiments, R2is alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is halo. In certain embodiments, R2is Cl. In certain embodiments, R3is alkyl or aryl. In certain embodiments, R3is aryl.In certain embodiments, R3is, wherein each R9is independently selected from halo, alkyl, and alkoxy; and m is 0-5.MSK-20525In certain embodiments, m is 0-2. In certain embodiments, m is 0. In certain embodiments, m is 1 or 2.certain embodiments, R3is R or. In certain embodiments, R9is alkyl. In certain embodiments, R9is C1-C3 alkyl. In certain embodiments, R9is halo. In certain embodiments, R9is F, Cl, or Br. In certain embodiments, R9is alkoxy. In certain embodiments, R9is methoxy. In certain embodiments, R3is methyl,In certain embodiments, R4is H or methyl. In certain embodiments, R4is H.In certain embodiments, Z1is CH or N. In certain embodiments, Z1is CH. In certain embodiments, Z1is N.In certain embodiments, Z2and Z3are each CH. In certain embodiments, Z2is N and Z3is CH.In certain embodiments, the compound is selected from:MSK-20525MSK-20525MSK-20525MSK-20525MSK-20525MSK-20525MSK-20525or pharmaceutically acceptable salt thereof of any one thereof.In certain embodiments, the compound is selected from:of any one thereof.MSK-20525In certain embodiments, the compound isthereof.MSK-20525thereof.MSK-20525In certain aspects, the present disclosure provides a composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.In certain aspects, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present disclosure wherein the compound is present in an amount effective to treat a cancer. In certain embodiments, the cancer expresses a RAS pathway mutation, optionally wherein the RAS pathway mutation is KRAS-G13D.In certain aspects, the present disclosure provides a method of treating a subject suffering from a cancer, the method comprising administering to the subject an effective amount of a compound of the present disclosure. In certain embodiments, the cancer expresses a RAS pathway mutation, optionally wherein the RAS pathway mutation is KRAS-G13D. In certain embodiments, the cancer is selected from lung cancer, pancreatic cancer, ovarian cancer, myeloma, leukemia, liver melanoma, and colon cancer. In certain embodiments, the cancer is colon cancer.In certain aspects, the present disclosure provides a medicament for treating a cancer in a subject, the medicament comprising a compound of the present disclosure. In certain embodiments, the medicament further comprises a pharmaceutically acceptable carrier. In certain embodiments, the medicament comprises an effective amount of the compound for treating the cancer.

[0090] Methods

[0091] Disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present disclosure, wherein the compound is present in an amount effective to treat a cancer.

[0092] In some embodiments, wherein the cancer expresses a RAS pathway mutation such as KRAS-G13D, optionally wherein the cancer is a colon cancer.

[0093] Disclosed herein is a method of treating a subject suffering from a cancer, the method comprising administering to the subject an effective amount of a compound of the present disclosure.

[0094] In some embodiments, the method wherein the cancer expresses a RAS pathway mutation such as KRAS-G13D, optionally wherein the cancer is a colon cancer.MSK-20525

[0095] Disclosed herein is a medicament for treating a cancer in a subject, the medicament comprising a compound of the present disclosure.

[0096] In some embodiments, wherein the medicament further comprises a pharmaceutically acceptable carrier.

[0097] In some embodiments, wherein the medicament comprises an effective amount of the compound for treating the cancer.Pharmaceutical Compositions

[0098] In an aspect, a composition is provided that includes a compound of any embodiment disclosed herein, a pharmaceutically acceptable carrier or one or more excipients, fillers, or agents (collectively referred to hereafter as “pharmaceutically acceptable carrier” unless otherwise indicated and / or specified). In a related aspect, a medicament for treating cancer in a subject is provided that includes a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier. The medicament of any embodiment herein may include an effective amount of the compound for treating cancers such as colon cancer. In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective to treat a cancer; and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer may be colon cancer. In further related aspects, the present technology provides methods including a compound of any aspect or embodiment disclosed herein and / or a composition of any embodiment disclosed herein and / or a medicament of any embodiment disclosed herein.

[0099] “Effective amount” refers to the amount of a compound or composition required to produce a desired effect. One example of an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, reduction of a tumor mass. In any aspect or embodiment disclosed herein (collectively referred to herein as “any embodiment herein,” “any embodiment disclosed herein,” or the like) of the compositions, pharmaceutical compositions, and methods including compounds of the present technology, the effective amount may be an amount effective in treating a tumor and / or shrinking a tumor. By way of example, the effective amount of any embodiment herein including a compound of the present technology may be from about 0.01 µg to about 200 mg of the compound (such asMSK-20525from about 0.1 µg to about 50 mg of the compound or about 10 µg to about 20 mg of the compound). The methods and uses according to the present technology may include an effective amount of a compound of any embodiment disclosed herein. In any aspect or embodiment disclosed herein, the effective amount may be determined in relation to a subject. As used herein, a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate. Typically, the subject is a human, and, preferably, a human suffering from or suspected of suffering from pain. The term “subject” and “patient” can be used interchangeably.

[0100] Thus, the instant present technology provides pharmaceutical compositions and medicaments including a compound of any embodiment disclosed herein (or a composition of any embodiment disclosed herein) and a pharmaceutically acceptable carrier. The compositions may be used in the methods and treatments described herein. The pharmaceutical composition may be packaged in unit dosage form. The unit dosage form may be effective in treating a cancer (such as colon cancer). The unit dosage form may be effective in treating a tumor by reducing a tumor volume when administered to a subject in need thereof. Generally, a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology may vary from 1 × 10–4 g / kg to 1 g / kg, preferably, 1 × 10–3 g / kg to 1.0 g / kg. Dosage of a compound of the present technology may also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg.Suitable unit dosage forms, include, but are not limited to parenteral solutions, oral solutions, powders, tablets, pills, gelcaps, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, mucoadherent films, topical varnishes, lipid complexes, liquids, etc.

[0101] The pharmaceutical compositions and medicaments may be prepared by mixing one or more compounds and / or compositions of the present technology with pharmaceutically acceptable carriers, excipients, binders, diluents or the like. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The instantMSK-20525compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir.Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injections. The following dosage forms are given by way of example and should not be construed as limiting the instant present technology.

[0102] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents, or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

[0103] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[0104] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, com oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol),MSK-20525petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[0105] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0106] For injection, the pharmaceutical formulation and / or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these.

[0107] Compounds of the present technology may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars and / or sugar alcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols are typically used for delivery of compounds of the present technology by inhalation.

[0108] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds of the present technology include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, forMSK-20525example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Absorption enhancers can also be used to increase the flux of the compounds of the present technology across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane (e.g., as part of a transdermal patch) or dispersing the compound in a polymer matrix or gel.

[0109] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0110] The formulations of the present technology may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

[0111] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and / or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.

[0112] Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology.

[0113] Those skilled in the art are readily able to determine an effective amount by simply administering a compound of the present technology to a patient in increasing amounts until, for example, there is a reduction in the mass of a tumor in a subject. TheMSK-20525compounds of the present technology can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is sufficient. The specific dosage used, however, can vary or may be adjusted as considered appropriate by those of ordinary skill in the art. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the B-cell malignancy (e.g., non-Hodgkin lymphoma or chronic lymphocytic leukemia) associated with the tumor, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

[0114] Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology. Effectiveness of the compositions (as well as determination of effective amounts) and methods of the present technology may also be demonstrated by a decrease in the mass of a tumor and / or slowing the growth of a tumor and / or affecting an increase in the therapeutic responsiveness of a cancer to another therapeutic agent.

[0115] For each of the indicated conditions described herein, test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo-treated or other suitable control subjects.

[0116] The compounds of the present technology can also be administered to a patient along with other conventional therapeutic agents that may be useful in the treatment of tumors or in vaccination. The administration may include oral administration, parenteral administration, or nasal administration. In any of these embodiments, the administration may include intratumoral injections, subcutaneous injections, intravenous injections, intraperitoneal injections, or intramuscular injections. In any of these embodiments, the administration may include oral administration. The methods of the present technology can also include administering, either sequentially or in combination with one or more compounds of the present technology, a conventional therapeutic agent in an amount that can potentially or synergistically be effective for the treatment a cancer (e.g., colon cancer).MSK-20525

[0117] In one aspect, a compound of the present technology is administered to a patient in an amount or dosage suitable for therapeutic use. Generally, a unit dosage comprising a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations can also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology can vary from 1 × 10−4g / kg to 1 g / kg, preferably, 1 × 10−3g / kg to 1.0 g / kg. Dosage of a compound of the present technology can also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg.

[0118] In another aspect, the present technology provides methods of identifying a target of interest including contacting the target of interest with a detectable or imaging effective quantity of a labeled compound of the present technology. A detectable or imaging effective quantity is a quantity of a labeled compound of the present technology necessary to be detected by the detection method chosen. For example, a detectable quantity can be an administered amount sufficient to enable detection of binding of the labeled compound to a target of interest. Suitable labels are known by those skilled in the art and can include, for example, radioisotopes, radionuclides, isotopes, fluorescent groups, biotin (in conjunction with streptavidin complexation), and chemiluminescent groups. Upon binding of the labeled compound to the target of interest, the target may be isolated, purified and further characterized such as by determining the amino acid sequence.

[0119] The terms “associated” and / or “binding” can mean a chemical or physical interaction, for example, between a compound of the present technology and a target of interest. Examples of associations or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions and complexes. Associated can also refer generally to “binding” or “affinity” as each can be used to describe various chemical or physical interactions. Measuring binding or affinity is also routine to those skilled in the art. For example, compounds of the present technology can bind to or interact with a target of interest or precursors, portions, fragments, and peptides thereof and / or their deposits.

[0120] As indicated previously in this disclosure, in an aspect a method of treating a subject suffering from a cancer is provided, where the method includes administering to theMSK-20525subject an effective amount of a compound of any embodiment disclosed herein or administering an effective amount of a composition of any embodiment disclosed herein. In any embodiment herein of the method, the administering may include intratumoral administration. In any embodiment herein, the cancer may be colon cancer.

[0121] In any embodiment herein, the administering may further include administration of a chemotherapeutic agent such as an alkylating agent; a nitrosourea; an antimetabolite; an anthracycline; a topoisomerase II inhibitor; a mitotic inhibitor; an anti-estrogen; a progestin; an aromatase inhibitor; an anti-androgen; an LHRH agonist; a corticosteroid hormone; a DNA alkylating agent; a taxane; a vinca alkaloid; a microtubule poison, or a combination of any two or more thereof. In any embodiment herein, the administering may further include administration of a chemotherapeutic agent such as busulfan, cisplatin, carboplatin, oxaliplatin, an octahedral platinum (IV) compound, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechlorethamine (nitrogen mustard), melphalan, temozolomide, carmustine (BCNU), lomustine (CCNU), 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine, pemetrexed, daunorubicin, doxorubicin (Adriamycin), epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide (VP-16), teniposide, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, L-asparaginase, dactinomycin, thalidomide, tretinoin, imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), rituximab (Rituxan), bevacizumab (Avastin), ipilimumab, nivolumab (Opdivo), pembrolizumab (Ketruda), tamoxifen, fulvestrant, anastrozole, exemestane, letrozole, megestrol acetate, bicalutamide, flutamide, leuprolide, goserelin, or a combination of any two or more thereof.

[0122] In any embodiment herein, the administering may include local administration of the compound to a site in the subject including the cancer or local administration of the composition to a site in the subject including the cancer. In any embodiment herein, the administering may include oral, rectal, nasal, vaginal, transdermal, intravenous, intramuscular, or inhalation administration. In any embodiment herein, the administering may include injection of the compound into the site in the subject including the cancer or proximal to the site in the subject including the cancer.

[0123] The examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds of the present technology. The examples herein are also presented in order toMSK-20525more fully illustrate the preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects or embodiments of the present technology described above. The variations, aspects or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects, or embodiments of the present technology.EXAMPLESExample 1: Materials, Reagents, and General Methods

[0124] Reagents and Cell Lines. Cell lines were purchased from ATCC. Antibodies were purchased from Cell Signaling, Abeam, and Sigma. Gel electrophoresis supplies were purchased from Biorad and Thermo Fisher. DNA plasmids were purchased from GenScript and reagents for NanoBRET assays were purchased from Promega. Mouse studies were conducted at WuXi AppTec and the Antitumor Assessment Core (MSKCC). All solvents were purchased from Fisher Scientific or Sigma-Aldrich and were used as received; anhydrous solvents were used for chemical reactions, and HPLC grade solvents were used for aqueous workups, recrystallizations and chromatography. Chemical reagents were purchased from Sigma, Fisher, MedChem Express, Aaron Chemicals, Ambeed, Aablocks, and WuXi AppTec and were used as received. Reactions were run as described in the individual procedures using standard double manifold and syringe techniques. Glassware was dried by baking in an oven at 130 °C for 12h prior to use or was flame dried. The pH of aqueous solutions was estimated using pH paper. Vacuum filtrations were carried out using a house vacuum line (about 100 torr). In the individual procedures, the phrases “concentration under vacuum” and “concentrated to dryness” mean that solvent was removed on a rotary evaporator using a diaphragm pump (with an automatic vacuum regulator) and remaining traces of volatiles were removed on a high-vacuum (<1 torr) oil pump. Unless specified otherwise, the term “flask” refers to the round-bottomed variety.

[0125] NMR Assays.1H NMR spectra were recorded at 600 MHz or as otherwise noted on a Bruker spectrometer and are reported in ppm using the residual solvent signal (dimethylsulfoxide-d6 = 2.50 ppm; methanol-d4 = 3.31 ppm, water-d2 = 4.79 ppm, and chloroform-d = 7.26 ppm) as an internal standard. Data are reported as: {(shift), [(s=singlet, d=doublet, dd=doublet of doublets, ddd=doublet of a doublet of doublets, t=triplet, dt=doublet of triplets, q=quartet, m=multiplet, br=broad, ap=apparent), (. / =coupling constantMSK-20525in Hz), (integration)]}. Proton-decoupled13C NMR spectra were recorded at 151 MHz on a Bruker spectrometer and are reported in ppm using the residual solvent signal (dimethylsulfoxide-d6 = 39.5 ppm) as an internal standard.19F NMR spectra were recorded at 376 MHz on a Bruker spectrometer and are reported in ppm; compounds with only one signal were integrated relative to a known amount of the internal standard.

[0126] Chromatography Assays. Reactions were monitored by TLC using EMD silica gel 60 F254 (250 pm) glass-backed plates (visualized by UV fluorescence quenching and stained with basic KMnCh solution) and by liquid chromatography -tandem mass spectrometry (LC-MS). Analysis by reverse-phase LC-MS was carried out as noted or otherwise on a Waters system (Acquity Premier UPLC-MS), with a C18 column (2.1 mm x 100 mm, 1.7 pm particle size) with a multi wavelength detector, eluted at 0.4 mL / min, and using a 8 min linear gradient method with a mobile phase consisting of water (0.05% trifluoroacetic acid (TFA) added) / acetonitrile (0.04% TFA added): 95:5 -> 5:95 (0-5 min), held at 5:95 (5-6.45 min), 5:95 — 95:5 (6.45-6.5 min), and held at 95:5 (6.5-8 min). Sample runs were monitored using alternating positive / negative electrospray ionization (150-1200 amu) and UV detection. Automated preparative normal-phase chromatography was carried out as noted or otherwise with a Teledyne CombiFlash NextGen 300+ purification system with a diode array detector (runs were monitored at 254 and 280 nm). Pre-packed silica gel cartridges (4, 12, 24 and 40 g; 40-63 pm irregular particle size) were employed for normalphase (silica gel) chromatography, eluting at 13, 30, 40, and 60 mL / min respectively.Preparative reverse-phase chromatography was carried out as noted or otherwise with a Waters system using a C18 column (30 mm x 100 mm, 5 pm particle size) with a multi wavelength detector, eluting at 24 mL / min; crude samples were injected with an autosampler, typically in a 30:70 mixture of acetonitrile / water (0.1-0.95 mL / inj ection).Example 2: Synthesis of Compound 54

[0127] Synthesis and Characterization of Compound 54-1.MSK-2052554-1A mixture of Compound 53-2 (4-bromo-5-chloro- \-tetrahydropyr:in-4-yl-pyridin-2-amine) (1.60 g, 5.49 mmol, 1 equiv.), Compound g (4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane) (6.97 g, 27.4 mmol, 5 equiv ), KO Ac (2.69 g, 27.4 mmol, 5 equiv ), Pd(dppf)C12 (402 mg, 549 pmol, 0.1 equiv.) in toluene (32.0 mL) at 25 °C was degassed and purged with N2 three times, and then the mixture was heated to 120 °C and stirred at 120 °C for 2 h under N2 atmosphere. LC-MS showed Compound 53-2 was consumed and the desired m / z was detected. The mixture was cooled to 25 °C and poured into H2O (50 mL), then the aqueous phase was extracted with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (50.0 mL x 1), dried with anhydrous Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiCL, petroleum ether / EtOAc = 100 / 1 to 0 / 1, petroleum ether / EtOAc = 0 / 1, Rf = 0.15), then the fraction was concentrated to give Compound 54-1 ([5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]boronic acid) (600 mg, crude) as brown oil. LC-MS: m / z = 257.1 [M+H]+.

[0128] Synthesis and Characterization of Compound 54-2.KOAc, Pd(dppf)CI2toluene, H2O, 25 ~ 100 °C, 6 hrsYield over two steps: 19.3% 54-1 54-2A mixture of Compound 54-1 ([5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyljboronic acid) (550 mg, 1.93 mmol, 1 equiv ), Compound h (methyl 5-bromothiazole-2-carboxylate) (514 mg, 2.32 mmol, 1.2 equiv.), KOAc (568 mg, 5.79MSK-20525mmol, 3 equiv.), Pd(dppf)C12 (141 mg, 193 pmol, 0.1 equiv.) in H2O (1.10 mL) and toluene (11.0 mL) at 25 °C was degassed and purged with N2 three times, and then the mixture was heated to 100 °C and stirred at 100 °C for 6 h under N2 atmosphere. LC-MS showed Compound 54-1 was consumed and the desired m / z was detected. The mixture was cooled to 25 °C and poured into H2O (50.0 mL), then the aqueous phase was extracted with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (50.0 mL x 1), dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiCL, petroleum ether / EtOAc = 100 / 1 to 3 / 1, petroleum ether / EtOAc = 1 / 1, Rf = 0.20), then the fraction was concentrated. The crude product was purified by prep-HPLC (column: Waters XBridge® Cl 8 150 mm x 50 mm, 10 pm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 33%-63% acetonitrile (0.04% TFA) over 11.0 min), then the aqueous phase was extracted with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (50.0 mL x 1), dried with anhydrous Na2SO4, filtered, and concentrated to give Compound 54-2 (Methyl 5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylate) (400 mg, 1.06 mmol, 19.3% yield, 93.5% purity) as a yellow solid. LC-MS: m / z = 354.0 [M+H]+.1H NMR: (400 MHz, DMSO ) <58.45 (s, 1H), 8.16 (s, 1H), 6.99 (br d, J= 7.6 Hz, 1H), 6.81 (s, 1H), 3.95 (s, 3H), 3.86 (br d, J= 11.2 Hz, 2H), 3.40 (br t, J= 10.4 Hz, 3H), 1.86 (br d, J= 12.0 Hz, 2H), 1.49 - 1.36 (m, 2H).

[0129] Synthesis and Characterization of Compound 54-3.LiOH«H2O THF, H2O, 25 °C, 2 hrscrude 54-254-3To a solution of Compound 54-2 (methyl 5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylate) (400 mg, 1.05 mmol, 1 equiv.) in THF (4.00 mL) and H2O (4.00 mL) was added LiOH•H2O (88.2 mg, 2.10 mmol, 2 equiv.). The mixture was stirred atMSK-2052525 °C for 2 h. LC-MS showed Compound 54-3 was consumed and the desired m / z was detected. The mixture was concentrated to remove most of the THF, then adjusted to pH 4-5 with 1 M HC1, filtered, and the filter cake was concentrated to give Compound 2-3 (5- [5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylic acid) (420 mg, crude) as a yellow solid. LC-MS: m / z = 340.0 [M+H]+.

[0130] Synthesis and Characterization of Compound 54-4.54-3 54-4To a solution of Compound 54-3 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylic acid) (90.0 mg, 242 pmol, 1 equiv.) inNMP (1.00 mL) was added Compound e ((15)-2-azido-l-(3-chlorophenyl)ethanamine) (67.8 mg, 291 pmol, 1.2 equiv., HC1), HOBt (39.3 mg, 291 pmol, 1.2 equiv.) and EDCI (93.0 mg, 485 pmol, 2 equiv.) and DIEA (62.6 mg, 485 pmol, 84.4 pL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 54-3 was consumed and the desired m / z was detected. The reaction mixture was poured into H2O (20.0 mL), and the aqueous phase was extracted with EtOAc (20.0 mL x 2). The organic layers were combined and washed with brine (20.0 mL x 5), dried with anhydrous Na2SO4, filtered, and concentrated to give Compound 54-4 (A-[(15)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (196 mg, crude) as yellow oil. LC-MS: m / z = 518.0 [M+H]+.

[0131] Synthesis and Characterization of Compound 54.MSK-20525Compound 54To a solution of Compound 54-4 ( \-|( LS)-2-azido-l-(3-chlorophenyl)ethyl|-5-|5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (170 mg, 255 pmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (101 mg, 383 pmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 54-4 was consumed and the desired m / z (retention time (RT) = 0.497 min) was detected. The mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18 150 mm x 25 mm, 10 pm; mobile phase: [H2O (0.225% FA)-acetonitrile]; gradient: 12%-42% acetonitrile (0.04% TFA) over 15.0 min), then it was lyophilized to give a crude product. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm x 25 mm, 10 pm; mobile phase: [H2O (10 mM NHJTCC^-acetonitrile]; gradient: 38%-68% acetonitrile (0.04% TFA) over 9.0 min), then it was lyophilized. Compound 54 (A-|(LS’)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (38.7 mg, 76.8 pmol, 7.27% yield, 97.8% purity) was obtained as a yellow solid. LC-MS: m / z = 492.3 [M+H]+.1H NMR: (400 MHz, DMSO-tL) <58.36 (s, 1H), 8.15 (s, 1H), 7.47 (s, 1H), 7.39 - 7.29 (m, 3H), 6.96 (br d, J= 7.2 Hz, 1H), 6.79 (s, 1H), 5.00 - 4.85 (m, 1H), 3.98 - 3.82 (m, 3H), 3.40 (brt, J= 10.8 Hz, 3H), 3.01 - 2.88 (m, 2H), 1.87 (br d, J= 12.8 Hz, 2H), 1.48 - 1.36 (m, 2H).Example 3: Synthesis of Compounds 55-P1 and 55-P2.

[0132] Synthesis and Characterization of Compound 55-1.MSK-20525HOBt, EDCI, DIEA NMP, 0 ~ 25 °C, 2 hrs crude54-3 55-1To a solution of Compound 54-3 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylic acid) (250 mg, 684 pmol, 1 equiv.) in NMP (3.00 mL) was added Compound f (2-azido-l-[3-fluoro-5-(trifluoromethyl)phenyl]ethanamine) (263 mg, 821 pmol, 1.2 equiv., HC1), HOBt (111 mg, 821 pmol, 1.2 equiv.) and EDCI (262 mg, 1.37 mmol, 2 equiv.) and DIEA (177 mg, 1.37 mmol, 238 pL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 54-3 was consumed and the desired m / z was detected. The mixture was cooled to 25 °C and poured into H2O (50.0 mL), then the aqueous phase was extracted with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (50.0 mL x 5), dried with anhydrous Na2SC>4, filtered, and concentrated in vacuum at 35 °C to give Compound 55-1 (A-[2-azido-l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (530 mg, crude) as yellow oil. LC-MS: m / z = 570.1 [M+H]+.

[0133] Synthesis and Characterization of Compound 55-2.THF, H2O, 25 °C, 12 hrs two steps yield: 69.1 %55-2MSK-20525To a solution of Compound 55-1 (7V-[2-azido-l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (500 mg, 789 pmol, 1 equiv.) in THF (4.50 mL) and H2O (0.50 mL) was added PPh₃ (310 mg, 1.18 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 55-1 was consumed and the desired m / z was detected. The mixture was concentrated. The filtrate was purified by prep-HPLC (column: Waters XBridge® C18 150 mm x 50 mm, 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-acetonitrile]; gradient: 42%-72% acetonitrile (0.04% TFA) over 11.0 min), then it was lyophilized to give Compound 55-2 (7V-[2-amino-l-[3-fluoro-5- (trifluoromethyl)phenyl]ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (260 mg, 476 pmol, 69.1% yield, 99.6% purity) as a yellow solid. LC-MS: m / z = 544.2 [M+H]+.

[0134] Synthesis and Characterization of Compounds 55-P1 and 55-P2.SFCyield: 37.9%55-2Compound 55-2 was purified by SFC (column: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 pm); mobile phase: [CCL-MeOH (0.1% NEb’FhO)]; B%: 63%, isocratic elution mode), then it was concentrated. The residue was dissolved in acetonitrile (2 mL) and H2O (15 mL), and lyophilized to give product. Compound 55-P2 (7V-[(ll?)-2-amino-l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (50.2 mg, 89.9 pmol, 18.9% yield, 97.4% purity) was obtained as a yellow solid. Compound 55-P1 (7V-[(Ly)-2-amino-l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino) -4-pyridyl]thiazole-2-carboxamide) (50.2 mg, 90.5 pmol, 19.0% yield, 98.0% purity) was obtained as a yellow solid. Compound 55-P1 LC-MS: m / z = 544.3 [M+H]+. SFC: RT = 1.501 min, enantiomerically enriched to 97.3% under 220 nm.1H NMR: (400 MHz, DMSO-d6)88.37 (s, 1H), 8.14 (s, 1H), 7.69 - 7.51 (m, 3H), 6.97 (d, J= 7.6 Hz, 1H), 6.79 (s, 1H),MSK-205255.05 (br t, J = 6.4 Hz, 1H), 3.97 - 3.80 (m, 3H), 3.46 - 3.34 (m, 3H), 3.06 - 2.89 (m, 2H), 1.92 - 1.82 (m, 2H), 1.49 - 1.35 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -61.022, -110.839.Compound 55-P2 LC-MS: m / z = 544.3 [M+H]+. SFC: RT = 0.973 min, enantiomerically enriched to 99.3% under 220 nm.1H NMR: (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7.58 (br t, J= 10.4 Hz, 2H), 6.97 (d, J= 7.6 Hz, 1H), 6.79 (s, 1H), 5.05 (br t, J= 6.4 Hz, 1H), 3.98 - 3.81 (m, 3H), 3.45 - 3.34 (m, 3H), 3.04 - 2.90 (m, 2H), 1.89 - 1.83 (m, 2H), 1.47 - 1.37 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -61.022, -110.839.Example 4: Synthesis of Compound f

[0135] Synthesis and Characterization of Compound f-2.TMSCN, TiO(i-Pr)4NH3 / MeOH, 25 °C, 12 hrs yield: 67.5 %f-2To a solution of Compound f-1 (3-fluoro-5-(trifluoromethyl)benzaldehyde) (5.00 g, 26.0 mmol, 1 equiv.) in NH3 / MeOH (7 M, 50.0 mL, 13.5 equiv.) was added TiO(i-Pr)4 (8.88 g, 31.2 mmol, 9.22 mL, 1.2 equiv.) at 25 °C and stirred at 25 °C for 2 h. Then TMSCN (2.58 g, 26.0 mmol, 3.26 mL, 1 equiv.) was added to the mixture at 25 °C and the mixture was stirred at 25 °C for 12 h. LC-MS showed Compound f-1 was consumed and the desired m / z was detected. The mixture was poured into ice H2O (100 mL). After stirring, the mixture was filtered through celite, washed with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (100 mL x 1), dried with anhydrous Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography (SiCL, petroleum ether / EtOAc = 100 / 1 to 10 / 1, petroleum ether / EtOAc = 3 / 1, Rf = 0.4), then the fraction was concentrated. Compound f-2 (2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]acetonitrile) (3.83 g, 17.6 mmol, 67.5% yield) was obtained as yellow oil. LC-MS: m / z = 219.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 5.22 (br t, J= 7.6 Hz, 1H), 3.04 (br d, J= 8.0 Hz, 2H).

[0136] Synthesis and Characterization of Compound f-3.MSK-20525HCI / dioxane(2 M) MeOH, 25 - 60 °C, 12 hrs yield: 70.5 %f-2To a solution of Compound f-2 (2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]acetonitrile) (3.83 g, 17.6 mmol, 1 equiv.) in MeOH (70.0 mL) was added HCl / dioxane (2 M, 70.0 mL, 7.97 equiv.) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 12 h. LC-MS showed Compound f-2 was consumed and the desired m / z wa detected. The mixture was cooled to 25 °C and concentrated to remove most of MeOH and HCl / dioxane. The mixture was dissolved in EtOAc (50.0 mL) and adjusted pH to 8 with NaHCOs solution. Then the aqueous phase was extracted with EtOAc (50.0 mL x 2). The organic layers were combined and washed with brine (100 mL x 1), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum at 35 °C to give Compound f-3 (methyl 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]acetate) (4.44 g, 12.4 mmol, 70.5% yield, 70% purity) as yellow oil. LC-MS: m / z = 252.2 [M+H]+. 'H NMR: (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.62 - 7.56 (m, 2H), 4.74 (s, 1H), 3.62 (s, 3H).

[0137] Synthesis and Characterization of Compound f-4.(BOC)2O, TEA DCM, 25 °C, 12 hrsyield: 70.6 %To a solution of Compound f-3 (methyl 2-amino-2-[3-fluoro-5- (trifluoromethyl)phenyl] acetate) (4.34 g, 12.1 mmol, 1 equiv.) and TEA (3.67 g, 36.3 mmol, 5.05 mL, 3 equiv.) in CH2Cl2 (30.0 mL) was added (Boc)2O (3.17 g, 14.5 mmol, 3.33 mL, 1.2 equiv.) in CH2Cl2 (10 mL) at 25 °C. After addition, the mixture was stirred at 25 °C for 12 h. LC-MS showed Compound f-3 was consumed and the desired m / z was detected.MSK-20525The mixture was poured into H2O (50 mL), then the aqueous phase was extracted with CH2CI2 (50.0 mL x 2). The organic layers were combined and washed with brine (100 mL x 1), dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiCL, petroleum ether / EtOAc = 100 / 1 to 10 / 1, petroleum ether / EtOAc = 3 / 1 Rf = 0.60), then the fraction was concentrated. Compound f-4 (methyl 2-(terf-butoxycarbonylamino)-2-[3-fluoro-5-(trifluoromethyl)phenyl]acetate) (3.00 g, 8.54 mmol, 70.61% yield) was obtained as yellow oil. LC-MS: m / z = 252.2 [M+H]+.1H NMR:(400 MHz, DMSO-d6) δ 8.01 (br d, J= 8.4 Hz, 1H), 7.69 (s, 1H), 7.64 (br t, J= 8.4 Hz, 2H), 5.48 (br d, J= 8.4 Hz, 1H), 3.64 (s, 3H), 1.39 (s, 9H).

[0138] Synthesis and Characterization of Compound f-5.DIBAL-H THF, 0 °C, 2 hrs crudeTo a solution of Compound f-4 (methyl 2-(tert-butoxycarbonylamino)-2-[3-fluoro-5-(trifluoromethyl)phenyl]acetate) (2.65 g, 6.83 mmol, 1 equiv., HC1) in THF (20.0 mL) was degassed and purged with N2 three times. Then added DIBAL-H (1 M, 34.2 mL, 5 equiv.) at 0 °C. The mixture was stirred at 0 °C for 2 h. TLC (petroleum ether: EtOAc = 3: 1) indicated Compound f-4 was consumed and one new spot (Rf = 0.30) was formed. The mixture was poured into ice H2O (100 mL) and filtered, the filter cake was washed with EtOAc (10.0 mL x 5), then the filtrate was extracted with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (100 mL x 1), dried with anhydrous Na2SO4, filtered, and concentrated to give Compound f-5 ( / ‘cr / '-butyl N-[l-[3-fluoro-5- (trifluoromethyl)phenyl]-2-hydroxyethyl]carbamate) (2.4 g, crude) as a yellow solid. LC-MS: m / z = 224.1 (M-100+H)+.1H NMR: (400 MHz, MeOD) δ 7.49 (s, 1H), 7.35 (br dd, J= 9.6, 15.2 Hz, 2H), 4.70 (br s, 1H), 3.75 - 3.65 (m, 2H), 1.52 - 1.32 (m, 9H).

[0139] Synthesis and Characterization of Compound f-6.MSK-20525MsCI DCM, 0 -25 °C, 1 hrtwo steps yield: 74.0%f-5 f-6To a solution of Compound f-5 (tert-butyl 7V-[l-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxy ethyl] carbamate) (2.20 g, 6.49 mmol, 1 equiv.) in CH2Cl2 (“DCM”; 22.0 mL) was added TEA (1.31 g, 13.0 mmol, 1.81 mL, 2 equiv.) and MsCl (1.12 g, 9.78 mmol, 757 μL, 1.51 equiv.) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 1 hr. LC-MS showed Compound f-5 was consumed and the desired m / z (RT = 0.610 min) was detected. The mixture was poured into ice NH4CI (50.0 mL), then the aqueous phase was extracted with CH2CI2 (50.0 mL x 2). The organic layers were combined and washed with brine (50.0 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give Compound f-6 ([2-(tert-butoxycarbonylamino)-2-[3-fluoro-5- (trifluoromethyl)phenyl] ethyl] methanesulfonate) (2.80 g, 6.32 mmol, 74.0% yield, 90.6% purity) as yellow oil. LC-MS: m / z = 302.0 (M-100+H)+.1H NMR: (400 MHz, DMSO-d6) δ 7.80 (br d, J= 8.4 Hz, 1H), 7.68 - 7.59 (m, 3H), 5.04 (br d, J= 5.6 Hz, 1H), 4.37 - 4.24 (m, 2H), 3.18 (s, 3H), 1.38 (s, 9H).

[0140] Synthesis and Characterization of Compound f-7.NaN3, DMF, 25 - 50 °C, 12 hrscrudef-6 f-7To a solution of Compound f-6 ([2-(tert-butoxycarbonylamino)-2-[3-fluoro-5-(trifluoromethyl)phenyl] ethyl] methanesulfonate) (2.80 g, 6.32 mmol, 1 equiv.) in DMF (28.0 mL) was added NaNs (0.84 g, 12.9 mmol, 2.04 equiv.) at 25 °C. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. TLC (petroleum ether / EtOAc = 5 / 1) indicated Compound f-6 (Rf = 0.10) was consumed and one new spot (Rf = 0.50) was formed. TheMSK-20525mixture was cooled to 25 °C and poured into ice NaHCO3 (50.0 mL), then the aqueous phase was extracted with EtOAc (50.0 mL x 3). The organic layers were combined and washed with brine (50.0 mL x 4), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum at 35 °C. The residue was purified by column chromatography (SiCL, petroleum ether / EtOAc = 100 / 1 to 10 / 1, petroleum ether / EtOAc = 5 / 1, Rf = 0.50), then the fraction was concentrated to give Compound f-7 (tert-butyl 7V-[2-azido-l-[3-fluoro-5-(trifluoromethyl) phenyljethyljcarbamate) (2.00 g, crude) as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.78 (br d, J= 8.8 Hz, 1H), 7.65 (s, 1H), 7.59 (br d, J= 8.8 Hz, 2H), 4.96 - 4.83 (m, 1H), 3.54 - 3.47 (m, 2H), 1.38 (s, 9H).

[0141] Synthesis and Characterization of Compound f.HCI / dioxane (2 M) - ►25 °C, 3 hrstwo steps yield: 79.1 %f-7To a solution of Compound f-7 (tert-butyl 7V-[2-azido-l-[3-fluoro-5-(trifluoromethyl)phenyl] ethyl] carbamate) (1.90 g, 5.16 mmol, 1 equiv.) was added HCI / dioxane (2 M, 36.0 mL, 14 equiv.) at 25 °C for 3 h. LC-MS showed Compound f-7 was consumed and the desired m / z (RT = 0.439 min) was detected. The mixture was concentrated to give Compound f (2-azido-l-[3-fluoro-5-(trifluoromethyl)phenyl]ethanamine) (1.60 g, 5.00 mmol, 97.05% yield, 89% purity, HC1) as yellow oil. LC-MS: m / z = 249.1 [M+H]+'H NMR: (400 MHz, DMSO-d6) δ 8.96 (br s, 3H), 7.89 (s, 1H), 7.85 (br d, J= 9.6 Hz, 1H), 7.80 (br d, J= 8.4 Hz, 1H), 4.71 (t, J= 6.4 Hz, 1H), 4.00 - 3.82 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -61.166, -109.668.Example 5: Synthesis of Compound 57

[0142] Synthesis and Characterization of Compound 57-1.MSK-20525To a solution of Compound 54-2 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylic acid) (90.0 mg, 242 pmol, 1 equiv.) inNMP (1.00 mL) was added Compound c ((15)-2-azido-l-(3-chloro-5-fluorophenyl)ethanamine) (73.0 mg, 291 pmol, 1.2 equiv., HC1), HOBt (39.3 mg, 291 pmol, 1.2 equiv.) and EDCI (92.9 mg, 485 pmol, 2 equiv.) and DIEA (62.6 mg, 485 pmol, 84.4 pL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 54-3 was consumed and the desired m / z was detected. The reaction mixture was poured into H2O (20.0 mL), the aqueous phase was extracted with EtOAc (20.0 mL x 2). The organic layers were combined and washed with brine (20.0 mL x 5), dried with anhydrous Na2SO4, filtered, and concentrated to give Compound 57-1 (A-[(15)-2-azido-l-(3-chloro-5-fluorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (215 mg, crude) as yellow oil. LC-MS: m / z = 536.0 [M+H]+.

[0143] Synthesis and Characterization of Compound 57.PPh3THF, H2O, 25 °C, 12 hrs two steps yield: 35.3%Compound 57MSK-20525To a solution of Compound 57-1 (N-[(1S)-2-azido-1-(3-chloro-5-fluorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (190 mg, 290 pmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (114 mg, 435 pmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 57-1 was consumed and the desired m / z was detected. The mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna™ Cl 8 150 mm x 25 mm, 10 pm; mobile phase: [H2O (0.225% FA) -acetonitrile]; gradient: 12%-42% acetonitrile (0.04% TFA) over 15.0 min), then it was lyophilized to give crude product. The crude product was purified by prep-HPLC (column: Waters XB ridge® 150 mm x 25 mm, 10 pm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 38%-68% acetonitrile (0.04% TFA) over 9.0 min), then it was lyophilized. Compound 57 (7V-[(LS)-2-amino-l-(3-chloro-5-fluorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (44.9 mg, 85.6 pmol, 29.5% yield, 97.3% purity) was obtained as a yellow solid. LC-MS: m / z = 510.1 [M+H]+. 'H NMR: (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.15 (s, 1H), 7.40 - 7.19 (m, 3H), 6.97 (d, J= 7.6 Hz, 1H), 6.79 (s, 1H), 5.01 - 4.87 (m, 1H), 3.95 -3.83 (m, 3H), 3.44 - 3.36 (m, 3H), 3.01 - 2.87 (m, 2H), 1.86 (br d, J= 12.0 Hz, 2H), 1.49 -1.37 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -110.861.Example 6: Synthesis of Compound 151

[0144] Synthesis and Characterization of Compound 151-2.DIPEA, DMSO140 °C, 16 hYield: 86%To a solution of Compound 151-1 (5-chloro-2-fluoro-4-iodopyridine) (600 mg, 2.33 mmol, 1 equiv.) in DMSO (11.7 mL), isopropylamine (0.397 mL, 276 mg, 4.66 mmol, 2 equiv.) and DIPEA (0.812 mL, 602 mg, 4.66 mmol, 2 equiv.) were added at room temperature. The reaction mixture was stirred at 140 °C for 16 h. LC-MS reflected full consumption of Compound 151-1 and detection of the desired m / z. The reaction mixture was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic layer was washed with brine (50MSK-20525mL x 3), dried with anhydrous Na2SC>4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 12 g; mobile phase: [hexanes-EtOAc]; gradient: 0%-20% EtOAC over 23 min). The desired fractions were concentrated and dried to afford Compound 151-2 (5-chloro-4-iodo-A-isopropylpyridin-2-amine) (594 mg, 2.00 mmol, 86% yield) as a pale yellow solid. TLC: A / 0.33 (10% EtOAc / hexanes). *H-NMR (600 MHz, CDC13): 88.02 (s, 1H), 6.89 (s, 1H), 4.36 (s, 1H), 3.82 (h, J= 6.7 Hz, 1H), 1.24 (d, J= 6.4 Hz, 6H).13C{1H}-NMR (151 MHz, CDCl3): δ 156.4, 146.0, 123.6, 117.2, 109.8, 43.4, 22.8. LC-MS (ESI) m / z = ([M+H]+) 297.1.

[0145] Synthesis and Characterization of Compound 151-3.XPhos-Pd G3, K3PO4 THF, H2O, 40 °C, 22 h Yield: 97%151-3Compound 151-2 (5-chloro-4-iodo-N-isopropylpyridin-2-amine) (29.7 mg, 100 pmol, 1 equiv.), methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (29.5 mg, 110 pmol, 1.1 equiv.), and K3PO4 (63.7 mg, 300 pmol, 3 equiv.) was suspended in THF (0.83 mL) and H2O (0.17 mL), and the mixture was sparged with argon for 10 min. XPhos-Pd G3 (1.69 mg, 2 pmol, 0.02 equiv.) was then added, and the suspension was stirred at 40 °C under argon for 4 h. Additional methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (13.4 mg, 50 pmol, 0.5 equiv.) and XPhos-Pd G3 (1.69 mg, 2 pmol, 0.02 equiv.) was then added, and the suspension was stirred at 40 °C under argon for 18 h. LC-MS analysis reflected full consumption of Compound 151-2 and detection of the desired m / z. The reaction mixture was diluted in EtOAc (25 mL) and washed with H2O (25 mL x 2) and brine (25 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 4 g; mobile phase: [hexanes-EtOAc]; gradient: 5%-20% EtOAc over 38 min). The desired fractions were concentrated and dried to afford Compound 151-3 (methyl 5-(5-chloro-2-(isopropylamino)pyridin-4-MSK-20525yl)thiophene-2-carboxylate) (30.1 mg, 96.8 pmol, 97% yield) as an orange oil. TLC:RfO.18 (10% EtOAc / hexanes). 'H-NMR (600 MHz, CDC13): 88.06 (s, 1H), 7.71 (d, J= 3.9 Hz, 1H), 7.39 (d, J= 4.0 Hz, 1H), 6.40 (s, 1H), 4.46 (d, J= 7.8 Hz, 1H), 3.84 (s, 3H), 3.80 (m, 1H), 1.18 (d, J = 6.4 Hz, 6H).13C{1H}-NMR (151 MHz, CDCl3): δ 162.4, 156.9, 148.9, 144.9, 140.1, 134.4, 133.4, 128.9, 116.7, 107.0, 52.4, 43.5, 22.9. LC-MS (ESI) m / z = ([M+H]+) 311.1.

[0146] Synthesis and Characterization of Compound 151-4.LiOH. H2O THF, H2O 80 °C, 1 h Yield: 83%151-4Compound 151-3 (methyl 5-(5-chloro-2-(isopropylamino)pyridin-4-yl)thiophene-2-carboxylate) (30.1 mg, 96.8 pmol, 1 equiv.) and LiOH·H2O (20.3 mg, 484 pmol, 5 equiv.) was suspended in THF (0.48 mL) and H2O (0.48 mL). The mixture was stirred at 80 °C for 1 h. LC-MS analysis reflected full consumption of Compound 151-3 and detection of the desired m / z. The reaction mixture was acidified with concentrated hydrochloric acid to below pH 3, diluted with about 50:50 acetonitrile / H2O (about 3 mL) to solubilize remaining solids, then purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 22%-27% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford Compound 151-4 (5-(5-chloro-2-(isopropylamino)pyridin-4-yl)thiophene-2-carboxylic acid) (23.8 mg, 80.1 pmol, 83% yield) as a yellow solid.1H-NMR (600 MHz, MeOH-d4): δ 8.10 (s, 1H), 7.83 (d, J= 4.0 Hz, 1H), 7.68 (d, J= 3.9 Hz, 1H), 7.11 (s, 1H), 3.96 (h, J= 6.4 Hz, 1H), 1.83 (d, J= 6.4 Hz, 6H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.9, 152.4, 144.4, 141.5, 137.9, 133.1, 130.8, 116.3, 112.7, 44.0, 20.8. LC-MS (ESI) m / z = ([M+H]+) 297.2.

[0147] Synthesis and Characterization of Compound 151.MSK-20525151-4Compound 151To a solution of Compound 151-4 (5-(5-chloro-2-(isopropylamino)pyridin-4-yl)thiophene-2-carboxylic acid) (23.8 mg, 80.0 pmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 280 pmol, 3.5 equiv.) was added, and the solution was stirred for 30 min at 0 °C. (5)-2-Amino-2-(3-chlorophenyl)ethan-l-ol hydrochloride (16.7 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 151-4 and detection of the desired m / z. The reaction mixture was diluted in EtOAc (4 mL) and washed with H2O (4 mL x 3) and brine (4 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 4 g; mobile phase: [CH2Cl2-MeOH]; gradient: l%-4% MeOH over 15 min). The desired fractions were concentrated and dried to afford Compound 151 ((. S’)-5-(5-chloro-2-(isopropylamino)pyridin-4-yl)-\-( l-(3-chlorophenyl)-2-hydroxyethyl)thiophene-2-carboxamide) (5.41 mg, 12.0 pmol, 15% yield) as a yellow solid. TLC: R / 0.29 (5% MeOH / CH2Cl2).1H-NMR (600 MHz, MeOH-d4): δ 8.07 (s, 1H), 7.92 (d, J= 3.9 Hz, 1H), 7.71 (d, J= 4.0 Hz, 1H), 7.46 (m, 1H), 7.36 (m, 2H), 7.31 (m, 1H), 7.10 (s, 1H), 5.17 (t, J = 5.9 Hz, 1H), 3.95 (hep, J = 6.4 Hz, 1H), 3.89 (d, J = 6.6 Hz, 2H), 1.32 (d, 6.4 Hz, 6H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.0, 152.2, 144.6, 142.5, 142.2, 139.9, 134.0, 130.9, 129.7, 128.5, 127.2, 126.8, 125.2, 116.3, 112.5, 64.1, 56.0, 44.0, 20.8. LC-MS (ESI) m / z = ([M+H]+) 450.1.Example 7: Synthesis of Compound 152

[0148] Synthesis and Characterization of Compound 152-1.MSK-20525ClHN DIPEA, DMSOF 140 °C, 18 h151-1 Yield: 86%152-1To a solution of Compound 151-1 (5-chloro-2-fluoro-4-iodopyridine) (1.03 g, 4.00 mmol, 1 equiv.) in DMSO (20.0 mL) was added tetrahydro-2H-pyran-4-amine (809 mg, 8 mmol, 2 equiv.) and DIPEA (1.03 g, 8.00 mmol, 1.39 mL, 2 equiv.) at room temperature. The mixture was stirred at 140 °C for 18 h. LC-MS analysis reflected full conversion of Compound 151-1 and detection of the desired m / z. The reaction mixture was partitioned between H2O (200 mL) and EtOAc (200 mL). The organic layer was washed with brine (200 mL x 3), dried with anhydrous Na2SC>4, filtered, and concentrated to afford a crude product. The crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 24 g; mobile phase: [hexanes-EtOAc]; gradient: 10%-30% EtOAc over 27 min). The desired fractions were concentrated and dried to afford Compound 152-1 (5-chloro-4-iodo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine) (1.162 g, 3.433 mmol, 86% yield) as a pale yellow solid. TLC: A / 0.28 (25% EtOAc / hexanes). *H-NMR (600 MHz, CDCI3): 88.03 (s, 1H), 6.93 (s, 1H), 4.42 (d, J= 8.0 Hz, 1H), 4.01 (dt, J= 12.0, 3.6 Hz, 2H), 3.81 (m, 1H), 3.55 (td, J= 11.6, 2.3 Hz, 2H), 2.04 (m, 2H), 1.92 (m, 2H).13CfH}-NMR (151 MHz, CDCI3): 8155.9, 145.9, 124.1, 117.9, 109.8, 66.7, 47.7, 33.3. LC-MS (ESI) m / z = ([M+H]+) 339.1.

[0149] Synthesis and Characterization of Compound 152-2.Dioxane, H2O, 40 °C, 2 d Yield: 87%152-2MSK-20525Compound 152-1 (5-chloro-4-iodo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine) (339 mg, 1.00 mmol, 1 equiv.), methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (295 mg, 1.1 mmol, 1.1 equiv.), and K3PO4 (637 mg, 3.00 mmol, 3 equiv.) was suspended in dioxane (2.5 mL) and H2O (2.5 mL), and the mixture was sparged with argon for 10 min. XPhos-Pd G3 (16.9 mg, 20.0 pmol, 0.02 equiv.) was then added, and the suspension was stirred at 40 °C under argon for 18 h. Additional XPhos-Pd G3 (33.9 mg, 40.0 pmol, 0.04 equiv.) and dioxane (5 mL) was then added, and the suspension was stirred at 45 °C under argon for another 24 h. Additional methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (215 mg, 0.8 mmol, 0.8 equiv.) and XPhos-Pd G3 (16.9 mg, 20.0 pmol, 0.02 equiv.) was then added, and the suspension was stirred at 45 °C under argon for another 6 h. LC-MS analysis reflected near-complete consumption of Compound 152-1 and detection of the desired m / z. The reaction mixture was diluted in H2O (50 mL) and extracted with EtOAc (50 mL * 3). The organic layers were combined and washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 12 g; mobile phase:[hexanes-EtOAc]; gradient: 15%-40% EtOAc over 33 min). The desired fractions were concentrated and dried to afford Compound 152-2 (methyl 5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylate) (308 mg, 0.874 mmol, 87% yield) as a yellow solid. TLC: A / 0.12 (25% EtOAc / hexanes).1H-NMR (600 MHz, CDCI3): 88.16 (s, 1H), 7.81 (d, J= 3.9 Hz, 1H), 7.48 (d, J= 3.9 Hz, 1H), 6.53 (s, 1H), 4.59 (d, J= 7.8 Hz, 1H), 4.03 (dt, J= 12.1, 3.5 Hz, 2H), 3.89 (m, 1H), 3.57 (td, J= 11.6, 2.2 Hz, 2H), 2.06 (m, 2H), 1.56 (m, 2H).13CfH}-NMR (151 MHz, CDCI3): 8162.4, 156.3, 148.6, 144.5, 140.3, 134.6, 133.4, 129.0, 117.3, 107.8, 66.8, 52.4, 47.8, 33.3, 24.9. LC-MS (ESI) m / z = ([M+H]+) 353.3.

[0150] Synthesis and Characterization of Compound 152-3.MSK-20525LiOH. H2O THF, H20 80 °C, 1 h Yield: 58%152-3Compound 152-2 (methyl 5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylate) (303 mg, 0.860 mmol, 1 equiv.) and LiOH•H2O (180 mg, 4.30 mmol, 5 equiv.) was suspended in THF (2.2 mL) and H2O (2.2 mL). The mixture was stirred at 80 °C for 1 h. LC-MS analysis reflected full consumption of Compound 152-2 and detection of the desired m / z. The reaction mixture was acidified with concentrated hydrochloric acid to below pH 3, diluted with about 50:50 acetonitrile / H2O (about 12 mL) to solubilize remaining solids, then purified by prep-HPLC (column: Waters XBridge® C18 4.6 x 150 mm, 3.5 μm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 20%-30% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford Compound 152-3 (5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (170 mg, 0.501 mmol, 58% yield) as a yellow solid. 'H-NMR (600 MHz, DMSO-6): 88.12 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 6.97 (s, br, 1H), 6.76 (s, 1H), 3.86 (m, 3H), 3.40 (s, br, 2H), 1.86 (s, br, 2H), 1.42 (s, br, 2H).13C{1H}-NMR (151 MHz, DMSO-6): 8163.1, 163.0, 157.5, 148.2, 143.8, 139.3, 136.4, 133.7, 129.9, 114.8, 109.5, 66.4, 47.0, 33.1. LC-MS (ESI) m / z = ([M+H]+) 339.2.

[0151] Synthesis and Characterization of Compound 152.MSK-20525To a solution of Compound 152-3 (5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (27.1 mg, 80.0 μmol, 1 equiv.) and HATU (30.4 mg, 80.0 μmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 μL, 36.2 mg, 210 μmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (S)-2-Amino-2-(3-chlorophenyl)ethan-1-ol hydrochloride (16.7 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 152-3 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 μm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 28%-38% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 152 ((S)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)thiophene-2-carboxamide) (25.4 mg, 51.6 pmol, 64% yield) as a yellow solid. 'H-NMR (600 MHz, MeOH-6 / 4): 88.10 (s, 1H), 7.92 (d, J= 4.0 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.46 (s, 1H), 7.36 (m, 2H), 7.30 (m, 1H), 7.13 (s, 1H), 5.17 (t, J= 6.6 Hz, 1H), 4.00 (m, 3H), 3.90 (m, 3H), 3.56 (td, J= 11.7, 2.1 Hz, 2H), 2.02 (m, 2H), 1.64 (m, 2H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.0, 152.3, 144.7, 142.5, 142.2, 139.9, 138.1, 134.0, 130.9, 129.7, 128.5, 127.2, 126.8, 125.2, 116.5, 112.4, 66.0, 64.1, 56.0, 53.7, 31.9. LC-MS (ESI) m / z = ([M+H]+) 492.3.Example 8: Synthesis of Compound 153

[0152] Synthesis and Characterization of Compound 153To a solution of Compound 152-3 (5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (27.1 mg, 80.0 pmol, 1 equiv.) andMSK-20525HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. ( )-2-Amino-2-(3-chloro-5-fluorophenyl)ethan-l-ol hydrochloride (18.1 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 152-3 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 μm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 30%-40% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 153 ((S)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-N-(1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)thiophene-2-carboxamide) (23.9 mg, 46.8 pmol, 59% yield) as a yellow solid.1H-NMR (600 MHz, MeOH-t / 4): 88.12 (s, 1H), 7.92 (d, J= 4.0 Hz, 1H), 7.71 (d, <7= 4.0 Hz, 1H), 7.30 (s, 1H), 7.14 (m, 3H), 5.16 (t,.7= 6.4 Hz, 1H), 4.01 (dt, J = 11.6, 3.3 Hz, 2H), 3.90 (m, 3H), 3.56 (td, J= 11.7, 2.1 Hz, 2H), 2.01 (ddd, J= 12.7, 4.5, 2.1 Hz, 2H), 1.64 (m, 2H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 164.9 (d,1JC, F= 248.4 Hz, 1C), 164.1, 154.3, 146.8, 146.4 (d,3JC, F = 7.8 Hz, 1C), 144.4, 142.1, 140.0, 136.9 (d,3JC, F = 10.7 Hz, 1C), 133.0, 130.7, 125.1 (d,4JC, F = 3.1 HZ, 1C), 118.8, 118.7, 116.7 (d,2JC, F = 25.3 Hz, 1C), 114.5 (d,2JC, F = 22.4 Hz, 1C), 68.0, 65.9, 57.8, 57.8, 50.2, 34.0. LC-MS (ESI) m / z = ([M+H]+) 510.2.Example 9: Synthesis of Compound 154

[0153] Synthesis and Characterization of Compound 154HATU, DIPEA DMF, 0 °C - rt, 30 min Yield: 55%152-3 Compound 154To a solution of Compound 152-3 (5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (27.1 mg, 80.0 pmol, 1 equiv.) andMSK-20525HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (5)-2-Amino-2-(3-bromophenyl)ethan-l-ol (17.3 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 152-3 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 μm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 28%-38% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford Compound 154 ((S)-N-(1-(3-bromophenyl)-2-hydroxyethyl)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (23.8 mg, 44.3 pmol, 55% yield) as a yellow solid. 1H-NMR (600 MHz, MeOH-d4): 88.11 (s, 1H), 7.91 (d, J= 4.0 Hz, 1H), 7.70 (d, J= 4.0 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 7.9, 2.0 Hz, 1H), 7.29 (t, J= 7.9 Hz, 1H), 7.12 (s, 1H), 5.16 (t, J= 6.5 Hz, 1H), 4.01 (m, 2H), 3.90 (m, 3H), 3.56 (td, J= 11.7, 2.1 Hz, 2H), 2.01 (ddd, J= 12.6, 4.5, 2.2 Hz, 2H), 1.64 (m, 2H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.0, 152.6, 144.4, 142.4, 142.4, 140.0, 138.5, 130.8, 130.2, 130.0, 129.8, 128.5, 125.7, 122.1, 116.6, 112.3, 66.0, 64.1, 56.0, 48.1, 32.0. LC-MS (ESI) m / z = ([M+H]+) 536.2.Example 10: Synthesis of Compound 155

[0154] Synthesis and Characterization of Compound 155To a solution of Compound 152-3 (5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (27.1 mg, 80.0 pmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 p. L, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (<S’)-2-Amino-2-MSK-20525(3-bromo-5-fluorophenyl)ethan-l-ol hydrochloride (21.6 mg, 80.0 pmoL 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 152-3 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 μm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 30%-40% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 155 ((S)-N-(l-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (32.0 mg, 57.7 pmol, 72% yield) as a yellow solid. 'H-NMR (600 MHz, MeOH-6 / 4): 88.10 (s, 1H), 7.92 (d, J= 4.1 Hz, 1H), 7.72 (d, J= 4.0 Hz, 1H), 7.45 (s, 1H), 7.28 (dt, J= 8.2, 2.1 Hz, 1H), 7.20 (dt, J= 9.6, 2.0 Hz, 1H), 7.15 (s, 1H), 5.15 (t, J = 6.5 Hz, 1H), 4.00 (m, 3H), 3.90 (m, 3H), 3.56 (td, J= 11.7, 2.1 Hz, 2H), 2.01 (ddd, J= 12.8, 4.5, 2.2 Hz, 2H), 1.65 (m, 2H).13CfH}-NMR (151 MHz, MeOH-tZ4): 8162.7 (d,= 249.6 Hz, 1C), 162.0, 152.1, 144.8, 144.6 (d,3JC, F = 7.5 Hz, 1C), 142.4, 139.9, 137.7, 131.0, 128.6, 126.0 (d,4JC, F = 3.0 HZ, 1C), 122.2 (d,3JC, F = 10.7 Hz, 1C), 117.6 (d,2JC, F = 24.9 Hz, 1C), 116.6, 112.9 (d,2JC, F = 22.3 Hz, 1C), 112.6, 66.0, 63.8, 55.7 (d,4JC, F = 1.7 Hz, 1C), 53.7, 48.2, 31.9. LC-MS (ESI) m / z = ([M+H]+) 554.2.Example 11: Synthesis of Compound 156

[0155] Synthesis and Characterization of Compound 156.To a solution of Compound 152-3 (5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (27.1 mg, 80.0 pmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-MSK-20525(3-(trifluoromethyl)phenyl)ethan-l-ol (16.4 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 152-3 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / FFO (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 30%-40% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 156 ((S)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-N-(2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)thiophene-2-carboxamide) (24.0 mg, 45.7 pmol, 57% yield) as a yellow solid. ‘H-NMR (600 MHz, MeOH-6 / 4): 88.10 (s, 1H), 7.93 (d, J = 4.1 Hz, 1H), 7.76 (s, 1H), 7.71 (m, 2H), 7.59 (m, 2H), 7.14 (s, 1H), 5.26 (t, J= 6.6 Hz, 1H), 4.01 (m, 2H), 3.93 (m, 1H), 3.89 (m, 2H), 3.56 (td, J= 11.7, 2.1 Hz, 2H), 2.01 (ddd, J= 12.8, 4.5, 2.2 Hz, 2H), 1.65 (m, 2H).13CfH}-NMR (151 MHz, MeOH-d4): δ 162.0, 152.2, 144.8, 142.5, 141.3, 139.9, 137.9, 131.0, 130.7, 130.4 (q,2JC, F = 32.0 Hz, 1C), 129.0, 128.6, 124.2 (q,= 271.5 Hz, 1C), 123.9 (q,3JC, F = 4.0 HZ, 1C), 123.4 (q,3JC, F = 3.9 HZ, 1C), 116.6, 112.5, 66.0, 64.0, 56.1, 48.2, 31.9. LC-MS (ESI) m / z = ([M+H]+) 526.3.Example 12: Synthesis of Compound 157

[0156] Synthesis and Characterization of Compound 157-2.DIPEA, DMSO140 °C, 3 d157-1 Yield: 38%To a solution of Compound 157-1 (2-fluoro-4-iodo-5-methylpyridine) (1.42 g, 6.00 mmol, 1 equiv.) in DMSO (12 mL), tetrahydro-2H-pyran-4-amine (1.24 mL, 1.21 g, 12.0 mmol, 2 equiv.) and DIPEA (2.09 mL, 1.55 g, 12.0 mmol, 2 equiv.) were added at room temperature. The reaction mixture was stirred at 140 °C for 3 d. LC-MS reflected full consumption of Compound 157-1 and detection of the desired m / z. The reaction mixture was diluted in EtOAc (150 mL), washed with H2O (150 mL x 3) and brine (150 mL), dried with anhydrousMSK-20525Na2SC>4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 24 g; mobile phase: [hexanes-EtOAc]; gradient: 10%-35% EtOAc over 37 min). The desired fractions were concentrated and dried to afford Compound 157-2 (4-iodo-5-methyl-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine) (0.721 g, 2.27 mmol, 38% yield) as a pale brown solid. TLC: A / 0.19 (25% EtOAc / hexanes). *H-NMR (600 MHz, CDCh): 57.86 (s, 1H), 6.93 (s, 1H), 4.29 (d, J= 8.0 Hz, 1H), 4.01 (dt, J= 12.0, 3.6 Hz, 2H), 3.80 (m, 1H), 3.56 (td, J= 11.6, 2.2 Hz, 2H), 2.26 (s, 3H), 2.04 (m, 2H), 1.51 (m, 2H).13CfH}-NMR(151 MHz, CDCh): 8156.1, 146.6, 125.5, 116.9, 113.5, 66.8, 47.6, 33.4, 23.2. LC-MS (ESI) m / z = ([M+H]+) 319.2.

[0157] Synthesis and Characterization of Compound 157-3.XPhos-Pd G3, K3PO4 Dioxane, H2O, 50 °C, 18 h Yield: 81%157-2 157-3Compound 157-2 (4-iodo-5-methyl-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine) (318 mg, 1.00 mmol, 1 equiv.), methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (483 mg, 1.8 mmol, 1.8 equiv.), and K3PO4 (637 mg, 3.00 mmol, 3 equiv.) was suspended in dioxane (4.2 mL) and H2O (0.8 mL), and the mixture was sparged with argon for 10 min. XPhos-Pd G3 (42.3 mg, 50.0 pmol, 0.05 equiv.) was then added, and the suspension was stirred at 50 °C under argon for 18 h. LC-MS analysis reflected full consumption of Compound 157-2 and detection of the desired m / z. The reaction mixture was diluted in EtOAc (100 mL) and extracted with H2O (100 mL x 2) and brine (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 12 g; mobile phase: [hexanes-EtOAc]; gradient: 25%-50% EtOAc over 33 min). The desired fractions were concentrated and dried to afford Compound 157-3 (methyl 5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylate) (270 mg, 0.811 mmol, 81% yield) as a yellow solid. TLC: Ay 0.28 (50% EtOAc / hexanes). 'H-NMR (600 MHz, CDCh): 58.01 (s, 1H), 7.80 (d, J= 3.9MSK-20525Hz, 1H), 7.17 (d, J= 3.9 Hz, 1H), 6.45 (s, 1H), 4.43 (d, J= 7.9 Hz, 1H), 4.02 (dt, J= 11.9, 3.5 Hz, 2H), 3.94 (s, 1H), 3.87 (m, 1H), 3.57 (td, J= 11.6, 2.2 Hz, 2H), 2.29 (s, 3H), 2.07 (m, 2H), 1.55 (m, 2H).13CfH}-NMR (151 MHz, CDC13): 8162.5, 156.4, 149.7, 147.9, 142.2, 133.7, 133.6, 127.6, 119.3, 107.2, 66.8, 52.3, 47.6, 33.5, 17.1. LC-MS (ESI) m / z = ([M+H]+) 333.3.

[0158] Synthesis and Characterization of Compound 157-4.LiOH. H2O 2-MeTHF, H2O 80 °C, 1 h Yield: 116%157-3 157-4Compound 157-3 (methyl 5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylate) (262 mg, 0.788 mmol, 1 equiv.) and LiOH•H2O (165 mg, 3.94 mmol, 5 equiv.) was suspended in 2-MeTHF (2.0 mL) and H2O (2.0 mL). The mixture was stirred at 80 °C for 1 h. LC-MS analysis reflected full consumption of Compound 157-3 and detection of the desired m / z. The reaction mixture was acidified with concentrated hydrochloric acid to below pH 3, diluted with about 50:50 acetonitrile / H2O (about 12 mL) to solubilize remaining solids, then purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 μm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 10%-22% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford Compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (291 mg, 0.912 mmol, 116% yield) as a yellow solid. ’H-NMR (600 MHz, MeOH-t / 4): 87.84 (s, 1H), 7.79 (s, 1H), 7.51 (s, 1H), 7.14 (s, 1H), 4.02 (d, J= 12.0 Hz, 1H), 3.88 (m, 1H), 3.57 (t, J= 11.6 Hz, 2H), 2.37 (s, 3H), 2.02 (d, J= 13.4 Hz, 2H), 1.67 (m, 2H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.9, 150.6, 149.1, 143.2, 137.4, 134.4, 133.4, 130.1, 120.2, 112.9, 65.9, 48.1, 31.8, 15.9. LC-MS (ESI) m / z = ([M+H]+) 319.3.

[0159] Synthesis and Characterization of Compound 157.MSK-20525To a solution of Compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (25.5 mg, 80.0 mol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. ( )-2-Amino-2-(3-chlorophenyl)ethan-l-ol hydrochloride (16.7 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 157-4 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 25%-30% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 157 ((. S')-\-(l-(3-chlorophenyl)-2-hydroxyethyl)-5-(5-methyl-2-((tetr:ihydro-2 / / -pyr:in-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (26.0 mg, 55.0 μmol, 69% yield) as a white solid. 'H-NMR (600 MHz, MeOH-d4): δ 7.93 (d, J= 4.0 Hz, 1H), 7.76 (s, 1H), 7.52 (d, J= 4.0 Hz, 1H), 7.45 (s, 1H), 7.37 (m, 2H), 7.30 (m, 1H), 7.12 (s, 1H), 5.17 (t, J= 6.6 Hz, 1H), 4.02 (m, 2H), 3.88 (d, J= 6.6 Hz, 1H), 3.84 (m, 1H), 3.57 (td, J= 11.7, 2.1 Hz, 2H), 2.37 (s, 3H), 2.01 (m, 2H), 1.66 (m, 2H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.0, 150.5, 149.2, 142.2, 142.0, 141.7, 134.3, 134.0, 130.2, 129.7, 128.9, 127.2, 126.8, 125.2, 120.3, 112.8, 65.9, 64.1, 56.0, 48.1, 31.8, 16.0. LC-MS (ESI) m / z = ([M+H]+) 472.4.Example 13: Synthesis of Compound 158

[0160] Synthesis and Characterization of Compound 158MSK-20525To a solution of Compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (25.5 mg, 80.0 pmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-chloro-5-fluorophenyl)ethan-l-ol hydrochloride (18.1 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 157-4 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (2 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 26%-32% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 158 ((. S')-5-(5-chloro-2-((tetr:ihydro-2 / / -pyr:in-4-yl):imino)pyridin-4-yl)-\-(l-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)thiophene-2-carboxamide) (23.7 mg, 48.4 pmol, 60% yield) as a white solid. 'H-NMR (600 MHz, MeOH-d4): δ 7.93 (d, J= 4.0 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J= 3.9 Hz, 1H), 7.31 (s, 1H), 7.15 (m, 2H), 7.13 (s, 1H), 5.16 (t, J= 6.5 Hz, 1H), 4.02 (m, 2H), 3.89 (d, J= 6.5 Hz, 2H), 3.85 (m, 1H), 3.57 (td, J= 11.7, 2.1 Hz, 2H), 2.37 (s, 3H), 2.02 (m, 2H), 1.66 (m, 2H).13CfH}-NMR (151 MHz, MeOH-d4): δ 162.8 (d, 1JC,F = 248.3 Hz, 1C), 162.0, 150.5, 149.2, 144.4 (d,3JC. F = 7.8 Hz, 1C), 141.8 (d,4JC. F = 1.5 Hz, 1C), 134.8 (d,3JC, F = 10.7 Hz, 1C), 134.3, 130.2, 129.0, 123.0, 123.0 (d,4JC, F = 3.1 HZ, 1C), 114.6 (d,2JC, F = 25.2 Hz, 1C), 112.8, 112.4 (d,2JC, F = 22.4 Hz, 1C), 65.9, 63.8, 55.7 (d,4JC, F = 1.8 Hz, 1C), 48.1, 31.8, 15.9. LC-MS (ESI) m / z = ([M+H]+) 490.3.Example 14: Synthesis of Compound 159

[0161] Synthesis and Characterization of Compound 159.MSK-20525HATU, DIPEA DMF, 0 °C - rt, 30 min Yield: 52%Compound 159To a solution of Compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (25.5 mg, 80.0 pmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-bromophenyl)ethan-l-ol (17.3 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 157-4 and detection of the desired m / z. The reaction mixture was diluted with 50:50 acetonitrile / H2O (2.1 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 25%-30% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 159 ((5)-A-(l-(3-bromophenyl)-2-hydroxyethyl)-5-(5-chloro-2-((tetrahydro-2 / / -pyr:in-4-yl):imino)pyridin-4-yl)thiophene-2-carboxamide) (21.4 mg, 41.5 pmol, 52% yield) as a white solid.1H-NMR (600 MHz, MeOH-d4): δ 7.93 (d, J= 4.0 Hz, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.53 (d, J= 4.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.41 (d, J= 7.7 Hz, 1H), 7.30 (t, J= 7.8 Hz, 1H), 7.12 (s, 1H), 5.16 (t, J= 6.6 Hz, 1H), 4.02 (m, 2H), 3.86 (m, 3H), 3.57 (td, J= 11.7, 2.1 Hz, 2H), 2.37 (s, 3H), 2.01 (m, 2H), 1.66 (m, 2H).13C{1H}-NMR (151 MHz, MeOH-d4): δ 162.0, 150.5, 149.2, 142.5, 142.1, 141.7, 134.3, 130.2, 130.2, 130.0, 129.8, 128.8, 125.7, 122.1, 120.3, 112.7, 65.9, 64.1, 56.0, 48.1, 31.8, 16.0. LC-MS (ESI) m / z = ([M+H]+) 516.3.Example 15: Synthesis of Compound 160

[0162] Synthesis and Characterization of Compound 160.MSK-20525To a solution of Compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (25.5 mg, 80.0 μmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-bromo-5-fluorophenyl)ethan-l-ol hydrochloride (21.6 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 157-4 and detection of the desired m / z. The reaction mixture was diluted with 50:50 acetonitrile / H2O (2.1 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 27%-32% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 160 ((S)-N-(l-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (24.5 mg, 45.9 pmol, 57% yield) as a white solid. 'H-NMR (600 MHz, MeOH-d4): δ 7.93 (d, J= 4.0 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J= 4.0 Hz, 1H), 7.45 (s, 1H), 7.28 (dt, J= 8.3, 2.1 Hz, 1H), 7.20 (dt, J= 9.5, 2.0 Hz, 1H), 7.13 (s, 1H), 5.15 (t, J= 6.4 Hz, 1H), 4.02 (m, 2H), 3.88 (d, J= 6.5 Hz, 2H), 3.85 (m, 1H), 3.57 (td, J= 11.7, 2.1 Hz, 2H), 2.37 (s, 3H), 2.02 (m, 2H), 1.66 (m, 2H).13CfH}-NMR (151 MHz, MeOH-d4): δ 162.7 (d, 1JC,F = 249.6 Hz, 1C), 162.0, 150.5, 149.2, 144.7 (d,3JC, F = 7.5 Hz, 1C), 141.8 (d,4JC, F = 2.0 Hz, 1C), 134.3, 130.2, 129.0, 126.0 (d,4JC, F = 3.1 Hz, 1C), 122.2 (d,3JC, F = 9.9 Hz, 1C), 120.3, 117.5 (d,2JC, F = 24.9 Hz, 1C), 112.9 (d,2JC, F = 22.3 Hz, 1C), 65.9, 63.8, 55.7 (d,4Jc, F = 1.8 Hz, 1C), 48.1, 31.8, 15.9. LC-MS (ESI) m / z = ([M+H]+) 534.3.Example 16: Synthesis of Compound 161

[0163] Synthesis and Characterization of Compound 161.MSK-20525To a solution of Compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (25.5 mg, 80.0 pmol, 1 equiv.) and HATU (30.4 mg, 80.0 pmol, 1 equiv.) in DMF (0.4 mL), DIPEA (48.8 pL, 36.2 mg, 210 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-(trifluoromethyl)phenyl)ethan-l-ol (16.4 mg, 80.0 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 157-4 and detection of the desired m / z. The reaction mixture was diluted with 50:50 acetonitrile / H2O (2.1 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase: [H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 27%-32% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 161 ((. S')-5-(5-chloro-2-((tetr:ihydro-2 / / -pyr:in-4-yl):iniino)pyridin-4-yl)-\-(2-hydroxy-l -(3-(trifluoromethyl)phenyl)ethyl)thiophene-2-carboxamide) (18.5 mg, 36.6 pmol, 46% yield) as a white solid. 'H-NMR (600 MHz, MeOH-d4): δ 7.94 (d, J= 3.9 Hz, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.59 (m, 2H), 7.53 (d, J= 4.0 Hz, 1H), 7.13 (s, 1H), 5.26 (t, J= 6.1 Hz, 1H), 4.02 (m, 2H), 3.92 (d, J= 6.6 Hz, 2H), 3.85 (m, 1H), 3.57 (td, J = 11.7, 2.1 Hz, 2H), 2.37 (s, 3H), 2.01 (m, 2H), 1.66 (m, 2H).13CfH}-NMR (151 MHz, MeOH-d4): δ 162.0, 150.5, 149.2, 142.0, 141.7, 141.3, 134.3, 130.6 (q, 2JC,F = 32.1 Hz, 1C), 130.3, 130.2, 129.0, 128.9, 125.2, 123.9 (q,3JC, F = 3.9 Hz, 1C), 123.4 (q,3JC, F = 3.9 Hz, 1C), 120.3, 112.7, 65.9, 64.0, 56.1, 48.1, 31.8, 15.9. LC-MS (ESI) m / z = ([M+H]+) 506.4.Example 17: Synthesis of Compound 162

[0164] Synthesis and Characterization of Compound 162-2.MSK-20525XPhos-Pd G3, K3PO4Dioxane, H2O, rt-40 °C, 19 hcrude 162-2162-1Compound 162-1 (2,4,5-trichloropyrimidine) (22.9 μL, 36.7 mg, 200 μmol, 1 equiv.), methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (59.0 mg, 220 μmol, 1.1 equiv.), and K3PO4 (127 mg, 600 μmol, 3 equiv.) was suspended in dioxane (0.83 mL) and H2O (0.17 mL), and the mixture was sparged with argon for 10 min. XPhos-Pd G3 (3.39 mg, 4.00 μmol, 0.02 equiv.) was then added, and the suspension was stirred at room temperature under argon for 3 h. The temperature was increased to 40 °C and the mixture was stirred for an additional 3 h. Further methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (26.8 mg, 100 μmol, 0.5 equiv.) was then added, and the mixture was stirred for an additional 16 h. LC-MS analysis then reflected the desired m / z, but also the presence of di- and tri-substituted reaction products despite remaining Compound 162-1 present. The reaction mixture was diluted in CH2CI2 (4 mL) and washed with H2O (4 mL x 3) and brine (4 mL), dried with anhydrous Na2SC>4, filtered, and concentrated to afford Compound 162-2 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiophene-2-carboxylate) (nominal: 57.8 mg, 200 μmol, crude) as an off-white solid. LC-MS (ESI) m / z = ([M+H]+) 289.1.

[0165] Synthesis and Characterization of Compound 162-3.DIPEA, DMSO 140 °C, 15 min 162-2 Two-step yield: 20%162-3To a solution of Compound 162-2 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiophene-2-carboxylate) (nominal: 57.8 mg, 200 μmol, 1 equiv.) in DMSO (0.5 mL), tetrahydro-2H-pyran-4-amine (31.1 μL, 30.4 mg, 300 μmol, 1.5 equiv.) and DIPEA (69.6 μL, 51.7 mg, 400 μmol, 2 equiv.) were added at room temperature. The reaction mixture was stirred at 140MSK-20525°C for 15 min. LC-MS reflected full consumption of Compound 162-2 and detection of the desired m / z. The reaction mixture was diluted in CH2Cl2 (4 mL) and washed with H2O (4 mL x 3) and brine (4 mL), dried with anhydrous Na2SC>4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 4 g; mobile phase: [hexanes-EtOAc]; gradient: 10%-35% EtOAc over 33 min). The desired fractions were concentrated and dried to afford Compound 162-3 (methyl 5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylate) (14.2 mg, 40.2 μmol, 20% yield over two steps) as an off-white solid. TLC: A / 0.17 (25% EtOAc / hexanes).1H-NMR (600 MHz, CDCI3): δ 8.22 (s, 1H), 8.09 (d, J= 4.1 Hz, 1H), 7.72 (d, J= 4.1 Hz, 1H), 5.09 (d, J= 7.6 Hz, 1H), 3.97 (m, 3H), 3.86 (s, 3H), 3.51 (t, J= 11.1 Hz, 2H), 2.01 (m, 2H), 1.51 (m, 2H).13CfH}-NMR (151 MHz, CDCh): 8162.6, 159.6, 159.2, 153.7, 152.7, 136.5, 133.7, 131.0, 114.8, 66.8, 52.4, 47.8, 33.0. LC-MS (ESI) m / z = ([M+H]+) 354.3.

[0166] Synthesis and Characterization of Compound 162-4.162-3 162-4Compound 162-3 (methyl 5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylate) (14.2 mg, 40.2 μmol, 1 equiv.) and LiOH•H2O (8.43 mg, 201 μmol, 5 equiv.) was suspended in 2-MeTHF (0.2 mL) and H2O (0.2 mL). The mixture was stirred at 80 °C for 5 h. LC-MS analysis reflected full consumption of Compound 162-3 and detection of the desired m / z. The reaction mixture was acidified with concentrated hydrochloric acid to below pH 3, diluted with about 30:70 acetonitrile / H2O (about 10 mL), and filtered to afford Compound 162-4 (5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (nominal: 13.7 mg, 40.2 μmol, crude) as an off-white solid. LC-MS (ESI) m / z = ([M+H]+) 340.2.

[0167] Synthesis and Characterization of Compound 162.MSK-20525Compound 162To a solution of Compound 162-4 (5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (nominal: 13.7 mg, 40.2 μmol, 1 equiv.) and HATU (15.3 mg, 40.2 μmol, 1 equiv.) in DMF (about 0.5 mL), DIPEA (about 30 μL, 40.4 mg, 313 μmol, 7.8 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (5)-2-Amino-2-(3-chlorophenyl)ethan-l-ol hydrochloride (8.38 mg, 40.2 pmol, 1 equiv.) was then added, and the solution was stirred at room temperature for an additional 30 min. LC-MS analysis reflected full consumption of Compound 162-4 and detection of the desired m / z. The reaction mixture was diluted with 30:70 acetonitrile / H2O (about 4 mL) and purified by prep-HPLC (column: Waters XBridge® C18 4.6 mm × 150 mm, 3.5 pm; mobile phase:[H2O (0.05% TFA)-acetonitrile (0.04% TFA)]; gradient: 35%-38% acetonitrile (0.04% TFA) over 12 min). The desired fractions were concentrated and dried to afford compound 162 ((. S)-5-(5-chloro-2-((tetr:ihydro-2 / / -pyr:in-4-yl):imino)pyrimidin-4-yl)-\-( l-(3-chlorophenyl)-2-hydroxyethyl)thiophene-2-carboxamide) (10.9 mg, 22.1 μmol, 55% yield over two steps) as a yellow solid.1H-NMR (600 MHz, MeOH-d4): δ 8.32 (s, 1H), 8.23 (d, J = 4.1 Hz, 1H), 7.85 (d, J=4.1 Hz, 1H), 7.47 (s, 1H), 7.37 (m, 2H), 7.30 (m, 1H), 5.18 (t, J = 6.6 Hz, 1H), 4.01 (m, 4H), 3.89 (d, J= 6.6 Hz, 2H), 3.57 (t, J= 11.6 Hz, 2H), 2.03 (m, 2H), 1.63 (m, 2H).13CfH}-NMR (151 MHz, MeOH-d4): δ 162.5, 142.3, 142.3, 134.0, 131.0, 130.1, 129.7, 128.8, 127.2, 126.9, 126.8, 125.2, 116.3, 114.4, 113.3, 66.6, 64.1, 55.9, 48.4, 48.2, 32.3. LC-MS (ESI) m / z = ([M+H]+) 493.3.Example 18: Synthesis of Compound 60MSK-20525General procedure for preparation of compound 60-2:DIEA, DMSO, 25- 135 °C, 12 hrsYield: 51.8%60-1To a solution of compound 60-1 (4-bromo-2-fluoro-5-methyl-pyridine) (2.00 g, 10.5 mmol, 1.00 eq) and compound 1-1a ((3S, 4S)-3-fluorotetrahydropyran-4-amine) (1.97 g, 12.6 mmol, 1.20 eq, HCl) in DMSO (20.0 mL) was added DIEA (4.08 g, 31.6 mmol, 5.50 mL, 3.00 eq) at 25 °C. The mixture was heated to 110 °C and stirred at 135 °C for 12 hrs. TLC (Petroleum ether / Ethyl acetate = 1 / 1) indicated compound 60-1 (Rf= 0.50) was consumed completely and one new spot (Rf = 0.30) was formed. The mixture was poured into ice H2O (60.0 mL), then the aqueous phase was extracted with ethyl acetate (50.0 mL * 2). The combined organic phase was washed with brine (60.0 mL * 4), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Dichloromethane / Ethyl acetate = 100 / 100 / 1 to 10 / 10 / 1, Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.30), then the fraction was concentrated to give compound 60-2 (4-bromo-N-[(3S, 4S)-3-fluorotetrahydropyran-4-yl]-5-methyl-pyridin-2-amine) (1.70 g, 5.46 mmol, 51.8% yield, 92.8% purity) as a yellow solid. LCMS:MSK-20525m / z = 291.0 (M+H)+. 'H NMR (400 MHz, DMSO-t / e): <57.86 (s, 1H), 6.89 (s, 1H), 6.66 (d, J= 8.0 Hz, 1H), 4.76 - 4.63 (m, 1H), 4.20 - 4.09 (m, 1H), 4.00 - 3.85 (m, 2H), 3.62 - 3.43 (m, 2H), 2.12 (s, 3H), 1.84 - 1.63 (m, 2\\)General procedure for preparation of compound 60-3:.KOAc, Pd(dppf)CI2toluene, 120 °C, 2 hrsYield: 70.0%60-3A mixture of compound 60-2 (4-bromo-N-[(3S, 4S)-3-fluorotetrahydropyran-4-yl]-5-methyl-pyridin-2-amine) (1.00 g, 3.46 mmol, 1.00 eq), compound l-2a (4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane) (4.39 g, 17.3 mmol, 5.00 eq), KO Ac (1.70 g, 17.3 mmol, 5.00 eq) and Pd(dppf)Cl2 (253 mg, 346 pmol, 0.10 eq) in toluene (20.0 mL) was degassed and purged with N2 for three times, and then the mixture was stirred at 120 °C for 2 hrs under N2 atmosphere. LCMS showed compound 60-2 was consumed completely and desired mass was detected. The mixture was cooled to 25 °C and poured into H2O (60.0 mL), then the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (80.0 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1, Petroleum ether / Ethyl acetate = 0 / 1, Rf= 0.20). The fraction was concentrated under vacuum to give compound 60-3 (N-[(3S,4S)-3-fluorotetrahydropyran-4-yl]-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine) (814 mg, 2.42 mmol, 70.0% yield) as a yellow solid. LCMS: m / z = 255.1 (M-82+H)+. 'H NMR: (400 MHz, CDCI3): 87.90 (s, 1H), 6.81 (s, 1H), 4.76 - 4.64 (m, 1H), 4.50 - 4.48 (m, 1H), 4.30 - 4.15 (m, 2H), 4.05 - 4.02 (m, 1H), 3.68 - 3.53 (m, 2H), 2.32 (s, 3H), 1.91 - 1.85 (m, 2H), 1.34 (s, 12H). General procedure for preparation of compound 60-4:MSK-20525OKOAc, Pd(dppf)CI2, toluene, H2O, 100 °C, 6 hrs Yield: 23.9%60-3 60-4A mixture of compound 60-3 (N-[(3S,4S)-3-fluorotetrahydropyran-4-yl]-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-2-amine) (616 mg, 1.83 mmol, 1.00 eq), compound 1-3a (methyl 5-bromothiazole-2-carboxylate) (488 mg, 2.20 mmol, 1.20 eq, KOAc (539 mg, 5.50 mmol, 3.00 eq) and Pd(dppf)Cl2 (134 mg, 183 µmol, 0.10 eq in toluene (12.0 mL) and H2O (1.20 mL) was degassed and purged with N2for three times, and then the mixture was stirred at 100 °C for 6 hrs under N2atmosphere. LCMS showed 21.5% of compound 60-3 (Rt = 0.266 min) remained and 29.8% of desired mass (Rt = 0.465 min) was detected. The mixture was cooled to 25 °C and poured into H2O (50.0 mL), then the aqueous phase was extracted with ethyl acetate (40.0 mL * 3). The combined organic phase was washed with brine (60.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 100 / 55 to 100 / 45, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.20). The fraction was concentrated under vacuum to give the residue (500 mg). The residue (500 mg) was purified by prep-HPLC (neutral condition: column: Waters xbridge 150*25 mm 10pm; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 24%-54% B over 10.0 mins). The eluent was concentrated in vacuum to remove acetonitrile and H2O, the residual aqueous was lyophilized to give compound 60-4 (methyl 5-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxylate) (170 mg, 438 pmol, 23.9% yield, 90.5% purity) as a yellow solid. LCMS: m / z = 352.1 (M+H)+.1H NMR: (400 MHz, DMSO-tfc): <58.28 (s, 1H), 7.97 (s, 1H), 6.76 (s, 1H), 6.67 (d, J= 8.2 Hz, 1H), 4.79 - 4.67 (m, 1H), 4.27 - 4.13 (m, 1H), 4.04 - 3.98 (m, 1H) 3.94 (s, 3H) 3.89 (dd, J = 11.6, 2.8 Hz, 1H), 3.55 - 3.45 (m, 2H), 2.21 (s, 3H), 1.80 - 1.73 (m, 1H), 1.69 - 1.65 (m, 1H)General procedure for preparation of compound 60-5:MSK-2052560—4 60-5To a solution of compound 60-4 (methyl 5-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxylate) (150 mg, 427 pmol, 1.00 eq) in THF (1.50 mL) and H2O (1.50 mL) was added LiOH•H2O (35.8 mg, 854 µmol, 2.00 eq at 25 °C.The mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 60-4 was consumed completely and desired mass (Rt = 0.354 min) was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous phase was adjusted pH = 5 by IN HC1 then the solids precipitated out. The suspension was filtered and washed with H2O (7.00 mL * 2). The filter cake was dried to give compound 60-5 (5-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxylic acid) (170 mg, crude) as a brown solid. The crude product was used into the next step. LCMS: m / z = 338.1 (M+H)+. ¹H NMR: (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.96 (s, 1H), 6.76 (s, 1H), 6.69 (d, J= 7.6 Hz, 1H), 4.79 - 4.67 (m, 1H), 4.24 - 4.13 (m, 1H), 4.01 - 3.87 (m, 2H), 3.68 - 3.51 (m, 2H), 2.21 (s, 3H), 1.80 - 1.66 (m, 2H)General procedure for preparation of compound 60-6:HOBt, EDCI, DIEA NMP, 0 - 30 °C, 12 hrs Crude60-5 60-6To a solution of compound 60-5 (5-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxylic acid) (170 mg, 504 pmol, 1.00 eq and compound a ((lS)-2-azido-l-(3-chlorophenyl) ethanamine) (141 mg, 605 pmol, 1.20 eq, HC1) in NMPMSK-20525(2.00 mL) was added HOBt (81.7 mg, 605 pmol, 1.20 eq), EDCI (193 mg, 1.01 mmol, 2.00 eq) and DIEA (130 mg, 1.01 mmol, 176 pL, 2.00 eq) at 0 °C. The mixture was stirred at 30 °C for 12 hrs. LCMS showed compound 60-5 was consumed completely and desired mass (Rt = 0.535 min) was detected. The reaction mixture was poured into H2O (8.00 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (20.0 mL * 4), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 60-6 (N-[(lS)-2-azido-l-(3-chlorophenyl) ethyl]-5-[2-[[ (3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxamide) (250 mg, crude) as brown oil. The crude product was used to the next step.LCMS: m / z = 516.1 (M+H)+.General procedure for preparation of Compound 60:PPh3THF, H2O, 25 °C, 12 hrs Yield: 9.86%60-6 Compound 60To a solution of compound 60-6 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxamide) (250 mg, 412 pmol, 1.00 eq) in THF (2.70 mL) and H2O (0.30 mL) was added PPh3(162 mg, 618 µmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 60-6 was consumed completely and desired mass (Rt = 0.429 min) was detected. The reaction mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (30.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (neutral condition: column: LUJA Sep Silica250*50 mm*5µm; mobile phase:[Hexane-EtOH]; gradient: 15%-55% B over 15.0 min). The eluent was concentrated in vacuum. The product was dissolved in acetonitrile (4.00 mL) and H2O (20.0 mL), the aqueous was lyophilized to give Compound 60 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]thiazole-2-carboxamide) (20.4 mg, 40.6 pmol, 9.86% yield, 97.3% purity) as aMSK-20525yellow solid. LCMS: m / z = 490.2 (M+H)+. ¹H NMR: (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.47 (s, 1H), 7.37 - 7.30 (m, 3H), 6.75 (s, 1H), 6.64 (d, J= 8.4 Hz, 1H), 4.93 (t, J= 6.0 Hz, 1H), 4.79 - 4.67 (m, 1H), 4.26 - 4.15 (m, 1H), 4.01 - 3.87 (m, 2H), 3.64 - 3.45 (m, 2H), 3.02 - 2.87 (m, 2H), 2.21 (s, 3H), 1.82 - 1.65 (m, 4H).19F NMR: (400 MHz, DMSO-d6): δ -203.8Example 19: Synthesis of Compound 61General procedure for preparation of compound 61-lb:To a solution of compound 61-1 (2,4-dichloro-5-methyl-pyrimidine) (10.0 g, 61.3 mmol, 1.00 eq in dioxane (100 mL) was added Pd(PPh3)4 (3.54 g, 3.07 mmol, 0.05 eq) and compound 2-la (trimethyl-(trimethylstannyl)stannane) (30.2 g, 92.0 mmol, 19.1 mL, 1.50 eq at 25 °C under N2. The mixture was heated to 90 °C and stirred at 90 °C for 12 hrs under N2. LCMS showed the compound 61-1 was consumed completely and the desired MS was detected. The reaction mixture was cooled to 25 °C and poured to sat. KF solution (300 mL) and stirred at 25 °C for 15 min. The suspension was filtered and the filtrate was extractedMSK-20525with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (100 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether = 0% to 4%, Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.60) and the fraction was concentrated to give compound 61-lb ((2-chloro-5-methyl-pyrimidin-4-yl)-trimethyl-stannane) (12.0 g, 41.2 mmol, 67.1% yield) as a white solid. LCMS: m / z = 293.0 (M+H)+.¹H NMR: (400 MHz, CDCl3): δ 8.27 - 8.15 (m, 1H), 2.33 (s, 3H), 0.53 - 0.32 (m, 9H).General procedure for preparation of compound 61-2:Cui, Pd(PPh3)4, DMF, 25-90 °C, 3 hrs Cl Yield: 76.5%61-1bA mixture of compound 61-lb ((2-chloro-5-methyl-pyrimidin-4-yl)-trimethyl-stannane) (10.1 g, 34.7 mmol, 1.10 eq), compound 1-3a (methyl 5-bromothiazole-2-carboxylate) (7.00 g, 31.5 mmol, 1.00 eq, Cui (1.20 g, 6.30 mmol, 0.20 eq), Pd(PPh3)4(1.82 g, 1.58 mmol, 0.05 eq) in DMF (70.0 mL) was degassed and purged with N2 for 3 times at 25 °C, then the mixture was heated to 90 °C and stirred at 90 °C for 3 hrs under N2 atmosphere. LCMS showed the compound l-3a was consumed completely and the desired MS was detected. The mixture was poured into water (700 mL) at 20 °C and extracted with ethyl acetate (300 mL * 3). The combined organic layers were washed with brine (300 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, 50% DCM in Ethyl acetate / Petroleum ether = 0% to 50%, Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.50) and the fraction was concentrated. The residue was triturated with petroleum ether / Ethyl acetate / DCM = 5: 1: 1 (6.00 mL) at 25 °C for 30 min. The suspension was filtered and the filter cake was dried to give compound 61-2 (methyl 5-(2-chloro-5-methyl-pyrimidin-4-yl) thiazole-2-carboxylate) (6.50 g, 24.1 mmol, 76.5% yield) as a yellow solid. LCMS: m / z = 270.0 (M+H)+. ¹H NMR: (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.75 (s, 1H), 3.96 (s, 3H), 2.57 (s, 3H).General procedure for preparation of compound 61-3:MSK-205252-2a <yNH2CsF, DIEA, DMSO, 25-60 °C, 6 hrs Yield: 60.5%61-2To the mixture of compound 61-2 (methyl 5-(2-chloro-5-methyl-pyrimidin-4-yl)thiazole-2-carboxylate) (1.60 g, 5.93 mmol, 1.00 eq and compound 2-2a (tetrahydropyran-4-amine) (900 mg, 8.90 mmol, 1.50 eq) in DMSO (16.0 mL) was added DIEA (2.30 g, 17.8 mmol, 3.10 mL, 3.00 eq) and CsF (901 mg, 5.93 mmol, 1.00 eq) at 25 °C, the mixture was stirred at 60 °C for 6 hrs. LCMS showed the compound 61-2 was consumed completely and the desired MS was detected. The mixture was cooled to 25 °C and poured into ice water (60.0 mL) then extracted with ethyl acetate (50.0 mL * 3). The combined organic layers were washed with brine (50.0 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate / 20% DCM in Petroleum ether = 0% to 60%, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.40) and the fraction was concentrated to give compound 61-3 (methyl 5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxylate) (1.20 g, 3.59 mmol, 60.5% yield) as a yellow solid. LCMS: m / z = 335.1 (M+H)+.1H NMR:(400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.32 (s, 1H), 7.28 - 7.14 (m, 1H), 4.08 - 3.99 (m, 1H), 3.94 (s, 3H), 3.88 (d, J= 10.0 Hz, 2H), 3.44 - 3.40 (m, 2H), 2.36 (s, 3H), 1.85 (d, J= 12.0 Hz, 2H), 1.59 - 1.45 (m, 2H).General procedure for preparation of compound 61-4:MSK-20525To a solution of Compound 61-3 (methyl 5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxylate) (1.00 g, 2.99 mmol, 1.00 eq) in THF (10.0 mL) and H2O (10.0 mL) was added LiOH•H2O (376 mg, 8.97 mmol, 3.00 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs. LCMS showed the Compound 61-3 was consumed completely and the desired MS was detected. The reaction mixture was extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were discarded. The aqueous phase was concentrated under reduced pressure at 35 °C. Then adjusted pH = 5 by IN HC1. The solids were precipitated out. The suspension was filtered and the filter cake was washed with H2O (3.00 mL * 3) and dried. Compound 61-4 (5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxylic acid) (700 mg, 1.75 mmol, 58.5% yield, 80.0% purity) was obtained as a yellow solid and used to next step directly. LCMS: m / z = 321.1 (M+H)+. ¹H NMR: (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 8.28 (s, 1H), 7.12 (d, J= 7.2 Hz, 1H), 3.88 (d, J= 10.8 Hz, 3H), 3.44 - 3.38 (m, 2H), 2.34 (s, 3H), 1.85 (d, J= 12.0 Hz, 2H), 1.55 - 1.47 (m, 2H).General procedure for preparation of compound 61-5:To a solution of Compound 61-4 (5-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 250 pmol, 1.00 eq and compound a ((lS)-2-azido-l-(3-chlorophenyl) ethanamine) (69.9 mg, 300 pmol, 1.20 eq, HC1) in NMP (1.00 mL) was added HOBt (40.5 mg, 300 pmol, 1.20 eq), EDCI (95.7 mg, 500 pmol, 2.00 eq and DIEA (129 mg, 999 pmol, 174 pL, 4.00 eq at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the Compound 61-4 was consumed completely and the desired MS was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 61-5 (N-MSK-20525[(lS)-2-azido-l-(3-chlorophenyl) ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxamide) (170 mg, crude) was obtained as yellow gum and used to next step directly. LCMS: m / z = 499.2 (M+H)+.General procedure for preparation of Compound 61:PPh3THF, H2O, 25 °C, 12 hrs Yield over two steps: 14.0%61-5 Compound 61To a solution of compound 61-5 (N-[(lS)-2-azido-l-(3-chlorophenyl) ethyl]-5-[5-methyl-2-(tetrahydro pyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxamide) (150 mg, 301 pmol, 1.00 eq in THF (6.00 mL) and H2O (0.60 mL) was added PPh3 (118 mg, 451 pmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 61-5 was consumed completely and the desired MS was detected. The reaction mixture was poured into IN HC1 (5.00 mL) and ethyl acetate (5.00 mL) and stirred at 25 °C for 10 min then extracted with ethyl acetate (10.0 mL * 3). The combined organic layers were discarded. The aqueous phase was adjusted pH to 8 by sat. NaHCCL solution then extracted with ethyl acetate (10.0 mL * 4). The combined organic layers were washed with brine (10.0 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250 * 50mm * 5µm; mobile phase: [Hexane-EtOH]; gradient: 20%-60% B over 15.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 61 (N-[(lS)-2-amino-l-(3-chlorophenyl) ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxamide) (20.6 mg, 42.2 pmol, 14.0% yield over two steps, 97.1% purity) as a yellow solid. LCMS: m / z = 473.2 (M+H)+. ¹H NMR: (400 MHz, DMSO-d6): δ 9.68 - 9.09 (m, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.46 (s, 1H), 7.39 - 7.29 (m, 3H), 7.16 (br d, J= 6.8 Hz, 1H), 5.01 - 4.82 (m, 1H), 3.87 (br d, J = 10.4 Hz, 3H), 3.38 (br t, J = 11.6 Hz, 2H), 3.08 -2.82 (m, 2H), 2.37 (s, 3H), 1.84 (brd, J= 13.2 Hz, 2H), 1.57 - 1.44 (m, 2H).MSK-20525Example 20: Synthesis of Compound 62oGeneral procedure for preparation of compound 62-2:isopentyl nitrite, CuBr2MeCN, 0 -80 °C, 2 hrsYield: 79.9%62-1 62-2To a solution of compound 62-1 (2,5-dichloropyrimidin-4-amine) (9.00 g, 54.9 mmol, 1.00 eq) in ACN (180 mL) was added isopentyl nitrite (19.3 g, 165 mmol, 22.2 mL, 3.00 eq) and CuBr2 (24.5 g, 110 mmol, 5.14 mL, 2.00 eq) at 0 °C. The mixture was heated to 80 °C and stirred at 80 °C for 2 hrs. TLC (Petroleum ether / Ethyl acetate = 5 / 1) showed compound 62-1 (Rf = 0.2) was consumed and a new main spot (Rf = 0.8) was formed. The reaction mixture was cooled to 25 °C and poured into water (200 mL), the aqueous phase was extracted with ethyl acetate (200 mL * 2). The combined organic phase was washed with brine (200 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the residue.The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 50 / 1, Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.80) and the fraction was concentratedMSK-20525to give compound 62-2 (4-bromo-2,5-dichloro-pyrimidine) (10.0 g, 43.9 mmol, 79.9% yield) as a white solid.1H NMR: (400 MHz, DMSO-tfc): 88.96 (s, 1H)General procedure for preparation of compound 62-2b:hexaethylditin, Pd(PPh3)2Cl2 dioxane, 100 °C, 3 hrsYield: 52.8%62-2A mixture of compound 62-2 (4-bromo-2,5-dichloro-pyrimidine) (10.0 g, 43.9 mmol, 1.00 eq in dioxane (100 mL) was added hexaethylditin (16.8 g, 51.4 mmol, 10.7 mL, 1.17 eq) and Pd(PPh3)2Ch (1.54 g, 2.19 mmol, 0.05 eq was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 3 hrs under N2. LCMS showed compound 62-2 was consumed and desired MS (Rt = 0.655 min) was detected. The mixture was cooled to 25 °C and poured into saturated KF solutions (200 mL) and stirred at 25 °C for 0.5 hr. The mixture was filtered and collected filtrate. Then the filtrate was extracted with ethyl acetate (200 mL * 2). The combined organic phase was washed with saturated KF solutions (200 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, 100% Petroleum ether, Petroleum ether / Ethyl acetate = 10 / 1, Rf = 0.70). The fraction was filtered and concentrated in vacuum to give compound 62-2b ((2,5-dichloropyrimidin-4-yl)-trimethyl-stannane) (7.40 g, 23.2 mmol, 52.8% yield, 97.8% purity) as a yellow solid. LCMS: m / z = 312.9 (M+H)+. 'H NMR: (400 MHz, CDCI3): 88.36 (s, 1H), 0.48 (s, 9H)General procedure for preparation of compound 62-3:OMe62-3MSK-20525A mixture of compound 62-2b ((2,5-dichloropyrimidin-4-yl)-trimethyl-stannane) (5.60 g, 17.6 mmol, 1.30 eq), compound 1-3a (methyl 5-bromothiazole-2-carboxylate) (3.00 g, 13.5 mmol, 1.00 eq), Cui (515 mg, 2.70 mmol, 0.20 eq), Pd(PPh3)4 (1.56 g, 1.35 mmol, 0.10 eq) in DMF (56.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3 hrs under N2 atmosphere. LCMS showed compound 62-2b was consumed and desired MS (Rt = 0.549 min) was detected. The reaction mixture was cooled to 25 °C and poured into H2O (300 mL), the aqueous phase was extracted with ethyl acetate (300 mL * 2). The combined organic phase was washed with brine (300 mL * 2), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give the residue. The residue was purified by column chromatography (SiCL, 30% DCM in Petroleum ether / Ethyl acetate = 100 / 1 to 5 / 1, Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.20) and the fraction was concentrated to give compound 62-3 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiazole-2-carboxylate) (2.50 g, 8.62 mmol, 63.7% yield, 100% purity) as a yellow solid. LCMS: m / z = 289.9 (M+H)+. 'H NMR: (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 9.07 (s, 1H), 3.97 (s, 3H)General procedure for preparation of compound 62-4:62-3 62-4To a solution of Compound 62-3 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiazole-2-carboxylate) (1.00 g, 3.45 mmol, 1.00 eq) and compound 1-la ((3S,4S)-3-fluorotetrahydropyran-4-amine) (590 mg, 3.79 mmol, 1.10 eq, HC1) in DMSO (10.0 mL) was added CsF (2.62 g, 17.2 mmol, 5.00 eq at 25 °C. The mixture was stirred at 80 °C for 2 hrs. LCMS showed Compound 62-3 was consumed and desired MS (Rt = 0.545 min) was detected. The reaction mixture was cooled to 25 °C. The mixture was filtered and the filtrate was poured into H2O (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL * 2). The combined organic phase was washed with brine (100 mL * 2), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give the residue. The residue was purified by triturated with Petroleum ether / Ethyl acetate = 5 / 1 (5 mL) at 25 °C for 10 min,MSK-20525filtered and the filter cake was dried over vacuum. Compound 62-4 (methyl 5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylate) (1.20 g, 3.05 mmol, 88.6% yield, 94.9% purity) was obtained as a yellow solid. LCMS: m / z = 373.0 (M+H)+. 'H NMR: (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 8.55 (s, 1H), 7.94 - 7.72 (m, 1H), 4.98 - 4.59 (m, 1H), 4.20 - 3.99 (m, 2H), 3.98 - 3.86 (m, 4H), 3.73 - 3.42 (m, 2H), 2.05 - 1.90 (m, 1H), 1.67 (d, J= 10.0 Hz, 1H)General procedure for preparation of compound 62-5:LiOH«H2O THF, H2O, 25 °C, 2 hrs Yield: 84.2%62-4 62-5To a solution of compound 62-4 (methyl 5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylate) (1.20 g, 3.05 mmol, 1.00 eq) in THF (12.0 mL) and H2O (12.0 mL) was added LiOH. H2O (256 mg, 6.11 mmol, 2.00 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 62-4 was consumed and desired MS (Rt = 0.474 min) was detected. The mixture was concentrated to remove most of THF, then adjusted pH to 3-4 with IM HC1, filtered and the filter cake was concentrated to give compound 62-5 (5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxylic acid) (1.20 g, 2.57 mmol, 84.2% yield, 76.9% purity) as a yellow solid. LCMS: m / z = 359.0 (M+H)+. 'H NMR: (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.54 (s, 1H), 7.88 - 7.68 (m, 1H), 4.88 - 4.68 (m, 1H), 4.20 - 4.07 (m, 1H), 4.05 - 3.98 (m, 1H), 3.91 (d, J= 8.4 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.54 - 3.48 (m, 2H), 2.02 -1.91 (m, 1H), 1.71 - 1.62 (m, 1H)General procedure for preparation of compound 62-6:MSK-20525EDCI, HOBt, DIEA, NMP, 0 -25 °C, 12 hrs crude62-5To a solution of compound 62-5 (5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 214 μmol, 1.00 eq) in NMP (1.00 mL) was added compound b ((lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethanamine) (64.6 mg, 257 pmol, 1.20 eq, HC1), HOBt (34.8 mg, 257 pmol, 1.20 eq) and EDCI (82.2 mg, 429 pmol, 2.00 eq and DIEA (111 mg, 858 pmol, 149 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed 11.1% compound 62-5 (Rt = 0.512 min) remained and desired MS (Rt = 0.668 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give compound 62-6 (N-[(lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (180 mg, crude) was obtained as yellow oil. LCMS: m / z = 555.1 (M+H)+.General procedure for preparation of Compound 62:To a solution of compound 62-6 (N-[(lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-MSK-20525carboxamide) (160 mg, 288 pmol, 1.00 eq) in THF (3.00 mL) and H2O (0.30 mL) was added PPh₃ (113 mg, 432 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 62-6 was consumed and desired MS (Rt = 0.543 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give the residue. The residue was purified by prep-HPLC(column: LUJA Sep Silica 250*50mm*5pm; mobile phase:[Hexane-EtOH]; gradient: 10%-50% B over 15.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 62 (N-[(lS)-2-amino-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (21.9 mg, 39.5 pmol, 19.3% yield, 95.3% purity) as a yellow solid. LCMS: m / z = 529.2 (M+H)+. 'H NMR: (400 MHz, DMSO-d6): δ 9.75 - 9.21 (m, 1H), 8.95 - 8.82 (m, 1H), 8.55 (s, 1H), 7.94 - 7.70 (m, 1H), 7.43 - 7.19 (m, 3H), 4.99 - 4.91 (m, 1H), 4.89 - 4.64 (m, 1H), 4.24 - 3.85 (m, 3H), 3.70 - 3.45 (m, 2H), 3.07 - 2.82 (m, 2H), 2.05 -1.83 (m, 2H), 1.73 - 1.61 (m, 1H).19F NMR: (400 MHz, DMSO-d6): δ - 110.844, -203.809, -203.988Example 21: Synthesis of Compound 63-P1 and Compound 63-P2MSK-20525H2NPPh3SFCGeneral procedure for preparation of compound 63-1:CsF, DIEA, DMSO, 25 - 60 °C, 12 hrs Yield: 85.1%62-3 63-1To a solution of compound 62-3 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiazole-2-carboxylate) (1.00 g, 3.45 mmol, 1.00 eq and compound 4-la (3-fluorotetrahydropyran-4-amine) (590 mg, 3.79 mmol, 1.10 eq, HC1) in DMSO (10.0 mL) was added CsF (524 mg, 3.45 mmol, 1.00 eq) and DIEA (1.34 g, 10.3 mmol, 1.80 mL, 3.00 eq at 25 °C. The mixture was stirred at 60 °C for 12 hrs. LCMS showed compound 62-3 was consumed and desired mass (RT = 0.547 min) was detected. The reaction mixture was cooled to 25 °C and poured into H2O (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL * 2). The combined organic phase was washed with brine (100 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the residue. The residue was purified byMSK-20525triturated with Petroleum ether / Ethyl acetate = 5 / 1 (5.00 mL) at 25 °C for 10 min, filtered and the filter cake was dried over vacuum to give compound 63-1 (methyl 5-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]thiazole-2-carboxylate) (1.15 g, 2.93 mmol, 85.1% yield, 95.1% purity) as ayellow solid. LCMS: m / z = 373.1 (M+H)+.1H NMR:(400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.55 (s, 1H), 8.13 - 7.83 (m, 1H), 4.66 - 4.43 (m, 1H), 4.27 - 4.10 (m, 1H), 4.04 - 3.98 (m, 1H), 3.95 (s, 3H), 3.88 - 3.79 (m, 1H), 3.57 - 3.37 (m, 2H), 2.09 - 1.99 (m, 1H), 1.67 - 1.53 (m, 1H)General procedure for preparation of compound 63-2:LiOH«H2O THF, H2O, 25 °C, 2 hrs Yield: 85.3%63-2To a solution of compound 63-1 (methyl 5-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]thiazole-2-carboxylate) (1.10 g, 2.81 mmol, 1.00 eq in THF (11.0 mL) and H2O (11.0 mL) was added LiOHH2O (236 mg, 5.61 mmol, 2.00 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 63-1 was consumed and desired mass (RT = 0.481 min) was detected. The mixture was concentrated to remove most of THF, then adjusted pH to 3 ~ 4 with 1 M HC1, filtered and the filter cake was concentrated to give compound 63-2 (5-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]thiazole-2-carboxylic acid) (1.00 g, 2.39 mmol, 85.3% yield, 85.9% purity) as a yellow solid. LCMS: m / z = 359.0 (M+H)+. 'H NMR: (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.54 (s, 1H) 8.02 - 7.86 (m, 1H), 4.66 - 4.46 (m, 1H), 4.17 (s, 1H), 4.07 - 3.95 (m, 1H), 3.87 - 3.78 (m, 1H), 3.47 (s, 2H), 2.05 - 1.90 (m, 1H), 1.69 - 1.51 (m, 1H)General procedure for preparation of compound 63-3:MSK-20525EDCI, HOBt, DIEA NMP, 0 ~ 25 °C, 12 hrs crude63-2To a solution of compound 63-2 (5-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]thiazole-2-carboxylic acid) (250 mg, 599 pmol, 1.00 eq) inNMP (2.50 mL) was added compound b ((lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethanamine) (180 mg, 718 pmol, 1.20 eq, HC1), HOBt (97.1 mg, 718 pmol, 1.20 eq) and EDCI (230 mg, 1.20 mmol, 2.00 eq and DIEA (309 mg, 2.39 mmol, 417 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed 7.86% compound 63-2 (RT = 0.513 min) remained and desired mass (RT = 0.667 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give compound 63-3 (N-[(lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethyl]-5- [5-chloro-2- [(3-fluorotetrahydropyran-4-yl)amino] pyrimidin-4-yl]thiazole-2-carboxamide) (410 mg, crude) as yellow oil. LCMS: m / z = 555.1 (M+H)+.General procedure for preparation of compound 63-4:PPh3THF, H2O, 25 °C, 12 hrs Yield over two steps: 41.0%63-4To a solution of compound 63-3 (N-[(lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]thiazole-2-carboxamide) (390 mg, 702 pmol, 1.00 eq) in THF (6.00 mL) and H2O (0.60 mL) was added PPh3(276 mg, 1.05 mmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compoundMSK-2052563-3 was consumed and desired mass (RT = 0.546 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give the residue. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5μm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min) and the eluent was concentrated under 30 °C and lyophilized to give compound 63-4 (N-[(lS)-2-amino-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]thiazole-2-carboxamide) (130 mg, 246 pmol, 41.0% yield, 100% purity) as yellow oil. LCMS: m / z = 529.1 (M+H)+.General procedure for preparation of Compound 63 P1& Compound 63 P2:SFCYield: 30.7%The residue was purified by prep-SFC (column: DAICEL CHIRALPAK IE (250mm*30mm, 10 pm); mobile phase: [CO2-MeOH: ACN = 4 : 1 (0.1% NH3H2O)]; B%: 55%, isocratic elution mode) and the eluent was concentrated to give the compound. The compound was diluted in ACN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 63_P1 (N-[(lS)-2-amino-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (20.94 mg, 38.6 pmol, 15.7% yield, 97.6% purity) as a yellow solid and Compound 63 P2 (N-[(lS)-2-amino-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (20.39 mg, 36.9 pmol, 15.0% yield, 95.7% purity) as a yellow solid. LCMS 63-P1: RT = 1.187 mins, m / z = 529.3 (M+H)+. SFC 63-P1: RT = 2.043 mins, 98.2% e.e under 220 nm. 'H NMR 63-Pl: (400 MHz, DMSO-d6): δ 9.65 - 9.26 (m, 1H), 8.92 - 8.83 (m, 1H), 8.55 (s, 1H), 8.06 - 7.83 (m, 1H), 7.43 - 7.20 (m, 3H), 5.02 - 4.88 (m, 1H), 4.42 (s, 1H), 4.27 - 4.07 (m, 1H), 4.06 - 3.92 (m, 1H), 3.88 - 3.75 (m, 1H), 3.55 - 3.38 (m, 2H), 3.06 - 2.84 (m, 2H), 2.06 - 1.94 (m, 1H), 1.69 - 1.49 (m, 1H).19F NMR63-P1: (400 MHz, DMSO-d6): δ - 110.826, -191.346, -MSK-20525191.960. LCMS 63-P2: RT = 1.184 mins, m / z = 529.3 (M+H)+. SFC 63-P2: RT = 2.157 mins, 96.5% e.e under 220 nm. 'H NMR 63-P2: (400 MHz, DMSO-d6): δ 9.65 - 9.28 (m, 1H), 8.92 - 8.83 (m, 1H), 8.58 - 8.49 (m, 1H), 8.05 - 7.86 (m, 1H), 7.39 - 7.17 (m, 3H), 5.03 -4.87 (m, 1H), 4.69 - 4.44 (m, 1H), 4.26 - 4.08 (m, 1H), 4.05 - 3.92 (m, 1H), 3.88 - 3.74 (m, 1H), 3.54 - 3.40 (m, 2H), 3.09 - 2.83 (m, 2H), 2.07 - 1.95 (m, 1H), 1.67 - 1.50 (m, 1H).19F NMR63-P2: (400 MHz, DMSO-d6): δ - 110.791, -111.285, -191.340, -191.948.Example 22: Synthesis of Compound 64General procedure for preparation of compound 64-1:NMP, 0-25 °C, 12 hrs crude64-1To a solution of compound 62-5 (5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 214 pmol, 1.00 eq) in NMP (1.00 mL) was added compound c ((lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl)ethanamine) (66.6 mg, 257 pmol, 1.20 eq, HC1), HOBt (34.8 mg, 257 pmol, 1.20 eq) and EDCI (82.2 mg, 429 pmol, 2.00 eq and DIEA (111 mg, 857 pmol, 149 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 62-5 consumed and desired MS (Rt = 0.684 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 andMSK-20525concentrated in vacuum to give compound 64-1 (N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (170 mg, crude) was obtained as yellow oil. LCMS: m / z = 563.2 (M+H)+.General procedure for preparation of Compound 64:PPh3THF, H2O, 25 °C, 12 hrs Yield over two steps: 18.6%To a solution of compound 64-1 (N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (150 mg, 266 pmol, 1.00 eq in THF (3.00 mL) and H2O (0.30 mL) was added PPh3 (105 mg, 400 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 64-1 was consumed and desired MS (Rt = 0.569 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give the residue. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase:[Hexane-EtOH]; gradient: 5%-45% B over 15.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 64 (N-[(lS)-2-amino-l-(3-fluoro-5-isopropyl-phenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (22.4 mg, 39.9 pmol, 18.6% yield, 95.6% purity) as a yellow solid. LCMS: m / z = 537.2 (M+H)+. 'H NMR: (400 MHz, DMSO-d6): δ 9.49 - 9.24 (m, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.91 - 7.71 (m, 1H), 7.11 (s, 1H), 7.06 - 6.92 (m, 2H), 5.00 - 4.62 (m, 2H), 4.16 - 3.86 (m, 3H), 3.69 - 3.46 (m, 2H), 3.03 - 2.81 (m, 3H), 2.05 - 1.88 (m, 2H), 1.75 - 1.63 (m, 1H), 1.19 (d, J = 7.2 Hz, 6H).19F NMR: (400 MHz, DMSO-d6): δ - 113.771, -203.803, -203.982MSK-20525Example 23: Synthesis of Compound 65General procedure for preparation of compound 65-1:60-4To a solution of compound 60-4 (5-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 250 pmol, 1.00 eq) and compound c ((lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl)ethanamine) (77.5 mg, 300 pmol, 1.20 eq, HC1) in NMP (1.00 mL) was added HOBt (40.5 mg, 300 pmol, 1.20 eq), EDCI (95.7 mg, 500 pmol, 2.00 eq and DIEA (129 mg, 999 pmol, 174 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the reactant 1 was consumed completely and the desired MS (Rt = 0.630 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure. Compound 65-1 (N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl) ethyl]-5-[5-methyl-2-(tetrahydro pyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxamide) (180 mg, crude) was obtained as yellow gum and used to next step directly. LCMS: m / z = 525.3 (M+H)+General procedure for preparation of Compound 65:MSK-20525PPh3THF, H2O, 25 °C, 12 hrsYield over two steps: 12.8%To a solution of compound 65-1 (N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl)ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (160 mg, 305 pmol, 1.00 eq) in THF (8.00 mL) and H2O (0.80 mL) was added PPh3 (120 mg, 457 pmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 65-1 was consumed completely and the desired MS (Rt = 0.542 min) was detected. The reaction mixture was poured into IN HC1 (5.00 mL) and ethyl acetate (5.00 mL) and stirred at 25 °C for 10 min then extracted with ethyl acetate (10.0 mL * 3). The combined organic layers were discarded. The aqueous phase was adjusted pH to 8 by sat. NaHCOs solution then extracted with ethyl acetate (10.0 mL * 4). The combined organic layers were washed with brine (10.0 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column:LUJA Sep Silica 250 * 50 mm * 5 pm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 65 (N-[(lS)-2-amino-l-(3-fluoro-5-isopropyl-phenyl) ethyl] -5-[5-methyl-2-(tetrahydropyr-an-4-ylamino) pyrimidin-4-yl]thiazole-2-carboxamide) (20.3 mg, 39.0 pmol, 12.8% yield over two steps, 95.6% purity) as a yellow solid. LCMS: m / z = 499.3 (M+H)+. 'H NMR: (400 MHz, DMSO4): <59.30 (dd, J= 2.4, 4.8 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.16 (d, J= 6.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J= 10.0 Hz, 1H), 6.96 (d, J= 10.0Hz, 1H), 4.93 (s, 1H), 3.96 - 3.80 (m, 3H), 3.38 (t, J= 11.2 Hz, 2H), 3.07 - 2.83 (m, 3H), 2.37 (s, 3H), 2.24 - 1.94 (m, 2H), 1.84 (dd, J= 1.2, 11.6 Hz, 2H), 1.57 - 1.45 (m, 2H), 1.19 (d, J= 6.8 Hz, 6H).19F NMR:(400 MHz, DMSO4): <5 -113.785Example 24: Synthesis of compound cMSK-20525General procedure for preparation of compound c-2:To a solution of compound c-2 ((2S)-2-amino-2-(3-bromo-5-fluoro-phenyl) ethanol (1.10 g, 4.07 mmol, 1.00 eq, HC1)) and TEA (1.23 g, 12.2 mmol, 1.70 mL, 3.00 eq) in DCM (11.0 mL) was added a solution of (Boc)2O (1.06 g, 4.88 mmol, 1.12 mL, 1.20 eq) in DCM (11.0 mL) at 0 °C. After addition, the mixture was warmed to 20 °C and stirred at 20 °C for 12 hrs. LCMS showed the compound c-2 was consumed completely and the desired MS (Rt = 0.571 min) was detected. The reaction mixture was poured into water (20.0 mL) extracted with dichloromethane (20.0 mL * 3). The combined organic layers were washed with brine (30.0 mL * 1), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.50) and the fraction was concentrated to give compound c-2 (tert-butyl N-[(lS)-l-(3-bromo-5-fluoro-phenyl)-2-hydroxy-ethyl] carbamate) (1.20 g, 3.59 mmol, 88.3% yield) as a white solid. LCMS: m / z = 234.0 (M-Boc+H)+. 'H NMR: (400 MHz, CDC13): <57.27 - 7.26 (m, 1H), 7.18 (td, J= 2.0, 8.0 Hz, 1H), 7.00 (td, J= 1.6, 9.2 Hz, 1H), 5.43 - 5.23 (m, 1H), 4.85 - 4.61 (m, 1H), 3.97 -3.72 (m, 2H), 1.45 (br s, 9H).General procedure for preparation of compound c-3:MSK-20525c-2To a solution of compound c-2 (tert-butyl N-[(lS)-l-(3-bromo-5-fluoro-phenyl)-2-hydroxy-ethyl] carbamate) (1.20 g, 3.59 mmol, 1.00 eq), compound c-3a (2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane) (1.81 g, 10.8 mmol, 3.00 eq) and K2CO3 (1.49 g, 10.8 mmol, 3.00 eq) in dioxane (24.0 mL) and H2O (2.40 mL) was added Pd(dppf)C12. CH2C12 (293 mg, 359 pmol, 0.10 eq under N2 at 25 °C. After addition, the mixture was degassed and purged with N2 for 3 times, the mixture was heated to 80 °C and stirred at 80 °C for 8 hrs under N2 atmosphere. LCMS showed compound c-2 was consumed completely and the desired MS (Rt = 0.577 min) was detected. The reaction mixture was cooled to 25 °C and poured into water (20.0 mL) at 20 °C and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.50) and the fraction was concentrated to give compound c-3 (tert-butyl N-[(lS)-l-(3-fluoro-5-isopropenyl-phenyl)-2-hydroxy-ethyl] carbamate) (2.00 g, 6.77 mmol, 94.3% yield) as a white solid. LCMS: m / z = 196.1 (M-Boc+H)+. 'H NMR: (400 MHz, CDCI3): <57.17 (s, 1H), 7.07 (td, J= 2.0, 10.0 Hz, 1H), 6.96 -6.91 (m, 1H), 5.39 (s, 1H), 5.31 (d, J= 5.6 Hz, 1H), 5.15 (s, 1H), 4.77 (s, 1H), 3.87 (dt, J = 4.0, 11.6 Hz, 2H), 2.13 (s, 3H), 1.45 (s, 9H).General procedure for preparation of compound c-4:MSK-20525To a solution of compound c-3 (tert-butyl N-[(lS)-l-(3-fluoro-5-isopropenyl-phenyl)-2-hydroxy-ethyl] carbamate) (1.00 g, 3.39 mmol, 1.00 eq) in MeOH (20.0 mL) was added Pd / C (504 mg, 474 pmol, 10.0% purity, 0.14 eq) under N2 at 25 °C. After addition, the mixture was degassed and purged with H2 for 3 times, the mixture was stirred at 25 °C for 3 hrs under H2 (50 psi) atmosphere. LCMS showed the compound c-3 was consumed completely and the desired MS (Rt = 0.586 min) was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Compound c-4 (tert-butyl N-[(lS)-l-(3-fluoro-5-isopropyl-phenyl)-2-hydroxy-ethyl] carbamate) (2.00 g, crude) was obtained as yellow oil and used to the next step directly. LCMS: m / z = 198.2 (M-Boc+H)+.'H NMR: (400 MHz, CDCI3): 86.93 (s, 1H), 6.89 - 6.80 (m, 2H), 5.23 (s, 1H), 4.75 (s, 1H), 3.97 - 3.76 (m, 2H), 2.90 (td, J= 7.2, 13.6 Hz, 1H), 1.45 (s, 9H), 1.25 - 1.23 (m, 6H).General procedure for preparation of compound c-5:To a solution of compound c-4 (tert-butyl N-[(lS)-l-(3-fluoro-5-isopropyl-phenyl)-2-hydroxy-ethyl] carbamate) (1.35 g, 4.54 mmol, 1.00 eq) in DCM (13.5 mL) was added TEA (689 mg, 6.81 mmol, 948 pL, 1.50 eq and MsCl (0.67 g, 5.85 mmol, 453 pL, 1.29 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 1.5 hrs under N2. LCMS showed the compound c-4 was consumed completely and the desired MS (Rt = 0.617 min) was detected. The mixture was poured into ice NH4CI (30.0 mL), then the aqueous phase was extracted with DCM (30.0 mL * 2). The combined organic phase was washed with brine (30.0 mL * 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. Compound c-5 ([(2S)-2-(tert-butoxycarbonylamino)-2-(3-fluoro-5-isopropyl-phenyl) ethyl] methanesulfonate) (1.70 g, crude) was obtained as yellow oil and used to next step directly. LCMS: m / z = 276.1 (M-Boc+H)+. 'H NMR: (400 MHz, CDCI3): 86.95 (s, 1H), 6.94 - 6.79 (m, 2H), 5.21 - 4.96 (m, 2H), 4.51 - 4.32 (m, 2H), 3.17 - 3.09 (m, 1H), 2.93 (s, 3H), 1.56 (s, 9H), 1.24 (d, J = 6.8 Hz, 6H).General procedure for preparation of compound c-6:MSK-20525NaN3- ► DMF, 25 -50 °C, 12 hrsYield over three steps: 65.5%c-5 c-6To a solution of compound c-5 ([(2S)-2-(tert-butoxycarbonylamino)-2-(3-fluoro-5-isopropyl-phenyl) ethyl] methanesulfonate) (1.60 g, 4.26 mmol, 1.00 eq in DMF (16.0 mL) was added NaNs (0.54 g, 8.31 mmol, 1.95 eq at 25 °C under N2. The mixture was heated to 50 °C and stirred at 50 °C for 12 hrs. LCMS showed the compound c-5 was consumed completely and the desired MS (Rt = 0.654 min) was detected. The mixture was cooled to 25 °C and poured into ice NaHCCh (80.0 mL), then the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum at 35 °C to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1, Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.60) and the fraction was concentrated to give compound c-6 (tert-butyl N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl) ethyl] carbamate) (0.90 g, 2.79 mmol, 65.5% yield over three steps) as yellow oil. LCMS: m / z = 223.1 (M-Boc+H)+. 'H NMR: (400 MHz, CDCI3): <56.94 (s, 1H), 6.91 - 6.81 (m, 2H), 5.20 - 4.73 (m, 2H), 3.84 - 3.53 (m, 2H), 2.91 (td, J= 6.8, 13.9 Hz, 1H), 1.45 (s, 9H), 1.25 (d, J= 7.2 Hz, 6H).19F NMR: (400 MHz, CDCI3): § -112.857General procedure for preparation of compound c:A solution of compound c-6 (tert-butyl N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl) ethyl] carbamate) (900 mg, 2.79 mmol, 1.00 eq in HCl / dioxane (2 M, 9.00 mL, 6.45 eq) was stirred at 25 °C for 12 hrs. LCMS showed the compound c-6 was consumed completely and the desired MS (Rt = 0.461 min) was detected. The reaction mixture was concentrated under reduced pressure at 35 °C. Compound c ((lS)-2-azido-l-(3-fluoro-5-isopropyl-MSK-20525phenyl) ethanamine) (630 mg, crude, HC1) was obtained as a white solid and used to next step directly. LCMS: m / z = 223.1 (M+H)+. 'H NMR: (400 MHz, DMSO-t / e). 38.92 (s, 3H), 7.36 (s, 1H), 7.30 (d, J= 9.6 Hz, 1H), 7.14 (d, J= 10.0 Hz, 1H), 4.50 (t, J= 6.4 Hz, 1H), 3.95 - 3.76 (m, 2H), 3.02 - 2.81 (m, 1H), 1.21 (d, J= 7.2 Hz, 6H).Example 25: Synthesis of Compound 66General procedure for preparation of compound 66-1:61-2A solution of compound 61-2 (methyl 5 -(2 -chloro- 5-methyl-pyrimidin- 4-yl) thiazole-2-carboxylate) (800 mg, 2.97 mmol, 1.00 eq), compound 1-la ((3S, 4S) -3-fluorotetrahydropyran-4-amine) (508 mg, 3.26 mmol, 1.10 eq, HCI), CsF (2.25 g, 14.8 mmol, 5.00 eq) in DMSO (8.00 mL) was stirred at 80 °C for 4 hrs. LCMS showed compound 2-2 was consumed and desired MS (Rt = 0.496 min) was detected. The reaction mixture was poured into ice water (40.0 mL), the mixture was extracted with ethyl acetate (30.0 mL * 5), the organic layers were filtered and the filtrate was dried with Na2SO4, then concentrated to give the residue, the cake was collected separately. The residue was purifiedMSK-20525by prep-HPLC (column: YMC-Gel SiL-HG 250*50 mm*10|im; mobile phase: [Heptane-EtOH]; gradient: l%-30% B over 15.0 min), the eluent was concentrated. Compound 66- 1 (Methyl 5-[2-[[(3S, 4S) -3-fluorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxylate) (610 mg, 1.42 mmol, 47.7% yield, 81.8% purity) was obtained as a yellow solid. LCMS: m / z = 353.0 (M+H)+. 'H NMR: (400 MHz, DMSO4): <58.59 (s, 1H), 8.36 (s, 1H), 7.26 (d, J= 4.8 Hz, 1H), 4.85 - 4.72 (m, 1H), 4.01 (t, J= 12.0 Hz, 2H), 3.94 (s, 3H), 3.93 - 3.89 (m, 1H), 3.55 - 3.48 (m, 2H), 2.38 (s, 3H), 1.99 - 1.91 (m, 1H), 1.68 - 1.65 (m, 1H).General procedure for preparation of compound 66-2:To a solution of Compound 66-1 (methyl 5 -[2 - [[(3S, 4S) - 3-fluorotetrahydropyran- 4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxylate) (580 mg, 1.35 mmol, 1.00 eq in THF (6.10 mL), H2O (6.10 mL) was added LiOH•H₂O (113 mg, 2.69 mmol, 2.00 eq) at 25 °C, the mixture was stirred at 25 °C for 1 hr. LCMS showed Compound 66-1 was consumed and the desired MS was detected. The mixture was extracted with ethyl acetate (10.0 mL * 3), the aqueous phase was adjusted pH to 6 with IM HC1, then the mixture was filtered, the cake was collected. The crude product was used to the next step without purification.Compound 66-2 (5- [2-[[(3S, 4S) -3-fluorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxylic acid) (208 mg, 505 pmoL 37.5% yield, 82.2% purity) was obtained as a light yellow solid. LCMS: m / z = 339.1 (M+H)+. 'H NMR: (400 MHz, DMSO ): 88.46 (s, 1H), 8.29 (s, 1H), 7.12 - 7.11 (m, 1H), 4.86 - 4.73 (m, 1H), 4.04 - 3.98 (m, 2H), 3.92 - 3.89 (m, 1H), 3.53 - 3.49 (m, 2H), 2.35 (s, 3H), 1.99 - 1.92 (m, 1H), 1.67 -1.64 (m, 1H).General procedure for preparation of compound 66-3:MSK-20525To a solution of compound 66-2 (5 -[2 -[[(3S, 4S) - 3-fluorotetrahydropyran- 4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxylic acid) (120 mg, 292 pmol, 1.00 eq), compound b ((IS) -2-azido-l-(3-chloro-5-fluoro-phenyl) ethanamine) (87.8 mg, 349 pmol, 1.20 eq, HC1) inNMP (1.20 mL) was added EDCI (112 mg, 583 pmol, 2.00 eq), HOBt (47.3 mg, 349 pmol, 1.20 eq), DIEA (151 mg, 1.17 mmol, 203 p, L, 4.00 eq) at 0 °C, the mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 66-2 was consumed and the desired MS was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SC>4, filtered and concentrated. The crude product was used into next step without purification, compound 66-3 (N-[(1S) -2-azido-l-(3-chloro-5-fluoro-phenyl) ethyl]-5-[2-[[(3S, 4S) -3-fluorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxamide) (155 mg, 243 pmol, 83.5% yield, 83.5% purity) was obtained as yellow oil. LCMS: m / z = 535.2 (M+H)+.General procedure for preparation of Compound 66:PPh3THF, H20, 15 - 30 °C, 24 hrs Yield: 18.4%To a solution of compound 66-3 (N-[(1S) - 2 -azido- 1 -(3-chloro-5-fluoro-phenyl) ethyl] -5-[2-[[(3S, 4S) -3-fluorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-MSK-205252-carboxamide) (135 mg, 212 pmol, 1.00 eq) in THF (3.60 mL), H2O (0.40 mL) was added PPh₃ (83.5 mg, 318 pmol, 1.50 eq), the mixture was stired at 15 °C for 12 hrs, the mixture was heated to 30 °C and stirred at 30 °C for 12 hrs. LCMS showed compound 66-3 was consumed and the desired MS (Rt = 0.508 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL * 3). The combined organic layers were washed with brine (30.0 mL * 3), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50 mm* 10pm; mobile phase: [Hexane-EtOH (0.1% NH3H2O)]; gradient: 15%-55% B over 15.0 min), the eluent was concentrated. Compound 66 (N-[(1S) -2-amino-l-(3-chloro-5-fluoro-phenyl) ethyl]-5-[2-[[(3S, 4S) -3-fluorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxamide) (20.9 mg, 39.1 pmol, 18.4% yield, 95.1% purity) was obtained as a yellow solid. LCMS: m / z = 509.2 (M+H)+. 'H NMR: (400 MHz, DMSO-t / e): 39.43 -9.37 (m, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.37 - 7.21 (m, 4H), 4.94 (t, J= 6.0 Hz, 1H), 4.87 -4.66 (m, 1H), 4.18 - 3.94 (m, 2H), 3.90 (dd, J= 11.2, 4.0 Hz, 1H), 3.67 - 3.41 (m, 3H), 3.06 -2.84 (m, 2H), 2.38 (s, 3H), 2.00 - 1.89 (m, 1H), 1.65 (d, J= 11.6 Hz, 1H).19F NMR: (400 MHz, DMSO4): 3 - 110.846, - 204.059Example 26: Synthesis of Compound 67General procedure for preparation of compound 67-2:MSK-20525HN67-2To a solution of compound 67-1 (4-bromo-5-chloro-2-fluoro-pyridine) (1.00 g, 4.75 mmol, 1.00 eq) and compound 2-2a (tetrahydropyran-4-amine) (577 mg, 5.70 mmol, 1.20 eq) in DMSO (10.0 mL) was added DIEA (1.84 g, 14.3 mmol, 2.48 mL, 3.00 eq) at 25 °C. The mixture was heated to 135 °C and stirred at 135 °C for 12 hrs. LCMS showed compound 67-1 was consumed completely and desired mass was detected. The reaction mixture was poured into ice H2O (50.0 mL), then the aqueous phase was extracted with ethyl acetate (40.0 mL * 2). The combined organic phase was washed with brine (70.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by recrystallization from ethyl acetate (6.00 mL) at 80 °C for 4 hrs. The mixture was cooled to 25 °C and the solid was precipitated. The mixture was filtered to give the solid and the solid was washed with petroleum ether / ethyl acetate = 3 / 1 (15.0 mL). The solid was dried under vacuum at 45 °C to give compound 67-2 (4-bromo-5-chloro-N-tetrahydropyran-4-yl-pyridin-2-amine) (900 mg, 3.09 mmol, 65.0% yield) as an off-white solid. LCMS: m / z = 293.0 (M+H)+.General procedure for preparation of compound 67-3:KOAc, Pd(dppf)CI2toluene, 120 °C, 2 hrsYield: 38.3%67-3A mixture of compound 67-2 (4-bromo-5-chloro-N-tetrahydropyran-4-yl-pyridin-2-amine) (900 mg, 3.09 mmol, 1.00 eq), compound 1-2a (4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane) (3.92 g, 15.4 mmol, 5.00 eq), KOAc (1.51 g, 15.4 mmol, 5.00 eq) and Pd(dppf)C12 (226 mg, 309 pmol, 0.10 eq) in toluene- Ill -MSK-20525(18.0 mL) was degassed and purged with N2 for three times, and then the mixture was stirred at 120 °C for 2 hrs under N2 atmosphere. LCMS showed compound 67-2 was consumed completely and desired mass was detected. The mixture was cooled to 25 °C and poured into H2O (60.0 mL), then the aqueous phase was extracted with ethyl acetate (50.0 mL * 2). The combined organic phase was washed with brine (80.0 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate / Dichloromethane = 20 / 1 / 1 to 0 / 1 / 1, Petroleum ether / Ethyl acetate = 0 / 1, Rf = 0.10). The fraction was concentrated under vacuum to give compound 67-3 (5-chloro-N-tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-2-amine) (400 mg, 1.18 mmol, 38.3% yield) as a yellow solid.LCMS: m / z = 426.0 (M+H)+.General procedure for preparation of compound 67-4:KOAc, Pd(dppf)CI2, toluene, H2O, 100 °C, 5 hrs Yield: 59.8%67-3 67-4A mixture of compound 67-3 (5-chloro-N-tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-2-amine) (400 mg, 1.18 mmol, 1.00 eq), compound 1-3a (methyl 5-bromothiazole-2-carboxylate) (393 mg, 1.77 mmol, 1.50 eq, KOAc (348 mg, 3.54 mmol, 3.00 eq) and Pd(dppf)C12 (86.4 mg, 118 pmol, 0.10 eq) in toluene (8.00 mL) and H2O (0.80 mL) was degassed and purged with N2 for three times, and then the mixture was stirred at 100 °C for 5 hrs under N2. TLC (Petroleum ether / Ethyl acetate = 0 / 1) indicated compound 67-3 (Rf= 0.05) was consumed completely and one new spot (Rf= 0.25) was formed. The mixture was cooled to 25 °C and poured into H2O (50.0 mL), then the aqueous phase was extracted with ethyl acetate (40.0 mL * 2). The combined organic phase was washed with brine (60.0 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1 / to 5 / 1, Petroleum ether / Ethyl acetate = 0 / 1, Rf= 0.25). The fraction was concentrated under vacuum to give compound 67-4 (methyl 5-[5-chloro-2-MSK-20525(tetrahydropyran-4-ylamino)-4-pyridyl] thiazole-2-carboxylate) (250 mg, 707 pmol, 59.8% yield) as a yellow solid.General procedure for preparation of compound 67-5:67-5To a solution of compound 67-4 (methyl 5-[5-chloro- 2-(tetrahydropyran-4-ylamino)-4-pyridyl] thiazole-2-carboxylate) (250 mg, 707 pmol, 1.00 eq) in THF (2.50 mL) and H2O (2.50 mL) was added LiOH’LLO (59.3 mg, 1.41 mmol, 2.00 eq). The mixture was stirred at 25 °C for 2 hrs. TLC (Petroleum ether / Ethyl acetate = 0 / 1) indicated compound 67-4 (Rf = 0.25) was consumed completely and one new spot (Rf = 0.00) was formed. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous phase was adjusted pH = 5 by IN HC1 then the solids precipitated out. The suspension was filtered and washed with H2O (10.0 mL * 2). The filter cake was dried to give compound 67-5 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl] thiazole-2-carboxylicacid) (200 mg, crude) as a yellow solid. The crude product was used to the next step. LCMS: m / z = 341.1 (M+H)+. 'H NMR: (400 MHz, DMSO-d₆): δ 8.39 (s, 1H), 8.15 (s, 1H), 6.97 (d, J= 7.6 Hz, 1H), 6.80 (s, 1H), 3.94 - 3.84 (m, 3H), 3.43 - 3.40 (m, 2H), 1.88 - 1.85 (m, 2H), 1.47 - 1.38 (m, 2H).General procedure for preparation of compound 67-6:HOBt, EDCI, DIEA NMP, 0 -30 °C, 12 hrs Crude67-5MSK-20525To a solution of compound 67-5 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylic acid) (130 mg, 339 pmol, 1.00 eq) and compound c ((lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl) ethanamine) (132 mg, 508 pmol, 1.50 eq, HC1) in NMP (1.50 mL) was added HOBt (55.0 mg, 407 pmol, 1.20 eq), EDCI (130 mg, 678 pmol, 2.00 eq and DIEA (131 mg, 1.02 mmol, 177 pL, 3.00 eq) at 0 °C. The mixture was stirred at 30 °C for 12 hrs. LCMS showed compound 67-5 was consumed completely and desired mass (Rt = 0.654 min) was detected. The reaction mixture was poured into H2O (8.00 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (20.0 mL * 4), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 67-6 (N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl) ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (300 mg, crude) as yellow oil. The crude product was used into the next step. LCMS: m / z = 544.2 (M+H)+.General procedure for preparation of Compound 67:67-6 Compound 67To a solution of compound 67-6 (N-[(lS)-2-azido-l-(3-fluoro-5-isopropyl-phenyl) ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (260 mg, 363 pmol, 1.00 eq) in THF (2.70 mL) and H2O (0.30 mL) was added PPh3(143 mg, 545 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 67-6 was consumed completely and desired mass (Rt = 1.399 mins) was detected. The reaction mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (30.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (neutral condition: column: LUJA Sep Silica250*50 mm*5µm; mobile phase:[Hexane-EtOH]; gradient: 10%-50% B over 15.0 min). The eluent was concentrated inMSK-20525vacuum. The product was dissolved in acetonitrile (4.00 mL) and H2O (20.0 mL), the aqueous was lyophilized to give Compound 67 (N-[(lS)-2-amino-l-(3-fluoro-5-isopropyl-phenyl) ethyl] -5- [5-chlor o-2-(tetrahydropyr an-4-ylam ino)-4-pyridyl] thiazole-2-carboxamide) (20.4 mg, 38.8 pmol, 10.7% yield, 98.6% purity) as a yellow solid. LCMS: m / z = 518.3 (M+H)+. 'H NMR: (400 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 7.11 (s, 1H), 7.04 - 6.95 (m, 3H), 6.79 (s, 1H), 4.93 (t, J= 6.0 Hz, 1H), 3.93 - 3.84 (m, 3H), 3.43 - 3.37 (m, 2H), 3.00 - 2.85 (m, 3H), 1.89 - 1.85 (m, 2H), 1.68 (s, 2H), 1.47 - 1.37 (m, 2H), 1.19 (d, J= 6.8 Hz, 6H).19F NMR: (400 MHz, DMSO-6): 8 - 113.8Example 27: Synthesis of Compound 68General procedure for preparation of compound 68-1:67-5 68-1To a solution of compound 67-5 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxylic acid) (130 mg, 341 pmol, 1.00 eq) and compound d ((lS)-2-azido-l-(3-methoxyphenyl) ethanamine) (93.4 mg, 409 pmol, 1.20 eq, HC1) in NMP (1.50 mL) was added HOBt (55.2 mg, 409 pmol, 1.20 eq), EDCI (131 mg, 681 pmol, 2.00 eq) and DIEA (88.0 mg, 681 pmol, 119 pL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 67-5 was consumed completely and desired mass (RT = 0.587 min) was detected. The reaction mixture was poured into H2O (8.00 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (20.0 mL * 4), dried with anhydrous Na2SC>4, filtered andMSK-20525concentrated in vacuum to give compound 68-1 (N-[(lS)-2-azido-l-(3-methoxyphenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole-2-carboxamide) (200 mg, crude) as yellow oil. LCMS: m / z = 514.1 (M+H)+.General procedure for preparation of Compound 68:68-1 Compound 68To a solution of compound 68-1 (N-[(lS)-2-azido-l-(3-methoxyphenyl) ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl] thiazole-2-carboxamide) (160 mg, 245 pmol, 1.00 eq in THF (1.80 mL) and H2O (0.20 mL) was added PPh3(96.3 mg, 367 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 68-1 was consumed completely and desired mass (RT = 0.475 min) was detected. The reaction mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (30.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (neutral condition: column: LUJA Sep Silica 250*50 mm*5 pm; mobile phase:[Hexane-EtOH]; gradient: 15%-55% B over 15.0 min). The eluent was concentrated in vacuum. The product was dissolved in acetonitrile (4.00 mL) and H2O (20.0 mL), the aqueous was lyophilized to give Compound 68 (N-[(lS)-2-amino-l-(3-methoxyphenyl) ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl] thiazole-2-carboxamide) (20.64 mg, 41.5 pmol, 17.0% yield, 98.2% purity) as ayellow solid. LCMS: m / z = 488.1 (M+H)+. 'H NMR: (400 MHz, DMSO-d₆): δ 9.29 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.24 (t, J= 8.0 Hz, 1H), 6.98 - 6.94 (m, 3H), 6.83 - 6.79 (m, 2H), 4.90 (s, 1H), 3.95 - 3.84 (m, 3H), 3.74 (s, 3H), 3.43 - 3.37 (m, 2H), 3.01 - 2.85 (m, 2H) 1.86 (dd, J= 12.4, 2.0 Hz, 2H), 1.65 (s, 2H), 1.47 - 1.37 (m, 2H).Example 28: Synthesis of Compound 69MSK-20525To a solution of compound 67-5 (5-[5-chloro- 2-(tetrahydropyran-4-ylamino)-4- pyridyl]thiazole-2-carboxylic acid) (130 mg, 341 |imol, 1.00 eq) and compound e ((lS)-2- azido-l-(3-fluoro-5-methoxy-phenyl) ethanamine) (101 mg, 409 pmol, 1.20 eq, HC1) in NMP (1.50 mL) was added HOBt (55.2 mg, 409 pmol, 1.20 eq), EDCI (131 mg, 681 pmol, 2.00 eq and DIEA (88.0 mg, 68.0 pmol, 119 pL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 67-5 was consumed completely and desired mass (RT = 0.592 min) was detected. The reaction mixture was poured into H2O (8.00 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (20.0 mL * 4), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give compound 69-1 (N-[(lS)-2-azido-l-(3-fluoro-5- methoxy-phenyl) ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]thiazole- 2-carboxamide) (240 mg, crude) as yellow oil. LCMS: m / z = 532.1 (M+H)+.General procedure for preparation of Compound 69:MSK-20525PPh3THF, H20, 25 °C, 12 hrs Yield: 13.1%To a solution of compound 69-1 (N-[(lS)-2-azido-l-(3-fluoro-5-methoxy-phenyl) ethyl]-5- [5-chloro-2-(tetrahydropyran-4-ylamino) -4-pyridyl]thiazole-2-carboxamide) (200 mg, 311 pmol, 1.00 eq) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (122 mg, 466 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 69-1 was consumed completely and desired mass (RT = 0.488 min) was detected. The reaction mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (30.0 mL), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (neutral condition: column: LUJA Sep Silica 250*50 mm*5 pm; mobile phase:[Hexane-EtOH]; gradient: 15%-55% B over 15.0 min). The eluent was concentrated in vacuum. The product was dissolved in acetonitrile (4.00 mL) and H2O (20.0 mL), the aqueous was lyophilized to give Compound 69 (N-[(lS)-2-amino-l-(3-fluoro-5-methoxy-phenyl) ethyl] -5- [5-chlor o-2-(tetrahydropyr an-4-ylam ino)-4-pyridyl] thiazole-2-carboxamide) (20.83 mg, 40.6 pmol, 13.1% yield, 98.6% purity) as a yellow solid. LCMS: m / z = 506.1 (M+H)+. 'H NMR: (400 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 6.97 (d, J= 7.6 Hz, 1H), 6.82 - 6.77 (m, 3H), 6.72 - 6.69 (m, 1H), 4.90 (t, J= 6.2 Hz, 1H), 3.97 - 3.84 (m, 3H), 3.75 (s, 3H), 3.43 - 3.37 (m, 2H), 3.02 - 2.85 (m, 2H), 1.88 - 1.85 (m, 2H), 1.64 (s, 1H), 1.47 - 1.37 (m, 2H).19F NMR: (400 MHz, DMSO-6): S - 111.8Example 29: Synthesis of compound eMSK-20525General procedure for preparation of compound e-2:e-2To the mixture of compound e-1 ((2S)-2-amino-2-(3-fluoro-5-methoxy-phenyl)ethanol) (540 mg, 2.44 mmol, 1.00 eq, HC1) in DCM (5.40 mL) was added BOC2O (638 mg, 2.92 mmol, 672 pL, 1.20 eq) and TEA (740 mg, 7.31 mmol, 1.02 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 10 hrs. LCMS showed compound e-1 was consumed and desired mass (RT = 0.525 min) was detected. The mixture was poured into H2O (50.0 mL) and extracted with DCM (50.0 mL * 2). The combined organic layers were washed with brine (50.0 mL * 2), dried over Na2SO4, filtered and concentrated in vacuum to give the residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1, product: Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.40) and the solvent was concentrated in vacuum to give compound e-2 (tert-butyl N-[(lS)-l-(3-fluoro-5-methoxy-phenyl)-2-hydroxy-ethyl]carbamate) (550 mg, 1.81 mmol, 74.3% yield, 93.9% purity) as a white solid. LCMS: m / z = 230.1 (M-55+H)+. 'H NMR: (400 MHz, DMSO-d₆): δ 7.22 (d, J= 8.0 Hz, 1H), 6.65 - 6.72 (m, 3H), 4.80 (t, J= 5.6 Hz, 1H), 4.54 - 4.42 (m, 1H), 3.75 (s, 3H), 3.46 (t, J= 6.0 Hz, 2H), 1.37 (s, 9H).General procedure for preparation of compound e-3:MSK-20525e-2 e-3To the mixture of compound e-2 (tert-butyl N-[(lS)-l-(3-fluoro-5-methoxy-phenyl)-2-hydroxy-ethyl] carbamate) (500 mg, 1.65 mmol, 1.00 eq in the DCM (5.00 mL) was added TEA (333 mg, 3.29 mmol, 458 pL, 2.00 eq) and MsCl (290 mg, 2.53 mmol, 196 pL, 1.54 eq at 0 °C, the mixture was stirred at 25 °C for 1.5 hrs. LCMS showed compound e-2 was consumed and desired mass (RT = 0.564 min) was detected. The mixture was poured into ice NH4CI (20.0 mL), then the aqueous phase was extracted with DCM (20.0 mL * 3). The combined organic phase was washed with brine (20.0 mL * 1), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give compound e-3 ([(2S)-2-(tert-butoxycarbonylamino)-2-(3-fluoro-5-methoxy-phenyl)ethyl] methanesulfonate) (670 mg, crude) was obtained as a yellow solid. LCMS: m / z = 264.1 (M-100+H)+.General procedure for preparation of compound e-4:NaN3, DMF, 25 ~ 50 °C, 12 hrs Yield over two steps: 97.9%e-3To the mixture of compound e-3 ([(2S)-2-(tert-butoxycarbonylamino)-2-(3-fluoro-5-methoxy-phenyl)ethyl] methanesulfonate) (670 mg, 1.84 mmol, 1.00 eq in the DMF (6.70 mL) was added NaNs (0.75 g, 11.5 mmol, 6.26 eq) at 25 °C under N2, the mixture was stirred at 50 °C for 12 hrs. LCMS showed compound e-3 was consumed and desired mass (RT = 0.611 min) was detected. The mixture was cooled to 25 °C and poured into ice NaHCCh (20.0 mL), then the aqueous phase was extracted with ethyl acetate (20.0 mL * 3). The combined organic phase was washed with brine (20.0 mL * 4), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum at 35 °C to give the residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 50 / 1 to 10 / 1, Petroleum ether / Ethyl acetate = 3 / 1, Rf = 0.70). The fraction was filtered andMSK-20525concentrated in vacuum to give compound e-4 (tert-butyl N-[(lS)-2-azido-l-(3-fluoro-5-methoxy-phenyl)ethyl]carbamate) (500 mg, 1.61 mmol, 97.9% yield) as a white solid. LCMS: m / z = 264.1 (M-100+H)+. 'H NMR: (400 MHz, DMSO-6): δ 6.66 - 6.60 (m, 2H), 6.59 - 6.53 (m, 1H), 5.14 - 4.73 (m, 2H), 3.81 (s, 3H), 3.68 - 3.54 (m, 2H), 1.45 (s, 9H).General procedure for preparation of compound e:HCl / dioxane (2 M) dioxane, 25 °C, 2 hrs HCIYield: 91.2%To the mixture of compound e-4 (tert-butyl N-[(lS)-2-azido-l-(3-fluoro-5-methoxy-phenyl)ethyl]carbamate) (500 mg, 1.61 mmol, 1.00 eq in dioxane (4.50 mL) was added HCl / dioxane (2 M, 10.0 mL, 12.4 eq) at 25 °C, the mixture was stirred at 25 °C for 2 hrs. LCMS showed compound e-4 was consumed and desired mass (RT = 0.390 min) was detected. The mixture was concentrated to give compound e ((lS)-2-azido-l-(3-fluoro-5-methoxy-phenyl)ethanamine) (370 mg, 1.47 mmol, 91.2% yield, 98.0% purity, HCI) as a white solid. LCMS: m / z = 211.1 (M+H)+. 'H NMR: (400 MHz, DMSO-6): δ 8.84 (s, 3H), 7.10 - 6.84 (m, 3H), 4.49 (t, J= 6.8 Hz, 1H), 3.91 - 3.75 (m, 5H).Example 30: Synthesis of Compound 70MSK-20525Compound 70 General procedure for preparation of compound 70-1:Pd2(dba)3, Xantphos, t-BuONa dioxane, 20 ~ 100 °C, 5 hrsYield: 52.5%70-1 c 70-1To a mixture of compound 70-lc (2,4-dibromo-5-chloro-pyridine) (600 mg, 2.21 mmol, 1.00 eq, compound 1-la ((3S,4S)-3-fluorotetrahydropyran-4-amine) (378 mg, 2.43 mmol, 1.10 eq, HC1) and t-BuONa (425 mg, 4.42 mmol, 2.00 eq) in dioxane (18.0 mL) was added Pd2(dba)3(202 mg, 221 pmol, 0.10 eq) and Xantphos (255 mg, 442 pmol, 0.20 eq) under N2 at 20 °C. The mixture was degassed and purged with N2 for 3 times, the mixture was heated to 100 °C and stirred at 100 °C for 5 hrs under N2 atmosphere. LCMS showed compound 11-lc was consumed and desired mass (RT = 0.510 min) was formed. The mixture was cooled down. Then poured into H2O (100 mL) and extracted with ethyl acetate (50.0 mL * 2). The combined organic phase was washed with brine (100 mL * 3), dried withMSK-20525anhydrous Na2SC>4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 30 / 1 to 10 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.50) to give compound 70-1 (4-bromo-5-chloro-N-[(3S,4S)-3-fluorotetrahydropyran-4-yl]pyridin-2-amine) (360 mg, 1.16 mmol, 52.5% yield) as a yellow solid. LCMS: m / z = 311.0 (M+H)+.'H NMR: (400 MHz, CDCl3): δ 8.05 (s, 1H), 6.74 (s, 1H), 4.85 - 4.58 (m, 2H), 4.27 - 4.13 (m, 2H), 4.10 - 4.01 (m, 1H), 3.69 - 3.48 (m, 2H), 1.99 - 1.82 (m, 2H).19F NMR: (400 MHz, CDCl3): δ - 206.035General procedure for preparation of compound 70-2c:\ / -Sn— Sn-11aHNPd(PPh3)2CI2dioxane, 20 ~ 100 °C, 2 hrsYield: 67.4%70-1 70-2cTo a mixture of compound 70-1 (4-bromo-5-chloro-N-[(3S,4S)-3-fluorotetrahydropyran-4-yl]pyridin-2-amine) (350 mg, 1.13 mmol, 1.00 eq and compound Ila (410 mg, 1.25 mmol, 259 pL, 1.11 eq) in dioxane (14.0 mL) was added Pd(PPh3)2C12 (79.3 mg, 113 pmol, 0.10 eq under N2 at 20 °C. The mixture was degassed and purged with N2 for 3 times, the mixture was heated to 100 °C and stirred at 100 °C for 2 hrs under N2 atmosphere. LCMS showed compound 70-1 was consumed and desired mass (RT = 0.500 min) was formed. The mixture was cooled down. Then poured into saturated KF aqueous solution (80.0 mL) slowly at 10-20 °C and extracted with ethyl acetate (50.0 mL * 2). The combined organic phase was washed with brine (80.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 30 / 0 to 12 / 1, Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.60) to give compound 70-2c (5-chloro-N-[(3S,4S)-3-fluorotetrahydropyran-4-yl]-4-trimethylstannyl-pyridin-2-amine) (300 mg, 762 pmol, 67.4% yield) as a light yellow solid. LCMS: m / z = 395.1 (M+H)+.1H NMR: (400 MHz, CDCl3): δ 7.95 (s, 1H), 6.47 (s, 1H), 4.82 - 4.49 (m, 2H), 4.30 - 4.03 (m, 3H), 3.70 -3.51 (m, 2H), 2.01 - 1.81 (m, 2H), 0.38 (s, 9H).19F NMR: (400 MHz, CDCl3): δ - 206.141MSK-20525General procedure for preparation of compound 70-3:Pd(PPh3)2CI2, Cui DMF, 20 ~ 90 °C, 3 hrsYield: 46.5% 70-2c 70-3To a mixture of compound 70-2c (5-chloro-N-[(3S,4S)-3-fluorotetrahydropyran-4-yl]-4-trimethylstannyl-pyridin-2-amine) (292 mg, 743 pmol, 1.10 eq and compound l-3a (150 mg, 675 pmol, 1.00 eq) in DMF (6.00 mL) was added Pd(PPh3)2Ch (47.4 mg, 67.5 pmol, 0.10 eq) and Cui (25.7 mg, 135 pmol, 0.20 eq under N2 at 20 °C. The mixture was degassed and purged with N2 for 3 times, the mixture was heated to 90 °C and stirred at 90 °C for 3 hrs under N2 atmosphere. LCMS showed 70-2c was consumed and desired mass (RT = 2.284 mins) was formed. The mixture was cooled down. Then poured into H2O (50.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic phase was washed with brine (50.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 30 / 0 to 2 / 1, Petroleum ether / Ethyl acetate = 1 / 2, Rf = 0.55) to give a crude product. The crude product was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 150*40mm*10 pm; mobile phase: [Hexane-EtOH]; gradient: 1%-15% B over 12.0 min). The eluent was concentrated in vacuum to give compound 70-3 (methyl 5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylate) (130 mg, 322 pmol, 46.5% yield, 92.3% purity) as a yellow solid. LCMS: m / z = 372.0 (M+H)+.General procedure for preparation of compound 70-4:LiOH H2O THF, H2O, 25 °C, 2 hrsYield: 95.2%70-3 70-4MSK-20525To a mixture of compound 70-3 (methyl 5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylate) (130 mg, 322 pmol, 1.00 eq) in THF (1.30 mL) and H2O (1.30 mL) was added LiOH·H2O (27.0 mg, 645 pmol, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 70-3 was consumed and desired mass (RT = 0.433 min) was formed. The mixture was concentrated in vacuum to give a resulting mixture. The resulting mixture was adjusted to pH = 3 with HC1 (1 M), then filtered and the filter cake was concentrated under reduced pressure to give compound 70-4 (5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylic acid) (110 mg, 307 pmol, 95.2% yield) as a light yellow solid. LCMS: m / z = 358.1 (M+H)+.General procedure for preparation of compound 70-5:HOBt, EDCI, DIEA NMP, 0~ 20 °C, 16 hrsCrude 70-4 70-5To the mixture of compound 70-4 (5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylic acid) (100 mg, 279 μmol, 1.00 eq) and compound a ((lS)-2-azido-l-(3-chlorophenyl)ethanamine) (78.1 mg, 335 pmol, 1.20 eq, HC1) inNMP (2.00 mL) was added HOBt (45.3 mg, 335 pmol, 1.20 eq), EDCI (107 mg, 558 pmol, 2.00 eq) and DIEA (144 mg, 1.12 mmol, 194 pL, 4.00 eq) at 0 °C, the mixture was warmed to 20 °C and stirred at 20 °C for 16 hrs. LCMS showed desired product mass (RT = 0.595 min) was formed. Then poured into H2O (30.0 mL) and extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (30.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 70-5 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxamide) (170 mg, crude) as yellow gum. LCMS: m / z = 536.1 (M+H)+.General procedure for preparation of Compound 70:MSK-20525PPh3THF, H2O, 20 °C, 60 hrs Yield over two steps: 16.5%70-5 Compound 70To the mixture of compound 70-5 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxamide) (160 mg, 298 pmol, 1.00 eq) in THF (2.70 mL) and H2O (0.30 mL) was added PPh3(117 mg, 447 pmol, 1.50 eq), the mixture was stirred at 20 °C for 60 hrs. LCMS showed compound 70-5 was consumed and desired mass (RT = 0.469 min) was formed. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (15.0 mL * 2). The combined organic phase was washed with brine (30.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50mm*10 μm; mobile phase: [Hexane-EtOH (0.1% NH3H2O)]; gradient: 15%-55% B over 15.0 min). The eluent was concentrated in vacuum and then dissolved in ACN / H2O = 1 / 10 (22.0 mL). The residual aqueous solution was lyophilized to give Compound 70 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxamide) (23.53 mg, 45.1 pmol, yield over two steps: 16.5%, 98.0% purity) as a yellow solid. LCMS: m / z = 510.1 (M+H)+. 'H NMR: (400 MHz, DMSO-6): δ 9.67 - 9.20 (m, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.48 (s, 1H), 7.38 - 7.30 (m, 3H), 7.13 (br d, J= 8.0 Hz, 1H), 6.96 (s, 1H), 4.96 (br t, J= 6.4 Hz, 1H), 4.83 - 4.63 (m, 1H), 4.30 - 4.10 (m, 1H), 4.03 - 3.87 (m, 2H), 3.65 -3.46 (m, 2H), 3.08 - 2.85 (m, 2H), 1.86 - 1.66 (m, 2H).19F NMR: (400 MHz, CDCl3): δ -203.725Example 31: Synthesis of Compound 71MSK-20525General procedure for preparation of compound 71-1:67-1 71-1To a mixture of compound 67-1 (4-bromo-5-chloro-2-fluoro-pyridine) (300 mg, 1.43 mmol, 1.00 eq and compound 12-la ((3S,4S)-3-methyltetrahydropyran-4-amine) (226 mg, 1.50 mmol, 1.05 eq, HC1) in DMSO (6.00 mL) was added DIEA (552 mg, 4.28 mmol, 744 pL, 3.00 eq) at 20 °C, the mixture was heated to 80 °C and stirred at 80 °C for 16 hrs. LCMS showed compound 71-1 (RT = 1.329 mins) was formed. The mixture was cooled down. Then poured into H2O (80.0 mL) and extracted with ethyl acetate (50.0 mL * 2). The combined organic phase was washed with brine (80.0 mL * 3), dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150*40mm*10 pm; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient: 36%-66% B over 14.0 min). The eluent was concentrated in vacuum to remove ACN. The residual aqueous solution was lyophilized toMSK-20525give compound 71-1 (4-bromo-5-chloro-N-[(3S,4S)-3-methyltetrahydropyran-4-yl]pyridin-2-amine) (150 mg, 488 pmol, 34.2% yield) as a yellow solid. LCMS: m / z = 307.0 (M+H)+.General procedure for preparation of compound 71-2:11a Pd(PPh3)2Cl2dioxane, 20 ~ 100 °C, 4 hrs Yield: 70.3%71-2To a mixture of compound 71-1 (4-bromo-5-chloro-N-[(3S,4S)-3-methyltetrahydropyran-4-yl]pyridin-2-amine) (150 mg, 488 pmol, 1.00 eq and compound Ila (260 mg, 793 μmol, 164 pL, 1.62 eq) in dioxane (3.00 mL) was added Pd(PPh3)2Cl2(34.3 mg, 48.8 μmol, 0.10 eq under N2 at 20 °C. The mixture was degassed and purged with N2 for 3 times, the mixture was heated to 100 °C and stirred at 100 °C for 4 hrs under N2 atmosphere. LCMS showed the desired mass (RT = 2.499 mins) was formed. The mixture was cooled down. Then poured into saturated KF aqueous solution (30.0 mL) slowly at 10 ~ 20 °C and extracted with ethyl acetate (15.0 mL * 2). The combined organic phase was washed with brine (30.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.60) to give compound 71-2 (5-chloro-N-[(3S,4S)-3-methyltetrahydropyran-4-yl]-4-trimethylstannyl-pyridin-2-amine) (140 mg, 343 pmol, 70.3% yield, 95.7% purity) as yellow gum. LCMS: m / z = 391.1 (M+H)+.General procedure for preparation of compound 71-3:Pd(PPh3)2CI2, Cui DMF, 20 - 90 °C, 3 hrs Yield: 47.8%MSK-20525To a mixture of compound 71-2 (5-chloro-N-[(3S,4S)-3-methyltetrahydropyran-4-yl]-4-trimethylstannyl-pyridin-2-amine) (134 mg, 330 pmol, 1.05 eq) and compound l-3a (70.0 mg, 315 pmol, 1.00 eq) in DMF (2.60 mL) was added Pd(PPh3)2Cl2(22.1 mg, 31.5 μmol, 0.10 eq and Cui (12.0 mg, 63.0 pmol, 0.20 eq) under N2 at 20 °C. The mixture was degassed and purged with N2 for 3 times, the mixture was heated to 90 °C and stirred at 90 °C for 3 hrs under N2 atmosphere. LCMS showed compound 71-2 was consumed and desired mass (RT = 0.992 min) was formed. The mixture was cooled down. Then poured into saturated KF aqueous solution (30.0 mL) slowly at 10 ~ 20 °C and extracted with ethyl acetate (20.0 mL * 2). The combined organic phase was washed with brine (30.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (Dichloromethane / Ethyl acetate = 2 / 1, Rf = 0.45) to give compound 71-3 (methyl 5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylate) (60.0 mg, 150 pmol, 47.8% yield, 92.5% purity) as a yellow solid. LCMS: m / z = 368.1 (M+H)+.General procedure for preparation of compound 71-4:LiOH H2O THF, H2O, 20 °C, 1 hrYield: 93.6%71-3 71-4To a mixture of compound 71-3 (methyl 5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylate) (60.0 mg, 150 pmol, 1.00 eq in THF (0.60 mL) and H2O (0.60 mL) was added LiOH·H2O (12.6 mg, 301 pmol, 2.00 eq) at 20 °C. The mixture was stirred at 20 °C for 1 hr. LCMS showed compound 71-3 was consumed and desired mass (RT = 0.420 min) was formed. The mixture was concentrated in vacuum to give a resulting mixture. The resulting mixture was adjusted to pH = 3 with HC1 (1 M), then filtered and the filter cake was concentrated under reduced pressure to give compound 71-4 (5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylic acid) (50.0 mg, 141 pmol, 93.6% yield) as a light yellow solid. LCMS: m / z = 354.1 (M+H)+.MSK-20525General procedure for preparation of compound 71-5:HOBt, EDCI, DIEA NMP, 0 - 20 °C, 12 hrsCrude 71-4 71-5To the mixture of compound 71-4 (5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxylic acid) (50.0 mg, 141 pmol, 1.00 eq) and compound a ((lS)-2-azido-l-(3-chlorophenyl)ethanamine) (39.5 mg, 169 pmol, 1.20 eq, HC1) inNMP (1.00 mL) was added HOBt (22.9 mg, 169 pmol, 1.20 eq), EDCI (54.1 mg, 282 pmol, 2.00 eq) and DIEA (73.0 mg, 565 pmol, 98.4 pL, 4.00 eq at 0 °C, the mixture was warmed to 20 °C and stirred at 20 °C for 12 hrs. LCMS showed desired mass (RT = 0.590 min) was formed. The mixture was poured into H2O (20.0 mL) and extracted with ethyl acetate (15.0 mL * 2). The combined organic phase was washed with brine (20.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 71-5 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxamide) (80.0 mg, crude) as yellow gum. LCMS: m / z = 533.9 (M+H)+.General procedure for preparation of Compound 71:PPh3THF, H2O, 20 °C, 60 hrs Yield over two steps: 32.0%71-5 Compound 71To the mixture of compound 71-5 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro- 2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxamide)MSK-20525(80.0 mg, 150 pmol, 1.00 eq) in THF (1.44 mL) and H2O (0.16 mL) was added PPh₃ (59.1 mg, 225 junol, 1.50 eq), the mixture was stirred at 20 °C for 60 hrs. LCMS showed compound 71-5 was consumed and desired mass (RT = 0.466 min) was formed. The mixture was poured into H2O (15.0 mL) and extracted with ethyl acetate (10.0 mL * 2). The combined organic phase was washed with brine (15.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50mm*10 μm; mobile phase: [Hexane-EtOH (0.1% NH3H2O)]; gradient: 15%-55% B over 15.0 min). The eluent was concentrated in vacuum and then dissolved in ACN / H2O = 1 / 10 (22.0 mL). The residual aqueous solution was lyophilized to give Compound 71 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]-4-pyridyl]thiazole-2-carboxamide) (22.96 mg, 43.5 pmol, yield over two steps: 32.0%, 96.0% purity) as a yellow solid. LCMS: m / z = 506.2 (M+H)+. 'H NMR: (400 MHz, DMSO ): 89.71 - 9.22 (m, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.47 (s, 1H), 7.39 - 7.29 (m, 3H), 7.00 - 6.88 (m, 2H), 4.95 (brt, J = 6.0 Hz, 1H), 4.14 (td, J= 8.0, 4.0 Hz, 1H), 3.84 - 3.69 (m, 1H), 3.59 - 3.43 (m, 3H), 3.09 -2.83 (m, 2H), 2.27 - 2.13 (m, 1H), 2.07 - 2.00 (m, 1H), 1.72 - 1.54 (m, 2H), 0.87 (d, J= 6.8 Hz, 3H).Example 32: Synthesis of Compound 72General procedure for preparation of compound 72-1:MSK-20525°V^NH2 2-2a DIEA, DMSO, 20 ~ 50 °C, 30 mins Yield: 89.9%62-3 72-1To the mixture of compound 62-3 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiazole-2- carboxylate) (400 mg, 1.38 mmol, 1.00 eq and compound 2-2a (tetrahydropyran-4- amine) (278 mg, 2.76 mmol, 2.00 eq) in the DMSO (4.00 mL) was added DIEA (356 mg, 2.76 mmol, 480 pL, 2.00 eq) at 20 °C, the mixture was stirred at 50 °C for 0.5 hr. LCMS showed the compound 62-3 was consumed completely and desired product (Rt = 0.503 min) was detected. The mixture was poured into H2O (50.0 mL) and extracted with ethyl acetate (50.0 mL * 2). The combined organic layers were washed with brine (50.0 mL * 2), dried over Na2SC>4, filtered and concentrated. The crude product was triturated with Petroleum ether / Ethyl acetate (6.00 mL, 1 / 1) at 20 °C for 10 min. Compound 72-1 (methyl 5-[5- chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylate) (440 mg, 1.24 mmol, 89.9% yield) was obtained as the yellow solid. LCMS: m / z = 355.2 (M+H)+.1H NMR: (400 MHz, DMSO-6): 89.00 - 8.86 (m, 1H), 8.53 (s, 1H), 7.92 - 7.56 (m, 1H), 3.95 (s, 3H), 3.88 (d, J= 10.4 Hz, 3H), 3.50 - 3.36 (m, 2H), 1.87 (d, J= 9.6 Hz, 2H), 1.62 - 1.44 (m, 2H).General procedure for preparation of compound 72-2:LiOH«H2O THE, H2O, 20 °C, 0.5 hrs crude72-1 72-2To the mixture of Compound 72-1 (methyl 5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylate) (200 mg, 563 pmol, 1.00 eq in the THF (2.00 mL) and H2O (2.00 mL) was added LiOH•H2O (47.3 mg, 1.13 mmol, 2.00 eq), theMSK-20525mixture was stirred at 20 °C for 30 mins. LCMS showed the Compound 72-1 was consumed completely and desired product (Rt = 0.481 min) was detected. The mixture was concentrated in vacuum to remove THF and adjusted to pH = 3 with 1.00 M HC1 aqueous solution, filtered and the filter cake was concentrated under reduced pressure to give a residue. Compound 72-2 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (200 mg, crude) was obtained as the yellow solid. LCMS: m / z = 341.0 (M+H)+. 'H NMR: (400 MHz, DMSO-6): d 14.65 - 13.92 (m, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 7.85 - 7.60 (m, 1H), 3.88 (d, J= 10.8 Hz, 3H), 3.51 - 3.42 (m, 1H), 1.90 - 1.76 (m, 2H), 1.59 - 1.47 (m, 2H).General procedure for preparation of compound 72-3:To the mixture of compound 72-2 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (150 mg, 440 pmol, 1.00 eq) and compound a ((lS)-2-azido-l-(3-chlorophenyl)ethanamine) (123 mg, 528 pmol, 1.20 eq, HC1) in theNMP (2.00 mL) was added EDCI (168 mg, 880 pmol, 2.00 eq), HOBt (71.3 mg, 528 pmol, 1.20 eq and DIEA (227 mg, 1.76 mmol, 306 pL, 4.00 eq) at 0 °C, the mixture was stirred at 20 °C for 12 hrs LCMS showed the compound 72-2 was consumed completely and desired product (Rt = 0.607 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate ( 20.0 mL * 2). The combined organic layers were washed with brine (20.0 mL * 2), dried overlS^SCU, filtered and concentrated. Compound 72-3 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (227 mg, crude) was obtained as the yellow oil. LCMS: m / z = 519.1 (M+H)+.General procedure for preparation of Compound 72:MSK-20525PPh3THF, H2O, 20 °C, 12 hrs Yield over two steps: 9.31%Compound 72To the mixture of compound 72-3 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (200 mg, 385 pmol, 1.00 eq) in the THF (1.80 mL) and H2O (0.200 mL) was added PPh3(151 mg, 577 pmol, 1.50 eq) at 20 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed the compound 72-3 was consumed completely and desired product (Rt = 0.459 min) was detected. The mixture was poured into HC1 (aq. 1.00 mol / L, 5.00 mL) and extracted with ethyl acetate (30.0 mL * 2). the aqueous phase was washed with sat-NaHCCL (aq.20.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic layers were washed with brine (30.0 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min), the solvent was concentrated, and ACN (1.00 mL) and H2O (15.0 mL) was added to the residue, then the product was lyophilized.Compound 72 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (20.37 mg, 41.0 pmol, 10.6% yield, 99.3% purity) was obtained as the yellow solid. LCMS: m / z = 493.1 (M+H)+. 'H NMR: (400 MHz, DMSO-6): <59.65 - 9.27 (m, 1H), 8.92 - 8.80 (m, 1H), 8.51 (s, 1H), 7.84 - 7.60 (m, 1H), 7.47 (s, 1H), 7.40 - 7.28 (m, 3H), 4.99 - 4.86 (m, 1H), 3.87 (d, J = 10.8 Hz, 3H), 3.46 - 3.36 (m, 2H), 3.06 - 2.84 (m, 2H), 1.89 - 1.78 (m, 2H), 1.58 - 1.45 (m, 2H).Example 33: Synthesis of Compound 73MSK-20525General procedure for preparation of compound 14-1EDCI, HOBt, DIEA NMP, 0 - 20 °C, 12 hrs crude72-2 73-1To the mixture of compound 72-2 (5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (150 mg, 440 pmol, 1.00 eq) and compound d ((lS)-2-azido-l-(3-methoxyphenyl) ethanamine) (120 mg, 528 pmol, 1.20 eq, HC1) in the NMP (2.00 mL) was added EDCI (168 mg, 880 pmol, 2.00 eq), HOBt (71.3 mg, 528 pmol, 1.20 eq and DIEA (227 mg, 1.76 mmol, 306 pL, 4.00 eq) at 0 °C, the mixture was stirred at 20 °C for 12 hrs LCMS showed the compound 72-2 was consumed completely and desired product (Rt = 0.585 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (20.0 mL * 2). The combined organic layers were washed with brine (20.0 mL * 2), dried overNa2SO4, filtered and concentrated. Compound 73-1 (N-[(lS)-2-azido-l-(3-methoxyphenyl) ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (239 mg, crude) was obtained as the yellow oil. LCMS: m / z = 515.2 (M+H)+.General procedure for preparation of Compound 73:MSK-2052573-1 Compound 73To the mixture of compound 73-1 (N-[(lS)-2-azido-l-(3-methoxyphenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (200 mg, 388 pmol, 1.00 eq) in the THF (1.80 mL) and H2O (0.200 mL) was added PPh3(152 mg, 582 pmol, 1.50 eq) at 20 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed the compound 73-1 was consumed completely and desired product (Rt = 0.443 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic layers were washed with brine (30.0 mL * 2), dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min), the solvent was concentrated, and ACN (1.00 mL) and H2O (15.0 mL) was added to the residue, then the product was lyophilized. Compound 73 (N-[(lS)-2-amino-l-(3-methoxyphenyl)ethyl]-5-[5-chloro-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (20.29 mg, 41.3 pmol, 10.6% yield, 99.7% purity) was obtained as the yellow solid. LCMS: m / z = 489.2 (M+H)+. 'H NMR: (400 MHz, DMSO-6): <59.44 -9.22 (m, 1H), 8.93 - 8.79 (m, 1H), 8.51 (s, 1H), 7.84 - 7.59 (m, 1H), 7.24 (t, J= 8.0 Hz, 1H), 7.04 - 6.91 (m, 2H), 6.81 (dd, J= 8.0, 2.0 Hz, 1H), 4.89 (br s, 1H), 3.98 - 3.82 (m, 3H), 3.73 (s, 3H), 3.46 - 3.36 (m, 2H), 3.04 - 2.83 (m, 2H), 1.97 - 1.70 (m, 3H), 1.58 - 1.42 (m, 2H).Example 34: Synthesis of compound dMSK-20525General procedure for preparation of compound d-2:BOC2O, TEA DCM, 0 ~ 20 °C, 1 hrYeld: 75.0%d-1 d-2To the mixture of compound d-1 ((2S)-2-amino-2-(3-methoxyphenyl)ethanol) (1.90 g, 11.3 mmol, 1.00 eq) in the DCM (19.0 mL) was added BOC2O (2.98 g, 13.6 mmol, 3.13 mL, 1.20 eq) and TEA (3.45 g, 34.0 mmol, 4.74 mL, 3.00 eq at 0 °C, the mixture was stirred at 20 °C for 1 hr. TLC (Petroleum ether / Ethyl acetate = 1 / 1) indicated compound d-1 (Rf = 0.10) was consumed completely and one new spot (Rf = 0.50) formed. The mixture was poured into H2O (35.0 mL) and extracted with ethyl acetate (50.0 mL * 2). The combined organic layers were washed with brine (50.0 mL * 2), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 30 / 1 to 2 / 1, product: Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.50), and the solvent was concentrated. Compound d-2 (tert-butyl N-[(lS)-2-hydroxy-l-(3-methoxyphenyl)ethyl] carbamate) (2.33 g, 8.53 mmol, 75.0% yield, 97.9% purity) was obtained as the white solid. LCMS: m / z = 290.2 (M+H)+.1H NMR: (400 MHz, DMSO r,)<57.34 - 7.27 (m, 1H), 6.94 - 6.78 (m, 3H), 5.21 (s, 1H), 4.76 (s, 1H), 3.94 - 3.70 (m, 5H), 1.45 (s, 8H).General procedure for preparation of compound d-3:MSK-20525cruded-2 d-3To a mixture of compound d-2 (tert-butyl N-[(lS)-2-hydroxy-l-(3-methoxyphenyl)ethyl] carbamate) (2.20 g, 8.23 mmol, 1.00 eq) and TEA (1.25 g, 12.3 mmol, 1.72 mL, 1.50 eq) in DCM (44.0 mL) was added MsCl (330 mg, 2.88 mmol, 222 pL, 0.35 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. LCMS showed compound d-2 was consumed and desired mass (Rt = 0.512 min) was formed. The reaction mixture was poured into H2O (200 mL), extracted with ethyl acetate (150 mL * 2). The combined organic phase was washed with brine (200 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuumto give a residue. Compound d-3 ([(2S)-2-(tert-butoxycarbonylamino)-2-(3-methoxyphenyl)ethyl] methanesulfonate) (3.00 g, crude) was obtained as a white solid. LCMS: m / z = 290.2 (M-55)+General procedure for preparation of compound d-4:Yield over two steps: 72.9%d-3 d-4To a mixture of compound d-3 ([(2S)-2-(tert-butoxycarbonylamino)-2-(3-methoxyphenyl)ethyl] methanesulfonate) (3.00 g, 8.69 mmol, 1.00 eq) in DMF (45.0 mL) was added azidosodium (1.64 g, 25.2 mmol, 2.90 eq) at 20 °C, the mixture was heated to 50 °C and stirred at 50 °C for 12 hrs. LCMS showed compound d-3 was consumed and desired mass (Rt = 1.015 mins) was formed. After cooled down. The mixture was slowly poured to sat-NaHCCL (aq. 200 mL), then extracted with EtOAc (100 mL * 5), the combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to give residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1, Petroleum ether / Ethyl acetate = 4 / 1, Rf = 0.55) to give a product. Compound d-4 (tert-butyl N-[(lS)-2-azido-l-(3-MSK-20525methoxyphenyl)ethyl] carbamate) (1.88 g, 6.33 mmol, 72.9% yield, 98.5% purity) was obtained as a white solid. LCMS: m / z = 291.2 (M-H)+General procedure for preparation of compound d:HCI / dioxane (2.00 M) dioxane, 20 °C, 12 hrs Yield: 95.2%d-4To a mixture of compound d-4 (tert-butyl N-[(lS)-2-azido-l-(3-methoxyphenyl)ethyl] carbamate) (1.88 g, 6.43 mmol, 1.00 eq in dioxane (9.40 mL) was added HCI / dioxane (2.00 M, 18.8 mL, 5.85 eq) at 20 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed compound d-4 was consumed and desired mass (Rt = 0.826 min) was formed. The mixture was concentrated in vacuum to give residue. Compound d ((lS)-2-azido-l-(3-methoxyphenyl)ethanamine) (1.40 g, 6.12 mmol, 95.2% yield, 100% purity, HC1) was obtained as a white solid. LCMS: m / z = 239.1 (M-H)+. 'H NMR: (400 MHz, MeOD): 87.39 (t, J= 8.0 Hz, 1H), 7.09 - 6.98 (m, 3H), 4.48 (dd, J= 8.4, 4.8 Hz, 1H), 3.94 -3.88 (m, 1H), 3.87 - 3.76 (m, 4H).Example 35: Synthesis of Compound 74General procedure for preparation of compound 74-1MSK-20525EDCI, HOBt, DIEA NMP, 0-25 °C, 12 hrscrude 62-5 74-1To a solution of compound 62-5 (5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 215 pmol, 1.00 eq) in NMP (1.00 mL) was added compound a ((lS)-2-azido-l-(3-chlorophenyl)ethanamine) (60.0 mg, 258 pmol, 1.20 eq, HC1), HOBt (34.8 mg, 256 pmol, 1.20 eq and EDCI (82.3 mg, 429 pmol, 2.00 eq and DIEA (111 mg, 859 p ol, 150 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed 13.2% compound 3-5 (Rt = 0.510 min) consumed and desired product (Rt = 0.658 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give compound 74-1 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethylJ-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (160 mg, crude) as yellow oil. LCMS: m / z = 537.1 (M+H)+General procedure for preparation of Compound 74:PPh3THF / H2O, 25 °C, 12 hrs Yield over two steps: 19.2%Compound 74To a solution of compound 74-1 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (140 mg, 261 pmol, 1.00 eq) in THF (3.00 mL) and H2O (0.30 mL) was added PPh3(103 mg,MSK-20525391 pmol, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 74-1 was consumed and desired MS (Rt = 0.534 min) was detected. The reaction mixture was poured into H2O (50.0 mL), the aqueous phase was extracted with ethyl acetate (50.0 mL * 3). The combined organic phase was washed with brine (50.0 mL * 2), dried with anhydrous Na2SC>4 and concentrated in vacuum to give the residue. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 74 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (21.54 mg, 41.2 pmol, 19.2% yield, 97.9% purity) as a yellow solid. LCMS: m / z = 511.1 (M+H)+.1H NMR: (400 MHz, DMSO-t / e): d 9.57 - 9.24 (m, 1H), 8.93 - 8.83 (m, 1H), 8.54 (s, 1H), 7.92 -7.72 (m, 1H), 7.47 (s, 1H), 7.40 - 7.24 (m, 3H), 5.01 - 4.55 (m, 2H), 4.22 - 3.84 (m, 3H), 3.66 - 3.43 (m, 2H), 3.05 - 2.82 (m, 2H), 2.03 - 1.84 (m, 2H), 1.72 - 1.72 (m, 1H).19F NMR: (400 MHz, DMSO4): d -203.815Example 36: Synthesis of Compound 75LiOH«H2O CsF, DIEA, 20 - 80 °C, 2 hrs THF / H2O, 20 °C, 05 hr Yield: 52 1% Yield: 799%EDCI, HOBt, DIEA NMP,0 -20 °C, 12 hrs crudeGeneral procedure for preparation of compound 75-1:MSK-2052562-3 75-1To the mixture of compound 62-3 (methyl 5-(2,5-dichloropyrimidin-4-yl)thiazole-2-carboxylate) (200 mg, 689 pmol, 1.00 eq and compound 12-la ((3S,4S)-3-methyltetrahydropyran-4-amine) (109 mg, 723 pmol, 1.05 eq, HC1) in the DMSO (3.00 mL) was added CsF (104 mg, 689 pmol, 1.00 eq) and DIEA (267 mg, 2.07 mmol, 360 pL, 3.00 eq) at 20 °C, the mixture was stirred at 80 °C for 2 hrs. LCMS showed the compound 62-3 was consumed completely and desired product (Rt = 0.517 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic layers were washed with brine (30.0 mL * 2), dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50mm*10pm; mobile phase: [Hexane-EtOH]; gradient: l%-20% B over 15.0 min). The solvent was concentrated. Compound 75-1 (methyl 5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylate) (140 mg, 359 pmol, 52.1% yield, 94.7% purity) was obtained as the yellow solid. LCMS: m / z = 369.2 (M+H)+. m NMR: (400 MHz, DMSO-6): 58.93 (s, 1H), 8.53 (s, 1H), 7.92 - 7.55 (m, 1H), 4.18 - 4.04 (m, 1H), 3.95 (s, 3H), 3.87 - 3.76 (m, 1H), 3.64 (dd, J= 11.2, 4.8 Hz, 1H), 3.50 (d, J= 10.4 Hz, 2H), 2.21 - 1.99 (m, 1H), 1.87 - 1.72 (m, 1H), 1.61 (d, J= 3.6 Hz, 1H), 0.88 (d, J = 7.2 Hz, 3H).General procedure for preparation of compound 75-2:MSK-20525To the mixture of Compound 75-1 (methyl 5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylate) (130 mg, 352 pmol, 1.00 eq) in the THF (1.30 mL) and H2O (1.30 mL) was added LiOH’FhO (29.5 mg, 704 pmol, 2.00 eq) at 20 °C, the mixture was stirred at 20 °C for 0.5 hr. LCMS showed the compound 75-1 was consumed completely and desired product (Rt = 0.500 min) was detected. The mixture was concentrated in vacuum to remove THF and adjusted pH to 3 with 1.00 M HC1 aqueous solution, filtered and the filter cake was concentrated under reduced pressure to give a residue. Compound 75-2 (5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 281 pmol, 79.9% yield) was obtained as the yellow solid. LCMS: m / z = 355.0 (M+H)+.General procedure for preparation of compound 75-3:EDCI, HOBt, DIEA NMP,0 ~ 20 °C, 12 hrs crude75-275-3To the mixture of Compound 75-2 (5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 281 pmol, 1.00 eq) and compound a ((lS)-2-azido-l-(3-chlorophenyl)ethanamine) (78.8 mg, 338 pmol, 1.20 eq, HC1) in the NMP (1.50 mL) was added EDCI (108 mg, 563 pmol, 2.00 eq), HOBt (45.7 mg, 338 pmol, 1.20 eq) and DIEA (145 mg, 1.13 mmol, 196 pL, 4.00 eq) at 0 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed the compound 75-2 was consumed completely and desired product (Rt = 0.632 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (20.0 mL * 2). The combined organic layers were washed with brine (20.0 mL * 2), dried over Na2SO4, filtered and concentrated.Compound 75-3 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl] amino]pyrimidin-4-yl]thiazole-2-carboxamide) (148 mg, crude) was obtained as the yellow oil. LCMS: m / z = 533.2 (M+H)+General procedure for preparation of Compound 75:MSK-20525PPh3THF, H2O, 20 °C, 12 hrs Yield over two steps: 14.2%Compound 75To the mixture of compound 75-3 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (120 mg, 224 pmol, 1.00 eq in the THF (1.80 mL) and H2O (0.200 mL) was added PPh₃ (88.5 mg, 337 pmol, 1.50 eq at 20 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed the compound 75-3 was consumed completely and desired product (Rt = 0.466 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic layers were washed with brine (30.0 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min), the solvent was concentrated, and ACN (1.00 mL) and H2O (15.0 mL) was added to the residue, then the product was lyophilized. Compound 75 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-chloro-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxamide) (20.48 mg, 40.1 jimol, 17.8% yield, 99.4% purity) was obtained as yellow solid. LCMS: m / z = 507.3 (M+H)+.1H NMR: (400 MHz, DMSO-tL): 89.58 - 9.28 (m, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 7.88 - 7.60 (m, 1H), 7.47 (s, 1H), 7.40 - 7.28 (m, 3H), 4.92 (t, J= 6.4 Hz, 1H), 4.20 - 3.97 (m, 1H), 3.89 - 3.72 (m, 1H), 3.62 (dd, J= 11.6, 4.8 Hz, 1H), 3.55 - 3.42 (m, 2H), 3.08 - 2.82 (m, 2H), 2.21 - 1.96 (m, 1H), 1.88 - 1.69 (m, 2H), 1.66 - 1.55 (m, 1H), 0.87 (d, J= 6.0 Hz, 3H).Example 37: Synthesis of Compound 76EDCI, HOBt, DIEA, NMP 0-25 °C, 12 hrs CrudeMSK-20525General procedure for preparation of compound 76-1:61-4To a solution of compound 61-4 (5-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 250 pmol, 1.00 eq) and compound b (lS)-2-azido-l-(3-chloro-5-fluoro-phenyl) ethanamine (75.2 mg, 300 pmol, 1.20 eq, HC1) in NMP (2.00 mL) was added HOBt (40.5 mg, 300 p ol, 1.20 eq), EDCI (95.7 mg, 499 pmol, 2.00 eq) and DIEA (129 mg, 999 pmol, 173.98 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 61-4 was consumed completely and the desired MS (Rt = 0.611 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 76-1 (N-[(lS)-2-azido-l-(3-chloro-5-fluoro-phenyl) ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxamide) (200 mg, crude) was obtained as yellow gum and used to next step directly. LCMS: m / z = 517.1 (M+H)+General procedure for preparation of Compound 76:PPh3- ► THF, H2O, 25 °C, 12 hrs Yield over two steps: 11.8%MSK-20525To a solution of compound 76-1 (N-[(lS)-2-azido-l-(3-chloro-5-fluoro-phenyl)ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxamide) (180 mg, 348 pmol, 1.00 eq) in THF (9.00 mL) and H2O (0.90 mL) was added PPh3 (137 mg, 522 pmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 76-1 was consumed completely and the desired MS (Rt = 0.525 min) was detected. The reaction mixture was poured into IN HC1 (5.00 mL) and ethyl acetate (5.00 mL) and stirred at 25 °C for 10 min, Then extracted with ethyl acetate (10.0 mL * 3). The combined organic layers were discarded. The aqueous phase was adjusted pH to 8 by sat. NaHCOs solution then extracted with ethyl acetate (10.0 mL * 4). The combined organic layers were washed with brine (10.0 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column:Welch Ultimate XB-SiOH 150 * 40mm * 10pm; mobile phase: [Hexane-EtOH]; gradient: 20%-50% B over 12.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 76 (N-[(lS)-2-amino-l-(3-chloro-5-fluoro-phenyl) ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin-4-yl] thiazole-2-carboxamide) (20.89 mg, 41.0 pmol, 11.8% yield over two steps, 96.4% purity) as a yellow solid. LCMS: m / z = 491.2 (M+H)+. 'H NMR: (400 MHz, DMSO-6): <59.55 - 9.18 (m, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 7.37 - 7.29 (m, 2H), 7.25 (d, J= 10.0 Hz, 1H), 7.17 (d, J= 6.8 Hz, 1H), 5.01 - 4.83 (m, 1H), 3.87 (d, J = 10.8 Hz, 3H), 3.39 (t, J= 11.2 Hz, 2H), 3.07 - 2.85 (m, 2H), 2.37 (s, 3H), 1.84 (d, J= 11.2 Hz, 2H), 1.58 - 1.46 (m, 2H).19F NMR: (400 MHz, DMSO4): S -110.866Example 38: Synthesis of Compound 77Compound 77 General procedure for preparation of compound 77-1:MSK-20525To a solution of compound 61-4 (5-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]thiazole-2-carboxylic acid) (100 mg, 250 pmol, 1.00 eq) and compound d ( (lS)-2-azido-1- (3-methoxyphenyl) ethan-amine) (68.5 mg, 300 pmol, 1.20 eq, HC1) in NMP (2.00 mL) was added HOBt (40.5 mg, 300 pmol, 1.20 eq), EDCI (95.7 mg, 500 pmol, 2.00 eq and DIEA (129 mg, 999 pmol, 174 pL, 4.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 61-4 was consumed completely and the desired MS (Rt = 0.580 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure. Compound 77-1 (N-[(lS)-2-azido-l-(3-methoxyphenyl) ethyl]-5-[5-methyl-2-(tetrahydropyran-4-ylamino) pyrimidin -4-yl] thiazole-2-carboxamide) (180 mg, crude) was obtained as yellow gum and used to next step directly. LCMS: m / z = 495.2 (M+H)+General procedure for preparation of Compound 77:77-1 Compound 77To a solution of compound 77-1 (N-[(lS)-2-azido-l-(3-methoxyphenyl) ethyl]-5-[5-methyl-2-(tetrahyro- pyran-4-ylamino) pyrimidin-4-yl]thiazole-2-carboxamide) (160 mg, 324 pmol, 1.00 eq) in THF (8.00 mL) and H2O (0.80 mL) was added PPh3(127 mg, 485MSK-20525pmol, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 77-1 was consumed completely and the desired MS (Rt = 0.501 min) was detected. The reaction mixture was poured into IN HC1 (5.00 mL) and ethyl acetate (5.00 mL) and stirred at 25 °C for 10 min, Then extracted with ethyl acetate (10.0 mL * 3). The combined organic layers were discarded. The aqueous phase was adjusted pH to 8 by sat. NaHCCh solution then extracted with ethyl acetate (10.0 mL * 4). The combined organic layers were washed with brine (10.0 mL * 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column:LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: 20%-60% B over 15.0 min) and the eluent was concentrated to give the compound. The compound was diluted in MeCN (1.00 mL) and water (10.0 mL) then lyophilized to give Compound 77 (N-[(lS)-2-amino-l- (3-methoxyphenyl) ethyl] -5-[5-methyl-2- (tetrahydropyran-4-ylamino) pyrimidin-4-yl]thi azole -2-carboxamide) (20.99 mg, 43.6 pmol, 13.5% yield over two steps, 97.4% purity) as a yellow solid. LCMS: m / z = 469.3 (M+H)+. 'H NMR: (400 MHz, DMSO-tL): d 9.43 - 9.12 (m, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.24 (t, J= 8.0 Hz, 1H), 7.19 -7.11 (m, 1H), 7.02 - 6.91 (m, 2H), 6.81 (dd, J= 2.0, 8.4 Hz, 1H), 4.90 (s, 1H), 3.38 (t, J= 11.6 Hz, 2H), 3.03 - 2.85 (m, 2H), 2.37 (s, 3H), 2.23 - 1.91 (m, 2H), 1.84 (d, J= 10.0 Hz, 2H), 1.58 - 1.45 (m, 2H).Example 39: Synthesis of Compound 78General procedure for preparation of compound 78-1MSK-20525EDCI, HOBt, DIEA NMP, 0 ~ 25 °C, 12 hrs Yield: 72.2%66-2 78-1To a solution of compound 66-2 (5 -[2 -[[(3S, 4S) - 3-fhiorotetrahydropyran- 4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxylic acid) (83.0 mg, 202 pmol, 1.00 eq), compound a ((IS) -2-azido-l-(3-chlorophenyl) ethanamine) (56.4 mg, 242 pmol, 1.20 eq, HC1) in NMP (2.00 mL) was added EDCI (77.3 mg, 403 pmol, 2.00 eq), HOBt (32.7 mg, 242 pmol, 1.20 eq), DIEA (104 mg, 807 pmol, 140 pL, 4.00 eq) at 0 °C, the mixture was stirred at 25 °C for 12 hrs. LCMS showed 14.8% of compound 66-2 (Rt = 1.596 mins) was remained and the desired MS (Rt = 2.760 mins) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (20.0 mL * 3). The combined organic layers were washed with brine (20.0 mL * 3), dried over Na2SC>4, filtered and concentrated. The crude product was used into next step without purification. Compoud 78-1 (N-[(1S) -2-azido-l-(3-chlorophenyl) ethyl]-5-[2-[[(3S, 4S) -3-fhiorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxamide) (208 mg, 291 pmol, 72.2% yield, 72.2% purity) was obtained as yellow liquid. LCMS: m / z = 517.2 (M+H)+General procedure for preparation of Compound 78:78-1To a solution of compound 78-1 (N-[(1S) - 2 -azido- 1 -(3-chlorophenyl) ethyl]-5-[2-[[(3S, 4S) -3-fhiorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxamide) (188 mg, 263 pmol, 1.00 eq) in THF (4.70 mL), H2O (0.50 mL) was added PPh3(103 mg, 395 pmol, 1.50 eq), the mixture was stirred at 15 °C for 12 hrs, the mixture was heated to 30 °C and stirred at 30 °C for 12 hrs. LCMS showed compound 78-1 was consumed and the desired MS (Rt = 0.499 min) was detected. TheMSK-20525mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL * 3). The combined organic layers were washed with brine (30.0 mL * 3), dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50 mm*10pm; mobile phase: [Hexane-EtOH (0.1% NH3H2O)]; gradient: 20%-60% B over 15.0 min), the eluent was concentrated. Compound 78 (N-[(1S) -2-amino-l-(3-chlorophenyl) ethyl]-5-[2-[[(3S, 4S) -3-fhiorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]thiazole-2-carboxamide) (20.25 mg, 39.8 pmol, 15.1% yield, 96.6% purity) was obtained as a yellow solid. LCMS: m / z = 491.2 (M+H)+.'H NMR: (400 MHz, DMSO ): <59.54 - 9.28 (m, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.47 -7.19 (m, 5H), 4.93 (s, 1H), 4.85 - 4.67 (m, 1H), 4.17 - 4.00 (m, 2H), 3.91 (dd, J= 10.8, 4.0 Hz, 1H), 3.67 - 3.44 (m, 3H), 3.05 - 2.87 (m, 2H), 2.39 (s, 3H), 2.01 - 1.88 (m, 1H), 1.71 -1.61 (m, 1H).19F NMR: (400 MHz, DMSO ): 8 - 204.051Example 40: Synthesis of Compound 79General procedure for preparation of compound 79-1:61-2To the mixture of compound 61-2 (methyl 5-(2-chloro-5-methyl-pyrimidin-4-yl)thiazole-2-carboxylate) (250 mg, 926 pmol, 1.00 eq) and compound 12-la ((3S,4S)-3-MSK-20525methyltetrahydropyran-4-amine) (154 mg, 1.02 mmol, 1.10 eq, HC1) in the DMSO (3.00 mL) was added CsF (704 mg, 4.63 mmol, 5.00 eq) at 20 °C, the mixture was stirred at 80 °C for 2 hrs. LCMS showed the compound 61-2 was consumed completely and desired product (Rt = 0.467 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic layers were washed with brine (30.0 mL * 2), dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: l%-30% B over 15.0 min), the solvent was concentrated. Compound 79-1 (methyl 5-[5-methyl-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylate) (170 mg, 466 pmol, 50.3% yield, 95.6% purity) was obtained as the yellow solid. LCMS: m / z = 349.3 (M+H)+. 'H NMR: (400 MHz, DMSO-t / e): 88.56 (s, 1H), 8.32 (s, 1H), 7.23 (br d, J= 2.8 Hz, 1H), 4.14 - 4.03 (m, 1H), 3.94 (s, 3H), 3.85 - 3.76 (m, 1H), 3.63 (dd, J= 11.2, 5.2 Hz, 1H), 3.55 - 3.44 (m, 2H), 2.36 (s, 3H), 2.16 - 2.06 (m, 1H), 1.85 - 1.70 (m, 1H), 1.59 (dd, J= 12.1, 2.8 Hz, 1H), 0.86 (d, J= 7.2 Hz, 3H).General procedure for preparation of compound 79-2:79-1 79-2To the mixture of Compound 79-1 (ethyl 5-[5-methyl-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylate) (160 mg, 459 pmol, 1.00 eq in the THF (1.60 mL) and H2O (1.60 mL) was added LiOH•H2O (38.5 mg, 918 pmol, 2.00 eq), the mixture was stirred at 20 °C for 0.5 hr. LCMS showed the Compound 79-1 was consumed completely and desired product (Rt = 0.405 min) was detected. The mixture was concentrated in vacuum to remove THF and adjusted to pH = 3 with 1.00 M HC1 aqueous solution, filtered and the filter cake was concentrated under reduced pressure to give a residue. Compound 79-2 (5-[5-methyl-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxylic acid) (120 mg,MSK-20525280 pmol, 61.1% yield, 78.3% purity) was obtained as the yellow solid. LCMS: m / z = 355.2 (M+H)+.General procedure for preparation of compound 79-3:To the mixture of Compound 79-2 (5-[5-methyl-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl] amino] pyrimidin-4-yl]thiazole-2-carboxylic acid) (120 mg, 358 pmol, 1.00 eq) and compound a ((lS)-2-azido-l-(3-chlorophenyl)ethanamine) (100 mg, 430 pmol, 1.20 eq, HC1) in the NMP (2.00 mL) was added EDCI (137 mg, 717 pmol, 2.00 eq), HOBt (58.1 mg, 430 pmol, 1.20 eq and DIEA (185 mg, 1.44 mmol, 250 pL, 4.00 eq) at 0 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed the Compound 79-2 was consumed completely and desired product (Rt = 0.569 min) was detected. The mixture was poured into H2O (30.0 mL) and extracted withethyl acetate (20.0 mL * 2). The combined organic layers were washed with brine (20.0 mL * 2), dried over Na2SO4, filtered and concentrated. Compound 79-3 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-methyl-2-[[(3S,4S)-3- methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (191 mg, crude) was obtained as the yellow oil. LCMS: m / z = 513.2 (M+H)+.General procedure for preparation of Compound 79:PPh3THF, H2O, 20 °C, 12 hrsYield over two steps: 11.8%Compound 79MSK-20525To the mixture of compound 79-3 (N-[(lS)-2-azido-l-(3-chlorophenyl)ethyl]-5-[5-methyl-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (170 mg, 331 pmol, 1.00 eq in the THF (1.80 mL) and H2O (0.200 mL) was added PPh3(130 mg, 497 pmol, 1.50 eq) at 20 °C, the mixture was stirred at 20 °C for 12 hrs. LCMS showed the compound 79-3 was consumed completely and desired product (Rt = 0.435 min) was detected. The mixture was poured into HC1 (aq. 1.00 mol / L, 5.00 mL) and extracted with ethyl acetate (30.0 mL * 2). The aqueous phase was washed with sat. NaHCO3 (aq. 20.0 mL) and extracted with ethyl acetate (30.0 mL * 2). The combined organic layers were washed with brine (30.0 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: LUJA Sep Silica 250*50mm*5pm; mobile phase: [Hexane-EtOH]; gradient: 10%-50% B over 15.0 min), the solvent was concentrated, and ACN (1.00 mL) and H2O (15.0 mL) was added to the residue, then the product was lyophilized. Compound 79 (N-[(lS)-2-amino-l-(3-chlorophenyl)ethyl]-5-[5-methyl-2-[[(3S,4S)-3-methyltetrahydropyran-4-yl]amino]pyrimidin-4-yl]thiazole-2-carboxamide) (20.76 mg, 42.4 pmol, 12.8% yield, 99.6% purity) was obtained as the yellow solid. LCMS: m / z = 487.2 (M+H)+. 'H NMR: (400 MHz, DMSO-6): d 9.49 - 9.27 (m, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.46 (s, 1H), 7.40 - 7.14 (m, 4H), 4.93 (d, J= 4.4 Hz, 1H), 4.20 - 3.98 (m, 1H), 3.90 - 3.75 (m, 1H), 3.70 - 3.58 (m, 1H), 3.53 - 3.42 (m, 2H), 3.11 - 2.82 (m, 2H), 2.37 (s, 3H), 2.16 - 2.06 (m, 1H), 1.86 - 1.70 (m, 2H), 1.63 - 1.52 (m, 1H), 0.86 (d, J= 6.8 Hz, 3H)Example 41: Synthesis of Compound 164General procedure for preparation of Compound 164Compound 164To a solution of the DIPEA salt of compound 162-4 (5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (12.8 mg, 27.3 pmol, 1 equiv.) and HATU (10.4 mg, 27.3 pmol, 1 equiv.) in DMF (0.14 mL), DIPEA (16.6 pL, 12.3MSK-20525mg, 95.5 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (. S’)-2-Amino-2-(3-bromophenyl)ethan-l-ol hydrochloride (5.90 mg, 27.3 pmoL 1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 162-4 and detection of the desired m / z. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 37%-40% B over 12 min). The desired fractions were concentrated and dried to afford Compound 164 ((. S)- \-(l-(3-bromophenyl)-2-hydroxyethyl)-5-(5-chloro-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (3.94 mg, 6.04 pmol, 22% yield) as a yellow solid.JH NMR (600 MHz, MeOD) 58.87 (d, J= 7.9 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J= 4.1 Hz, 1H), 7.85 (d, J= 4.1 Hz, 1H), 7.62 (t, J= 1.8 Hz, 1H), 7.46 (dd, J= 7.9, 2.0 Hz, 1H), 7.41 (d, J= 7.7 Hz, 1H), 7.30 (t, J= 7.8 Hz, 1H), 5.17 (q, J= 6.2 Hz, 1H), 4.06 - 3.97 (m, 3H), 3.88 (s, 1H), 3.58 (t, J= 11.7 Hz, 2H), 2.04 (dd, J= 14.1, 8.1 Hz, 2H), 1.68 - 1.58 (m, 2H).13C NMR (151 MHz, MeOD) 8162.6, 162.6, 142.5, 142.1, 142.1, 130.9, 130.2, 130.0, 129.8, 128.8, 125.7, 122.1, 66.6, 64.1, 56.0, 55.9, 32.3. LC-MS (ESI) m / z = ([M+H]+) 538.9.Example 42: Synthesis of Compound 167XPhos-Pd G3, K3PO4Dioxane, H2O, rt -40 °C, 19 h crude 167-1LIOH H2O 2-MeTHF, H2O HATU, DIPEA 80 °C, 3 h DMF, 0 °C - rt, 30 min Yield: 25% Yield: 43%General procedure for preparation of compound 167-2MSK-20525XPhos-Pd G3, K3PO4Dioxane, H2O, rt - 40 °C, 19 hcrude 167-2167-1Compound 167-1 (2,4-dichloro-5-methylpyrimidine) (117 pL, 163 mg, 1.00 mmol, 1 equiv.), methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (268 mg, 1.00 mmol, 1 equiv.), and K3PO4 (637 mg, 3.00 mmol, 3 equiv.) was suspended in dioxane (4.17 mL) and H2O (0.83 mL), and the mixture was sparged with Ar for 10 min. XPhos-Pd G3 (3.39 mg, 4.00 μmol, 0.02 equiv.) was then added, and the suspension was stirred at 40 °C for 3 h. Additional dioxane (5 mL) was then added, and the mixture was stirred for an additional 19 h. LC-MS analysis reflected the desired mlz. The reaction mixture was partitioned between CH2Cl2 (40 mL) and H2O (40 mL), and the aqueous layer was further extracted with CH2Cl2 (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried with anhydrous Na2SC>4, filtered, and concentrated to afford compound 167-2 (methyl 5-(2-chloro-5-methylpyrimidin-4-yl)thiophene-2-carboxylate) (nominal: 289 mg, 1.00 mmol, crude) as an off-white solid. TLC: A / 0.50 (10% EtOAc / hexanes). LC-MS (ESI) m / z = ([M+H]+) 288.5.General procedure for preparation of compound 167-3DIPEA, DMSO100 °C, 18 h167-2 Two-step yield: 10%167-3To a solution of compound 167-2 (methyl 5-(2-chloro-5-methylpyrimidin-4-yl)thiophene-2-carboxylate) (nominal: 289 mg, 1.00 mmol, 1 equiv.) in DMSO (2.5 mL), tetrahydro-2 / f-pyran-4-amine (155 pL, 152 mg, 1.50 mmol, 1.5 equiv.) and DIPEA (348 pL, 258 mg, 2.00 mmol, 2 equiv.) were added at rt. The reaction mixture was stirred at 100 °C for 18 h. LC-MS reflected full consumption of compound 167-2 and detection of the desired mlz. The reaction mixture was diluted in EtOAc (50 mL) and washed with H2O (50 mL x 2) and brine (50 mLMSK-20525x 2), dried with anhydrous Na2SC>4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 4 g; mobile phase: [hexanes-EtOAc]; gradient: 40%-60% B over 25 min). The desired fractions were concentrated and dried to afford compound 167-3 (methyl 5-(5-methyl-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylate) (32.5 mg, 97.5 pmol, 10% yield over two steps) as an impure colorless solid. TLC: A / 0.17 (25% EtOAc / hexanes). LC-MS (ESI) m / z = ([M+H]+) 333.7.General procedure for preparation of compound 167-4167-4Compound 167-3 (methyl 5-(5-methyl-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylate) (nominal: 32.5 mg, 97.5 pmol, 1 equiv.) and LiOH·H2O (20.5 mg, 487 pmol, 5 equiv.) was suspended in 2-MeTHF (0.49 mL) and H2O (0.49 mL). The mixture was stirred at 80 °C for 3 h. LC-MS analysis reflected full consumption of compound 167-3 and detection of the desired m / z. The reaction mixture was acidified with concentrated hydrochloric acid to below pH 3, diluted with H2O (approx. 5 mL), and centrifuged. The resulting pellet was resuspended in MeOH (5 mL) and centrifuged. The pellet was then dissolved in 5% DIPEA in MeOH (5 mL) and filtered. The filtrate was concentrated by rotary evaporation and dried over vacuum to afford compound 167-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (DIPEA salt, 10.8 mg, 24.0 pmol, 25% yield) as a white solid. Alternatively, compound 167-4 was isolated as an EtsN salt. LC-MS (ESI) m / z = ([M+H]+) 320.0.General procedure for preparation of Compound 167MSK-20525To a solution of compound 167-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (DIPEA salt, 10.8 mg, 24.0 pmol, 1 equiv.) and HATU (9.12 mg, 24.0 pmol, 1 equiv.) in DMF (0.12 mL), DIPEA (14.6 pL, 10.8 mg, 83.9 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (. S’)-2-Amino-2-(3-chlorophenyl)ethan-l-ol hydrochloride (4.99 mg, 24.0 pmol, 1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 167-4 and detection of the desired m / z. The reaction mixture was diluted with 40:60 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 26%-31% B over 12 min). The desired fractions were concentrated and dried to afford Compound 167 ((. S)- \-(l-(3-chlorophenyl)-2-hydroxyethyl)-5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (6.01 mg, 6.04 pmol, 43% yield) as a pale yellow solid.1H NMR (600 MHz, MeOD) 58.87 (d, J= 7.9 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J= 4.1 Hz, 1H), 7.85 (d, J= 4.1 Hz, 1H), 7.62 (t, J= 1.8 Hz, 1H), 7.46 (dd, J= 7.9, 2.0 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.30 (t, J= 7.8 Hz, 1H), 5.17 (q, J= 6.2 Hz, 1H), 4.06 - 3.97 (m, 3H), 3.88 (s, 1H), 3.58 (t, J= 11.7 Hz, 2H), 2.04 (dd, J= 14.1, 8.1 Hz, 2H), 1.68 - 1.58 (m, 2H).13C NMR (151 MHz, MeOD) 8162.3, 161.5, 152.6, 146.4, 142.2, 134.0, 132.1, 129.7, 129.2, 127.2, 126.8, 125.3, 115.5, 66.4, 64.1, 56.0, 48.2, 32.1, 16.1. LC-MS (ESI) m / z = ([M+H]+) 473.2.Example 43: Synthesis of Compound 169General procedure for preparation of Compound 169MSK-20525167-4To a solution of compound 167-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (EtsN salt, 13.6 mg, 32.3 pmol, 1 equiv.) and HATU (13.5 mg, 35.5 pmol, 1.1 equiv.) in DMF (0.16 mL), DIPEA (19.7 pL, 14.6 mg, 113 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-bromophenyl)ethan-l-ol hydrochloride (7.68 mg, 35.5 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 167-4 and detection of the desired m / z. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C43.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 22%-30% B over 12 min). The desired fractions were concentrated and dried to afford Compound 169 ((. S)- \-(l-(3-bromophenyl)-2-hydroxyethyl)-5-(5-methyl-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (5.68 mg, 9.00 pmol, 28% yield) as a colorless solid.1H NMR (600 MHz, MeOD) 58.21 (s, 1H), 7.99 (d, J= 4.2 Hz, 1H), 7.93 (d, J= 4.1 Hz, 1H), 7.62 (t, J= 1.9 Hz, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 7.7 Hz, 1H), 7.30 (t, J= 7.9 Hz, 1H), 5.18 (q, J= 6.2 Hz, 1H), 4.12 (s, 1H), 4.06 - 3.99 (m, 2H), 3.89 (d, J= 6.6 Hz, 2H), 3.60 (t, J = 11.7 Hz, 2H), 2.52 (s, 3H), 2.08 -2.02 (m, 2H), 1.75 - 1.65 (m, 2H), 1.33 - 1.29 (m, 1H).13CNMR(151 MHz, MeOD) 5162.7, 162.1, 150.7, 145.9, 144.6, 142.4, 132.8, 130.3, 130.0, 129.8, 129.3, 125.7, 122.1, 115.7, 66.3, 64.1, 56.0, 48.2, 32.0, 16.1. LC-MS (ESI) m / z = ([M+H]+) 517.2.Example 44: Synthesis of Compound 181General procedure for preparation of Compound 181MSK-20525Compound 181To a solution of the DIPEA salt of compound 162-4 (5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (13.0 mg, 27.7 pmol, 1 equiv.) and HATU (11.6 mg, 30.4 pmol, 1.1 equiv.) in DMF (0.14 mL), DIPEA (16.9 pL, 12.5 mg, 96.8 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (5)-2-amino-2-(m-tolyl)ethan-l-ol hydrochloride (4.60 mg, 30.4 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 162-4 and detection of the desired m / z. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C43.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 32%-38% B over 12 min). The desired fractions were concentrated and dried to afford Compound 181 ((. S)-5-(5-chloro-2-((tetrahydro-2 / / -pyr:in-4-yl)amino)pyrimidin-4-yl)-A-(2-hydroxy-l-(m-tolyl)ethyl)thiophene-2-carboxamide) (7.09 mg, 12.1 pmol, 44% yield) as a yellow solid. 'H NMR (600 MHz, MeOD) 58.33 (s, 1H), 8.25 - 8.21 (m, 1H), 7.85 (d, J= 4.1 Hz, 1H), 7.33 - 7.16 (m, 3H), 7.11 (d, = 7.3 Hz, 1H), 5.17 (t, J= 6.6 Hz, 1H), 4.06 - 3.97 (m, 3H), 3.92 - 3.85 (m, 2H), 3.57 (t, J= 11.7 Hz, 2H), 2.37 (d, J= 13.4 Hz, 3H), 2.03 (d, J= 12.6 Hz, 2H), 1.67 - 1.58 (m, 2H).13C NMR (151 MHz, MeOD) 8162.5, 158.8, 142.6, 139.6, 137.9, 131.0, 130.9, 128.6, 128.6, 128.5, 128.1, 127.8, 127.4, 127.3, 123.7, 66.6, 64.5, 56.4, 48.2, 32.3, 20.1. LC-MS (ESI) m / z = ([M+H]+) 473.0.Example 45: Synthesis of Compound 185General procedure for preparation of Compound 185MSK-20525- ► HATU, DIPEA DMF, 0 °C - rt, 1 h Yield: 60%To a solution of compound 167-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (EtsN salt, 13.9 mg, 32.9 pmol, 1 equiv.) and HATU (13.8 mg, 36.2 pmol, 1.1 equiv.) in DMF (0.16 mL), DIPEA (20.1 pL, 14.9 mg, 115 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-amino-2-(m-tolyl)ethan-l-ol hydrochloride (5.48 mg, 36.2 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 167-4 and detection of the desired mlz. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 25%-32% B over 12 min). The desired fractions were concentrated and dried to afford Compound 185 ((. S)- \-(2-hydroxy-l-( / n-tolyl)ethyl)-5-(5-inethyl-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (11.2 mg, 19.8 pmol, 60% yield) as a yellow solid. 'H NMR (600 MHz, MeOD) 88.20 (s, 1H), 8.05 (d, J= 4.2 Hz, 1H), 7.95 (d, J= 4.1 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.21 (d, J= 7.9 Hz, 1H), 7.12 (d, J= 7.3 Hz, 1H), 5.17 (t, J= 6.7 Hz, 1H), 4.15 (s, 1H), 4.02 (ddd, J= 16.0, 7.6, 4.0 Hz, 3H), 3.88 (d, J= 6.9 Hz, 2H), 3.63 - 3.56 (m, 2H), 2.54 (s, 3H), 2.36 (s, 3H), 2.08 - 2.03 (m, 2H), 1.76 - 1.66 (m, 2H).13CNMR(151 MHz, MeOD) 8 164.0, 162.0, 139.5, 137.9, 133.5, 129.2, 128.1, 127.9, 127.3, 123.7, 115.9, 66.2, 64.4, 56.5, 31.9, 20.1, 16.1. LC-MS (ESI) m / z = ([M+H]+) 453.0.Example 46: Synthesis of Compound 188MSK-20525General procedure for preparation of compound 188-1DIPEA, DMSO100 - 140 °C, 18 hYield: 27%188-1To a solution of compound 151 (5-chloro-2-fluoro-4-iodopyridine) (360 mg, 1.4 mmol, 1 equiv.) in DMSO (3.50 mL), (35',45)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride (240 mg, 1.54 mmol, 1.1 equiv.) and DIPEA (609 p, L, 452 mg, 3.5 mmol, 2.5 equiv.) were added at rt. The reaction mixture was stirred at 100 °C for 2 d. Additional DIPEA (122 pL, 90.4 mg, 0.7 mmol, 0.5 equiv.) was added, and the mixture was stirred at 140 °C for 6 h. LC-MS reflected near-complete consumption of compound 151 and detection of the desired m / z. The reaction mixture was diluted in EtOAc (30 mL), washed with H2O (30 mL x 3) and brine (30 mL), dried with anhydrous Na2SC>4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 12 g; mobile phase: [hexanes-EtOAc]; gradient: 10%-30% B over 20 min). The desired fractions were concentrated and dried to afford compound 188-1 (5-chloro-\-((3. S.4. S)-3-nuorotetrahydro-2 / / -pyran-4-yl)-4-iodopyridin-2-amine) (136 mg, 0.382 mmol, 27% yield) as a colorless, glassy solid. TLC:Rf 0.26 (25% EtOAc / hexanes). ¹H NMR (600 MHz, CDCl₃) δ 8.02 (s, 1H), 7.02 (s, 1H), 4.71MSK-20525(d, J = 49.0 Hz, 1H), 4.27 - 4.14 (m, 2H), 4.07 (ddd, J = 11.8, 4.2, 2.1 Hz, 1H), 3.57 (td, J = 12.6, 9.8 Hz, 2H), 1.93 (qd, J= 12.3, 4.6 Hz, 1H), 1.90 - 1.84 (m, 1H).13C NMR (151 MHz, CDC13) 8155.2, 145.2, 124.8, 119.5, 88.3, 87.2, 69.1, 69.0, 66.7, 48.9, 48.8, 27.8, 27.8.19F NMR (565 MHz, CDCI3) 8 -205.99 (s, IF). LC-MS (ESI) m / z = ([M+H]+) 357.1.General procedure for preparation of compound 188-2XPhos-Pd G3, K3PO4 Dioxane, H2O, 40 - 50 °C, 2 d Yield: 80%188-1 188-2Compound 188-1 (5-chloro-N-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-4-iodopyridin-2-amine) (133 mg, 374 pmol, 1 equiv.), methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (150 mg, 560 pmol, 1.5 equiv.), and K3PO4 (238 mg, 1.12 mmol, 3 equiv.) was suspended in dioxane (1.56 mL) and H2O (0.311 mL), and the mixture was sparged with Ar for 10 min. XPhos-Pd G3 (9.48 mg, 11.2 pmol, 0.03 equiv.) was then added, and the suspension was stirred at 40 °C under Ar for 21 h. Additional methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (20.0 mg, 74.7 pmol, 0.2 equiv.) and XPhos-Pd G3 (3.16 mg, 3.74 pmol, 0.01 equiv.) were added, and the reaction mixture was stirred at 50 °C under Ar for an additional 18 h. LC-MS analysis reflected full consumption of compound 188-1 and detection of the desired m / z. The reaction mixture was partitioned between EtOAc (25 mL) and H2O (25 mL). The aqueous layer was further extracted with EtOAc (15 mL x 2), and the combined organic layers were washed with brine (15 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 4 g; mobile phase: [hexanes-EtOAc]; gradient: 10%-30% B over 24 min). The desired fractions were concentrated and dried to afford compound 188-2 (methyl 5-(5-chloro-2-(((35,4»S)-3-fluorotetrahydro-2Z / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylate) (111 mg, 300 pmol, 80% yield) as a yellow solid. TLC: Rf 0.18 (50% EtOAc / hexanes). ¹H NMR (600 MHz, CDCl₃) δ 8.16 (s, 1H), 7.81 (d, J= 3.9 Hz, 1H), 7.49 (d, J= 3.9 Hz, 1H), 6.64 (s, 1H), 4.92 (s, 1H), 4.76 (d, J= 49.0 Hz, 1H), 4.23 (t, J= 12.8 Hz, 1H), 4.09 (ddd, J= 11.7, 4.1, 2.2 Hz, 1H), 3.94 (s, 3H), 3.69 (d, J= 13.4 Hz,MSK-205251H), 3.65 - 3.56 (m, 2H), 1.97 (qd, J= 12.2, 4.6 Hz, 1H), 1.95 - 1.89 (m, 1H).13C NMR (151 MHz, MeOD) 8162.2, 159.6, 159.3, 154.7, 143.0, 142.5, 141.4, 141.3, 130.2, 130.0, 129.9, 129.8, 128.4, 125.7, 122.1, 116.6, 110.8, 87.5, 86.4, 68.5, 68.4, 66.1, 64.1, 55.9, 49.3, 49.1, 48.2, 26.9, 26.9.19F NMR (565 MHz, CDC13) 8 -205.91 (s, IF). LC-MS (ESI) m / z = ([M+H]+) 371.2.General procedure for preparation of compound 188-3LiOH. H2O2-MeTHF, H2O80 °C, 19 h Yield: 100%188-2 188-3Compound 188-2 (methyl 5-(5-chloro-2-(((35',45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylate) (108 mg, 292 pmol, 1 equiv.) and LiOH. H2O (61.2 mg, 1.46 mmol, 5 equiv.) was suspended in 2-MeTHF (0.729 mL) and H2O (0.729 mL). The mixture was stirred at 80 °C for 19 h. LC-MS analysis reflected full consumption of compound 188-2 and detection of the desired m / z. The reaction mixture was acidified with concentrated hydrochloric acid to below pH 3, diluted with H2O, MeOH, and DMSO to solubilize remaining solids, then filtered. A significant amount of solids precipitated upon overnight storage at -20 °C. The mixture was concentrated by rotary evaporation and filtered. The filter cake was triturated with hexanes, then extracted with 5% EtsN in MeOH (2 mL x 3). The filtrate was concentrated and dried to afford compound 188-3 (5-(5-chloro-2-(((35',45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (EtsN salt, 133 mg, 291 pmol, 100% yield) as a pale yellow solid. ‘HNMR (600 MHz, MeOD) 88.04 (s, 1H), 7.54 (d, J= 3.8 Hz, 1H), 7.47 (d, J= 3.8 Hz, 1H), 6.85 (s, 1H), 4.22 (dddd, J= 30.2, 12.4, 5.0, 2.5 Hz, 1H), 4.12 (t, J= 12.5 Hz, 1H), 4.02 (dd, J= 11.7, 4.4 Hz, 1H), 3.65 - 3.56 (m, 1H), 3.06 (q, J= 7.3 Hz, 7H), 2.68 (s, 2H), 1.98 (qd, J= 12.5, 4.5 Hz, 1H), 1.80 (dd, J= 11.2, 3.3 Hz, 1H), 1.26 (t, J = 7.3 Hz, 11H).13C NMR (151 MHz, MeOD) 8168.0, 156.9, 147.2, 145.2, 141.0, 140.6, 129.4, 128.5, 116.4, 109.3, 88.0, 86.8, 68.8, 68.6, 66.5, 48.7, 48.5, 39.0, 27.2, 8.3.19F NMR (565 MHz, MeOD) 8 -207.38 (dddd, J= 49.5, 39.7, 29.7, 11.7 Hz, IF). LC-MS (ESI) m / z = ([M+H]+) 357.1.General procedure for preparation of Compound 188MSK-20525188-3To a solution of compound 188-3 (5-(5-chloro-2-(((35,45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (EtsN salt, 18.3 mg, 40.0 pmol, 1 equiv.) and HATU (16.7 mg, 44.0 pmol, 1.1 equiv.) in DMF (0.200 mL), DIPEA (17.4 pL, 12.9 mg, 100 pmol, 2.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-chlorophenyl)ethan-l-ol hydrochloride (9.16 mg, 44.0 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 188-3 and detection of the desired m / z. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 28%-38% B over 12 min). The desired fractions were concentrated and dried to afford Compound 188 (5-(5-chloro-2-(((3A,4A)-3-fluorotetrahydro-2Z / -pyran-4-yl)amino)pyridin-4-yl)-7V-((A)-l -(3-chlorophenyl)-2-hydroxyethyl)thiophene-2-carboxamide) (TFA salt, 11.00 mg, 17.6 pmol, 44% yield) as a white solid. 'H NMR (600 MHz, MeOD) 88.11 (s, 1H), 7.89 (dd, J= 4.0, 1.3 Hz, 1H), 7.64 (dd, J= 4.1, 1.3 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.39 - 7.33 (m, 2H), 7.33 - 7.27 (m, 1H), 7.04 (s, 1H), 5.17 (t, J= 6.7 Hz, 1H), 4.75 (d, J= 49.0 Hz, 1H), 4.25 - 4.10 (m, 3H), 4.05 - 3.98 (m, 1H), 3.89 (dd, J= 6.7, 1.4 Hz, 2H), 3.71 - 3.56 (m, 2H), 2.07 - 1.96 (m, 1H), 1.83 (dd, J = 13.1, 4.7 Hz, 1H).13CNMR(151 MHz, MeOD) 8 162.2, 159.6, 159.4, 154.9, 143.3, 142.3, 142.3, 141.3, 141.3, 134.0, 129.9, 129.7, 128.4, 127.2, 126.8, 125.2, 116.6, 110.7, 87.6, 86.4, 68.5, 68.4, 66.1, 64.1, 55.9, 49.2, 49.1, 27.0, 26.9.19FNMR(565 MHz, MeOD) 8 -77.48 (s, 5F), -207.08 (qt, J= 38.7, 11.5 Hz, IF). LC-MS (ESI) m / z = ([M+H]+) 510.2.Example 47: Synthesis of Compound 189General procedure for preparation of Compound 189MSK-20525HATU, DIPEA DMF, 0 °C - rt, 30 min Yield: 40%188-3 Compound 189To a solution of compound 188-3 (5-(5-chloro-2-(((35,45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (EtsN salt, 18.3 mg, 40.0 pmol, 1 equiv.) and HATU (16.7 mg, 44.0 pmol, 1.1 equiv.) in DMF (0.200 mL), DIPEA (17.4 pL, 12.9 mg, 100 pmol, 2.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(3-bromophenyl)ethan-l-ol hydrochloride (9.51 mg, 44.0 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 188-3 and detection of the desired m / z. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 28%-38% B over 12 min). The desired fractions were concentrated and dried to afford Compound 189 (A-((5)-l-(3-bromophenyl)-2-hydroxyethyl)-5-(5-chloro-2-(((35,45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (TFA salt, 10.7 mg, 16.0 pmol, 40% yield) as a white solid. 'H NMR (600 MHz, MeOD) 88.11 (s, 1H), 7.89 (d, J= 4.0 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.43 (ddd, J= 26.7, 8.0, 1.5 Hz, 2H), 7.30 (t, J= 7.8 Hz, 1H), 7.05 (s, 1H), 5.16 (t, J= 6.6 Hz, 1H), 4.75 (d, J= 49.0 Hz, 1H), 4.25 - 4.09 (m, 3H), 4.06 - 3.98 (m, 1H), 3.88 (d, J= 6.7 Hz, 2H), 3.69 (d, J= 13.4 Hz, 1H), 3.65 - 3.56 (m, 2H), 2.02 (ddd, J= 24.9, 12.8, 4.9 Hz, 1H), 1.87 - 1.81 (m, 1H).13CNMR(151 MHz, MeOD) 8162.2, 159.6, 159.3, 154.7, 143.0, 142.5, 141.4, 141.3, 130.2, 130.0, 129.9, 129.8, 128.4, 125.7, 122.1, 116.6, 110.8, 87.5, 86.4, 68.5, 68.4, 66.1, 64.1, 55.9, 49.3, 49.1, 48.2, 26.9, 26.9.19FNMR (565 MHz, MeOD) 8 -77.50 (s, 7F), -207.06 (qt, J= 39.0, 11.5 Hz, IF). LC-MS (ESI) m / z = ([M+H]+) 556.1.Example 48: Synthesis of Compound 190General procedure for preparation of Compound 190MSK-20525HATU, DI PEA DMF, 0 °C - rt, 30 min Yield: 43%188-3 Compound 190To a solution of compound 188-3 (5-(5-chloro-2-(((35,45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (EtsN salt, 18.3 mg, 40.0 pmol, 1 equiv.) and HATU (16.7 mg, 44.0 pmol, 1.1 equiv.) in DMF (0.200 mL), DIPEA (17.4 pL, 12.9 mg, 100 pmol, 2.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. (A)-2-Amino-2-(m-tolyl)ethan-l-ol hydrochloride (6.65 mg, 44.0 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 188-3 and detection of the desired mlz. The reaction mixture was diluted with 50:50 ACN / H2O (approx. 2 mL) and purified by prep-HPLC (column:Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 28%-38% B over 12 min). The desired fractions were concentrated and dried to afford Compound 190 (5-(5-chloro-2-(((35,45)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-\-((. S)-2-hydroxy-l-( / n-tolyl)ethyl)thiophene-2-carboxamide) (TFA salt, 10.3 mg, 17.0 pmol, 43% yield) as a white solid.1H NMR (600 MHz, MeOD) 88.12 (s, 1H), 7.90 (d, J= 4.0 Hz, 1H), 7.67 (d, J= 3.9 Hz, 1H), 7.24 (d, J = 7.1 Hz, 2H), 7.21 (d, J= 8.2 Hz, 1H), 7.11 (d, J= 9.5 Hz, 2H), 5.17 (t, J= 6.7 Hz, 1H), 4.76 (d, J = 49.2 Hz, 1H), 4.23 - 4.10 (m, 2H), 4.03 (ddd, J = 11.3, 4.4, 2.2 Hz, 1H), 3.87 (d, J = 6.8 Hz, 2H), 3.69 (d, J= 13.4 Hz, 1H), 3.65 - 3.56 (m, 2H), 2.36 (s, 3H), 2.08 - 1.98 (m, 1H), 1.88 - 1.81 (m, 1H).13CNMR(151 MHz, MeOD) 8 162.1, 159.3, 159.0, 154.0, 143.3, 142.2, 141.5, 140.6, 139.6, 137.9, 130.3, 128.3, 128.1, 127.8, 127.3, 123.7, 116.8, 116.5, 114.6, 111.3, 87.4, 86.2, 68.4, 68.3, 66.0, 64.5, 56.5, 49.5, 49.4, 48.4, 48.2, 26.9, 20.1.19F NMR (565 MHz, MeOD) 8 -77.58 (s, 12F), -206.98 (tt, J= 48.3, 27.9 Hz, IF). LC-MS (ESI) m / z = ([M+H]+) 490.3.Example 49: Synthesis of Compound 191MSK-20525O— s-ci 6 NaOH EtsN CH2CI2tBuOH / H^, 70 °C, 19 h O °C - rt, 90 min Yield: 99% crude 191-3NaBH4NiCI2.6H2O, MeOH O °C -rt, 1 h Two-step yield: 32%General procedure for preparation of compound 191-2To a solution of compound 191-1 ((5)-2-amino-2-(3-chlorophenyl)ethan-l-ol hydrochloride) (416 mg, 2.00 mmol, 1 equiv.) in 0.5 M aq. NaOH (4.80 mL, 2.40 mmol, 1.2 equiv.) andlBuOH (5 mL), Boc₂O (689 μL, 655 mg, 3 μmol, 1.5 equiv.) was added, and the solution was stirred for 19 h at 0 °C. LC-MS analysis reflected full consumption of compound 191-1 and detection of the desired m / z. The reaction mixture was partitioned between EtOAc (75 mL) and H2O (75 mL). The aqueous layer was further extracted with EtOAc (50 mL x 2), and the combined organic layers were washed with brine (75 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 12 g; mobile phase: [hexanes-EtOAc]; gradient: 15%-35% B over 25 min). The desired fractions were concentrated and dried to afford compound 191-2 ((5)-l-(ferf-butyl)-3-(l-(3-chlorophenyl)-2-hydroxyethyl)urea) (539 mg, 1.98 mmol, 99% yield) as a whiteMSK-20525solid. TLC: Rf 0.21 (25% EtOAc / hexanes). ¹H NMR (600 MHz, CDCl₃) δ 7.34 – 7.27 (m, 3H), 7.22 (d, J= 7.2 Hz, 1H), 5.32 - 5.28 (m, 1H), 4.78 (s, 1H), 3.89 (dd, J= 11.2, 4.1 Hz, 1H), 3.84 (t, J= 8.0 Hz, 1H), 1.89 (s, 2H), 1.47 (s, 10H).13C NMR (151 MHz, CDCh) 8 155.8, 141.8, 134.7, 130.0, 127.9, 126.8, 124.8, 80.2, 66.5, 56.2, 28.3. LC-MS (ESI) m / z = ([M+2H-Boc]+) 172.1.General procedure for preparation of compound 191-3Oii— s-ciIIoEt3N, CH2CI20 °C - rt, 90 mincrude191-3To a solution of 191-2 (( )-l-(tert-butyl)-3-(l-(3-chlorophenyl)-2-hydroxyethyl)urea) (533 mg, 1.96 mmol, 1 equiv.) and Et3N (328 pL, 238 mg, 2.35 mmol, 1.2 equiv.) in CH2CI2 (4.90 mL), methanesulfonyl chloride (167 pL, 247 mg, 2.16 mmol, 1.1 equiv.) was added over ice, and the solution was stirred at rt for 90 min. LC-MS analysis reflected full consumption of compound 191-2 and detection of the desired m / z. The reaction mixture was quenched with saturated aq. NH4CI (20 mL) and extracted with CH2Cl2 (20 mL x 3). The combined organic layers were dried with anhydrous Na2SC>4, filtered, and concentrated to afford compound 191-3 (( )-2-(3-(tert-butyl)ureido)-2-(3-chlorophenyl)ethyl methanesulfonate) (crude) as a white solid. TLC: Rf 0.17 (25% EtOAc / hexanes). ¹H NMR (600 MHz, CDCl₃) δ 7.24 (dd, J = 4.3, 2.3 Hz, 3H), 7.14 (dd, J= 6.6, 2.4 Hz, 1H), 5.13 (s, 1H), 4.93 (s, 1H), 4.39 (dd, J = 11.1, 4.7 Hz, 1H), 4.30 (dd, J= 10.7, 5.9 Hz, 1H), 2.87 (s, 3H), 1.37 (s, 9H). ¹³C NMR (151 MHz, CDCl₃) δ 154.9, 139.8, 134.9, 130.2, 128.5, 126.9, 124.9, 80.6, 70.8, 53.3, 45.8, 37.6, 31.6, 28.3, 22.7, 14.2, 14.1, 8.6. LC-MS (ESI) m / z = ([M+2H-Boc]+) 249.8.General procedure for preparation of compound 191-4NaN3DMF, 50 °C, 15 hYield: 78% over 2 steps191-3MSK-20525Compound 191-3 (( )-2-(3-(terf-butyl)ureido)-2-(3-chlorophenyl)ethyl methanesulfonate) (crude, 1.96 mmol nominal, 1 equiv.) and sodium azide (255 mg, 3.92 mmol, 2 equiv.) were dissolved in DMF (9.8 mL), and the solution was stirred for 15 h at 50 °C. LC-MS analysis reflected full consumption of compound 191-3 and detection of the desired m / z. The reaction mixture was quenched with saturated aq. NH4CI (10 mL), diluted with H2O (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were dried with anhydrous Na2SC>4, filtered, and concentrated, and the resulting crude product was purified by flash column chromatography (column: RediSep® Silver Silica Gel Disposable Flash Column, 12 g; mobile phase: [hexanes-EtOAc]; gradient: 0%-30% B over 20 min). The desired fractions were concentrated and dried to afford compound 191-4 ((A)-l-(2-azido-l-(3-chlorophenyl)ethyl)-3-(terf-butyl)urea) (455 mg, 1.53 mmol, 78% yield over 2 steps) as a white solid. TLC: Rf 0.57 (25% EtOAc / hexanes). ¹H NMR (600 MHz, CDCl₃) δ 7.36–7.29 (m, 3H), 7.22 (dd, J= 6.6, 2.4 Hz, 1H), 5.10 (s, 1H), 4.88 (s, 1H), 3.71 - 3.60 (m, 2H), 1.47 (s, 9H).13C NMR (151 MHz, CDCh) 8154.9, 134.8, 130.1, 128.2, 126.8, 124.7, 80.4, 55.5, 28.3. LC-MS (ESI) m / z = ([M+2H-Boc]+) 197.1.General procedure for preparation of compound 191-5HCI / dioxane0 °C - rt, 19 hYield: 94%191-4 191-5To a solution of compound 191-4 ((S)-1-(2-azido-1-(3-chlorophenyl)ethyl)-3-(tert-butyl)urea) (455 mg, 1.52 mmol, 1 equiv.) in dioxane (3.8 mL), 4 M HC1 in dioxane (3.8 mL, 15.2 mmol, 10 equiv.) was added over ice, and the solution was stirred at rt for 19 h. LC-MS analysis reflected full consumption of compound 191-4 and detection of the desired m / z. The reaction mixture was concentrated by rotary evaporation, then triturated with cold hexanes (10 mL x 5). The residue was dried to afford compound 191-5 ((A)-2-azido-l-(3-chlorophenyl)ethan-l-amine hydrochloride) (331 mg, 1.42 mmol, 94% yield) as a white solid. 'H NMR (600 MHz, MeOD) 87.57 (s, 1H), 7.53 - 7.46 (m, 2H), 7.44 (dq, J= 5.9, 3.0 Hz, 1H), 4.52 (dd, J= 7.9, 4.8 Hz, 1H), 3.92 (dd, J= 13.2, 4.8 Hz, 1H), 3.80 (dd, J= 13.2, 8.0 Hz, 1H).1H NMR (600 MHz, CDCh) 87.36 - 7.29 (m, 3H), 7.22 (dd, J= 6.6, 2.4 Hz,MSK-205251H), 5.10 (s, 1H), 4.88 (s, 1H), 3.71 - 3.60 (m, 2H), 1.47 (s, 9H). LC-MS (ESI) m / z = ([M+H]+) 197.1.General procedure for preparation of compound 191-6191-5 HATU, DI PEA DMF, 0 °C - rt, 30 min crude152-3 191-6To a solution of compound 152-3 (5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (TFA salt, 16.0 mg, 35.4 pmol, 1 equiv.) and HATU (14.8 mg, 38.9 pmol, 1.1 equiv.) in DMF (0.177 mL), DIPEA (21.6 pL, 16.0 mg, 124 pmol, 3.5 equiv.) was added over ice, and the solution was stirred for 5 min at 0 °C. Compound 191-5 ((5)-2-azido-l-(3-chlorophenyl)ethan-l-amine hydrochloride) (9.07 mg, 38.9 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 152-3 and detection of the desired m / z. The reaction mixture was diluted with EtOAc (4 mL), washed with H2O (4 mL x 2) and brine (4 mL), dried over anhydrous Na2SC>4, filtered, and concentrated to afford compound 191-6 ((. S)-\-(2-azido-l-(3-chlorophenyl)ethyl)-5-(5-chloro-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (crude) as a yellow-brown solid. LC-MS (ESI) m / z = ([M+H]+) 517.3.General procedure for preparation of Compound 191NaBH4NiCI2.6H2O, MeOH 0 °C - rt, 1 h Two-step yield: 32%MSK-20525To a solution of compound 191-6 (( )-7V-(2-azido-l-(3-chlorophenyl)ethyl)-5-(5-chloro-2-(( tet rahydro-2 / / -py ran-4-yl )amino)py ridin-4-yl )t hiophene-2-carboxam ide) (crude, 35.4 pmol nominal, 1 equiv.) in 5 mM NiCl₂·6H₂O in MeOH (354 μL, 1.77 μmol, 0.05 equiv.), NaBH₄ (13.4 mg, 354 pmol, 10 equiv.) was added over ice, and the solution was stirred for 1 h at 0 °C. LC-MS analysis reflected full consumption of compound 191-6 and detection of the desired m / z. The reaction mixture was quenched with H2O (1.4 mL, 4 vol.) and stirred at rt for 1 h, then acidified with 1 M aq. HC1 and diluted with ACN (approx. 2 mL) and purified by prep-HPLC (column: Waters XBridge® C183.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 25%-32% B over 12 min). The desired fractions were concentrated and dried to afford Compound 191 ((5)-A-(2-amino-l-(3-chlorophenyl)ethyl)-5-(5-chloro-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (2 TFA salt, 8.23 mg, 11.4 pmol, 32% yield over 2 steps) as a colorless solid. ¹H NMR (600 MHz, MeOD) δ 7.98 (s, 1H), 7.77 (d, J= 4.0 Hz, 1H), 7.53 (d, <7= 4.0 Hz, 1H), 7.42 (d, J= 2.1 Hz, 1H), 7.32 (s, 2H), 7.31 - 7.26 (m, 1H), 6.86 (s, 1H), 5.33 (dd, J= 10.1, 4.9 Hz, 1H), 3.88 (dt, J= 12.0, 3.4 Hz, 2H), 3.81 (ddt, J= 14.9, 10.4, 4.2 Hz, 1H), 3.44 (td, J= 11.7, 2.2 Hz, 2H), 3.36 (ddd, J= 21.6, 13.4, 9.6 Hz, 2H), 1.92 - 1.86 (m, 2H), 1.49 (qd, J= 11.3, 4.3 Hz, 2H).13C NMR (151 MHz, MeOD) δ 162.5, 154.5, 142.5, 142.2, 141.7, 140.7, 140.3, 134.6, 130.4, 130.0, 129.0, 128.4, 126.8, 125.1, 111.1, 66.2, 51.5, 42.8, 32.3. LC-MS (ESI) m / z = ([M+H]+) 491.2.Example 50: Synthesis of Compound 192_ 191-5 HATU, DIPEA DMF, O ’C - rt, 30 min crudeGeneral procedure for preparation of compound 192-1MSK-20525191-5 HATU, DIPEA DMF, 0 °C - rt, 30 min crude192-1To a solution of compound 157-4 (5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxylic acid) (TFA salt, 21.6 mg, 50.0 pmol, 1 equiv.) and HATU (20.9 mg, 55.0 pmol, 1.1 equiv.) in DMF (0.250 mL), DIPEA (30.5 pL, 22.6 mg, 175 pmol, 3.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. Compound 191-5 ((5)-2-azido-l-(3-chlorophenyl)ethan-l-amine hydrochloride) (12.8 mg, 55.0 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 157-4 and detection of the desired m / z. The reaction mixture was diluted with EtOAc (4 mL), washed with H2O (4 mL x 3) and brine (4 mL), dried over anhydrous Na2SC>4, filtered, and concentrated to afford compound 192-1 ((. S)-\-(2-azido-l-(3-chlorophenyl)ethyl)-5-(5-methyl-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (crude) as a yellow-green solid. LC-MS (ESI) m / z = ([M+H]+) 497.2.General procedure for preparation of Compound 192To a solution of compound 192-1 (( )-7V-(2-azido-l-(3-chlorophenyl)ethyl)-5-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (crude, 50.0 pmol nominal, 1 equiv.) in 0.75 mM NiCl₂·6H₂O in MeOH (333 μL, 0.250 μmol, 0.005 equiv.), NaBH₄ (4.73 mg, 125 pmol, 2.5 equiv.) was added, and the solution was stirred for 1MSK-20525h at rt. Additional NaBH₄ (14.2 mg, 375 μmol, 7.5 equiv.) was added over ice, and the solution was stirred for 30 min at 0 °C and 30 min at rt. 75 mM NiCl₂·6H₂O in MeOH (10 μL, 0.750 μmol, 0.02 equiv.) was added, and then NaBH₄ (18.9 mg, 500 pmol, 10 equiv.) was added over ice, and the solution was stirred for 5 min at 0 °C. MeOH (167 pL) was added, and the mixture was stirred for 1 h at rt. 75 mM NiCh.6H2O in MeOH (7.5 pL, 0.563 pmol, 0.015 equiv.) was added, and then NaBH4 (18.9 mg, 500 pmol, 10 equiv.) was added over ice, and the solution was stirred for 10 min at 0 °C, then for 16 h at rt. LC-MS analysis reflected full consumption of compound 192-1 and detection of the desired m / z. The reaction mixture was diluted with 25:75 ACN / H2O and acidified with 1 M aq. HC1, resulting in precipitation. The supernatant was purified by prep-HPLC (column: Waters XBridge® C18 3.5 pm, 4.6 x 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 20%-30% B over 12 min). The desired fractions were concentrated and dried to afford Compound 192 ((. S)- \-(2-amino-l-(3-chlorophenyl)ethyl)-5-(5-methyl-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyridin-4-yl)thiophene-2-carboxamide) (2 TFA salt, 7.43 mg, 10.6 pmol, 21% yield over 2 steps) as a colorless solid. ¹H NMR (600 MHz, MeOD) δ 7.81 (d, J = 4.0 Hz, 1H), 7.67 (s, 1H), 7.41 (t, J= 2.9 Hz, 2H), 7.32 (s, 2H), 7.32 - 7.25 (m, 1H), 7.01 (s, 1H), 5.33 (dd, J= 10.2, 4.8 Hz, 1H), 3.90 (dq, J= 11.2, 4.0 Hz, 2H), 3.74 (tt, J= 10.6, 4.1 Hz, 1H), 3.45 (td, J= 11.7, 2.1 Hz, 2H), 3.39 (dd, J= 13.1, 10.2 Hz, 1H), 3.33 (dd, J= 13.3, 4.8 Hz, 1H), 2.25 (s, 3H), 1.94 - 1.86 (m, 2H), 1.59 - 1.50 (m, 2H).13C NMR (151 MHz, MeOD) δ 162.2, 150.6, 149.0, 142.2, 141.3, 140.3, 134.6, 134.4, 130.4, 130.2, 129.4, 128.4, 126.8, 125.1, 120.2, 112.8, 65.9, 51.6, 48.1, 42.7, 31.8, 15.9. LC-MS (ESI) m / z = ([M+H]+) 471.1.Example 51: Synthesis of Compound 193191-5 NaBH4HATU, DIPEA NiCl26H2O, MeOH DMF, O °C - rt, 30 min 0 °C - rt, 2 h crude Two-step yield: 14%General procedure for preparation of compound 193-1MSK-20525191-5 HATU, DIPEA DMF, 0 °C - rt, 30 min crude193-1To a solution of compound 162-4 (5-(5-chloro-2-((tetrahydro-2 / / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxylic acid) (Li salt, 20.9 mg, 60.7 pmol, 1 equiv.) and HATU (25.4 mg, 66.7 pmol, 1.1 equiv.) in DMF (0.303 mL), DIPEA (26.4 pL, 19.6 mg, 152 pmol, 2.5 equiv.) was added, and the solution was stirred for 5 min at 0 °C. Compound 191-5 ((5)-2-azido-l-(3-chlorophenyl)ethan-l-amine hydrochloride) (15.6 mg, 66.7 pmol, 1.1 equiv.) was then added, and the solution was stirred at rt for an additional 30 min. LC-MS analysis reflected full consumption of compound 162-4 and detection of the desired m / z. The reaction mixture was diluted with CH2CI2 (4 mL), washed with H2O (4 mL x 3) and brine (4 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford compound 193-1 ((5)-7V-(2-azido-l-(3-chlorophenyl)ethyl)-5-(5-chloro-2-((tetrahydro-2Z / -pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (crude) as a viscous brown oil. LC-MS (ESI) m / z = ([M+H]+) 518.4.General procedure for preparation of Compound 193NaBH4NiCI2.6H2O, MeOH O °C - rt, 2 h Two-step yield: 14%To a solution of compound 193-1 ((S)-N-(2-azido-1-(3-chlorophenyl)ethyl)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (crude, 60.7 pmol nominal, 1 equiv.) in 5 mM NiCl₂·6H₂O in MeOH (607 μL, 3.03 μmol, 0.05 equiv.), NaBH4 (11.5 mg, 303 pmol, 5 equiv.) was added over ice, and the solution wasMSK-20525stirred for 90 min at 0 °C. Additional 5 mM NiCl₂·6H₂O in MeOH (607 μL, 3.03 μmol, 0.05 equiv.) was added, followed by NaBH₄ (11.5 mg, 303 pmol, 5 equiv.) over ice, and the solution was stirred for 30 min at 0 °C. LC-MS analysis reflected full consumption of compound 193-1 and detection of the desired mlz. The reaction mixture was diluted with H2O (approx. 1.5 mL) and stirred for 10 min at rt, then diluted with ACN (approx. 2 mL), filtered, and purified by prep-HPLC (column: Waters XBridge® C18 3.5 μm, 4.6 × 150 mm; mobile phase: [H2O (0.05% TFA)-ACN (0.04% TFA)]; gradient: 28%-34% B over 12 min). The desired fractions were concentrated and dried to afford Compound 193 ((S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-5-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)thiophene-2-carboxamide) (2 TFA salt, 6.28 mg, 8.73 pmol, 14% yield over 2 steps) as a yellow solid.1H NMR (600 MHz, MeOD) δ 8.36 (s, 1H), 8.24 (d, J = 4.1 Hz, 1H), 7.85 (d, J = 4.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.48 - 7.38 (m, 3H), 5.45 (dd, J= 9.8, 5.1 Hz, 1H), 4.01 (tt, J = 7.2, 4.2 Hz, 3H), 3.57 (t, J = 11.6 Hz, 2H), 3.53 - 3.43 (m, 2H), 2.02 (d, J= 12.9 Hz, 2H), 1.63 (qd, J= 11.8, 4.3 Hz, 2H).13C NMR (151 MHz, MeOD) δ 162.9, 141.3, 140.3, 134.6, 130.8, 130.4, 129.2, 128.4, 126.8, 125.1, 116.0, 113.3, 66.6, 51.5, 48.2, 42.8, 32.3, 29.4. LC-MS (ESI) m / z = ([M+H]+) 492.3.Example 52: IC50 Measurements of ERK Inhibitors

[0168] IC50 values against wild-type and mutant variants of ERK1 or ERK2 proteins measured. Cellular NanoBRET assays measure compound binding in the context of live cells based on tracer displacement, and as such activity is reported as the concentration that provides 50% inhibition or IC50. IC50 measurements for ERK inhibitors (ERKi) were conducted using the NanoBRET Nano-Gio Detection System (Promega) following the manufacturer’s instructions (Robers et al, 2019) with minor modifications. HEK293T cells were transfected with N-terminally NanoLuc tagged human ERKI (Uniprot P27361), ERK2 (Uniprot P28482), or their mutant constructs using polyethylenimine (PEI; Kyfora Bio, 24765-100; 1 mg / mL) as the transfection reagent. For transfections, ERK constructs were mixed with transfection carrier DNA (Promega, E4881) at a 1:9 mass ratio in Opti-MEM. For a 1-mL transfection mixture, 1 pg of each NanoLuc-ERK plasmid was combined with 9 pg of carrier DNA in 1 mL of Opti-MEM. PEI was then added at a 1:3 ratio (pg of DNA: pL of PEI). After a 20-minute incubation at room temperature, the plasmid-PEI complexes were combined with 20 parts by volume of HEK293T cells suspended at a density of 2 × 105perMSK-20525mL. The cells were then incubated in a humidified incubator at 37 °C with 5% CO₂ for 18-24 hours.

[0169] The next day, HEK293T cells were trypsinized and plated into white, non-binding surface 96-well plates (Corning-3990) at a density of 20,000 cells / well in Opti-MEM (Gibco-31985-070). Test compounds were initially dissolved in DMSO as concentrated stock solutions, followed by serial dilution in Opti-MEM to prepare 10x working stocks for final dose levels. Dose-response experiments were performed with final concentrations ranging from 10 pM to 1 pM in 10-fold dilutions. Compounds were added to the cells first, followed by a 20× K5 tracer (Promega, N2482; final concentration of 1 pM) prepared in DMSO / Tracer Dilution Buffer (Promega, N2191). The plates were incubated at 37 °C for 2 hours.NanoBRET Target Engagement Substrate (Promega, N2162) and Extracellular NanoLuc Inhibitor (Promega, N2162) were then added according to the manufacturer's protocol.BRET readings were obtained using a GloMax plate reader, and data were analyzed with GraphPad Prism 8 software.

[0170] NanoBRET is a highly sensitive measure of molecular proximity that is used to assess direct interactions between a small molecule ligand and protein target within living systems. In brief, the first component in this example would be wild-type or mutant ERK1 or ERK2 fused to Nanoluciferase (NLuc), which is a very bright, stable, and small engineered version of luciferase. When a NLuc-tagged target is expressed in live cells and reaches a tracer, a ‘reporter complex’ is formed from which BRET can be measured. In this assay, the tracer is a cell-permeable fluorescent probe compound that serves as an acceptor for light produced by a donor NLuc in the presence of substrate. NanoBRET enables competition experiments wherein direct binding of un-labeled compounds inhibit tracer binding, leading to loss of BRET. Quantifying the loss of BRET as a function of compound concentration generates a dose response, thereby providing live-cell drug target engagement information for wild-type and mutant forms of ERK1 or ERK2. In Tables 1 and 2 the BRET dose response data for the listed compounds are provided as IC50 values in nM units. Average IC50 values (Mean), standard deviation (S. D.), and the number of biological replicates (N) are provided in Tables 1 and 2.

[0171] As shown in Tables 1 and 2 below, the measured IC50 values of BVD-523 on wild-type ERK1 or ERK2 were 68.6 ± 24.3 nM and 66.3 ± 21.1 nM, respectively. However, on certain mutant variants (such as G186D-ERK1, Y36H-ERK2, and G37C-ERK2), BVD-MSK-20525523 IC50 values were reduced over 30-fold, ranging from about 2,200 nM to greater than 10,000 nM. In contrast, we identified several novel compounds with 2-fold to over 100-fold improvements in IC50 activity on wild-type and / or mutant forms of ERK1 or ERK2, including but not limited to Compounds 54, 55-P1, 57, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, and 162. For example, Compounds 54, 57, and 162 demonstrate lower IC50 values, reflecting more potent binding of these compounds relative to BVD-523 on wild-type ERK2, of about 24-fold, about 12-fold, and about 44-fold, respectively. On mutant forms of ERK2 that have been reported to drive resistance to RAS-pathway inhibitors, such as Y36H-ERK2 (Goetz et al. 2014; Jaiswal et al. 2018), Compounds 54 and 57 demonstrate about 129-fold, and about 85-fold improvements in binding relative to BVD-523, respectively. This data supports that compounds in the present invention are highly potent and less likely to succumb to previously identified drug-resistance mutations in ERK1 and ERK2 compared to BVD-523.Table 1. ERK1 cellular ICso values (nM) of the indicated ERK inhibitors as measured by BRETWild Type (WT) G186DERK Inhibitor Mean S. D. N Mean S. D. N BVD-523 68.6 24.3 6 2294.0 - 1 54 3.2 2.6 5 15.7 7.4 2 55-P1 14.0 18.2 3 - - - 55-P2 186.1 NA 1 - - - 57 4.6 4.0 4 26.9 - 1 60 7.1 NA 1 - - - 61 5.4 NA 1 - - - 62 6.4 NA 1 - - - 63-P1 4.8 NA 1 - - - 63-P2 4.9 NA 1 - - - 64 11.4 NA 1 - - - 65 8.6 NA 1 - - - 66 7.5 NA 1 - - - 67 33.6 NA 1 - - - 68 1.4 0.5 3 - - - 69 6.1 1.1 2 - - - 70 5.4 1.9 2 - - - 71 27.8 10.5 2 - - - 72 3.3 1.9 3 - - - 73 3.0 0.9 3 - - -74 4.3 3.2 2 - - - 75 42.0 5.0 2 - - - 76 5.1 4.0 2 - - - 77 4.3 0.1 2 - - - 78 3.0 NA 1 - - - 79 15.2 NA 1 - - - 151 39.2 18.8 2 - - - 152 3.0 1.8 2 - - - 153 6.3 2.5 2 - - - 154 3.7 1.9 2 - - - 155 6.2 3.1 2 - - - 156 12.6 4.4 2 - - - 157 8.0 2.3 2 - - - 158 9.8 0.3 2 - - - 159 6.4 2.1 2 - - - 160 11.4 9.2 2 - - - 161 53.2 45.8 2 - - - 162 1.5 0.1 2 - - -Table 2. ERK2 cellular IC50 values (nM) of the indicated compounds as measured by BRETWild Type (WT) Y36A Y36H G37C I56A ERK Mean S. D. N Mean S. D. N Mean S. D. N Mean S. D. N Mean S. D. N InhibitorBVD-523 66.3 21.1 9 1903.3 581.9 6 2950.0 - 1 10000.0 - 1 477.6 150.9 4 54 2.7 1.5 5 9.9 7.6 3 22.9 5.2 2 152.4 25.1 2 - - - 55-P1 10.9 7.3 3 17.2 - 1 - - - - - - - - - 55-P2 186.3 - 1 1661.0 - 1 - - - - - - - - - 57 5.3 1.3 4 18.3 7.3 2 34.8 - 1 144.2 - 1 - - - 60 8.4 NA 1 NA NA NA 323.7 NA 1 2307.0 NA 1 NA NA NA 61 8.3 NA 1 NA NA NA 34.2 NA 1 1657.0 NA 1 NA NA NA 62 7.7 NA 1 NA NA NA 43.3 NA 1 2132.0 NA 1 NA NA NA 63-P1 5.1 NA 1 NA NA NA 114.6 NA 1 1414.0 NA 1 NA NA NA 63-P2 5.1 NA 1 NA NA NA 41.6 NA 1 810.2 NA 1 NA NA NA 64 10.4 NA 1 NA NA NA 64.0 NA 1 601.5 NA 1 NA NA NA 65 6.0 NA 1 NA NA NA 31.4 NA 1 375.0 NA 1 NA NA NA 66 7.3 NA 1 NA NA NA 115.4 NA 1 1972.0 NA 1 NA NA NA 67 21.4 NA 1 NA NA NA 144.0 NA 1 398.5 NA 1 NA NA NA 68 1.9 1.6 3 1.6 1.6 1.6 36.8 17.0 2 517.4 122.3 2 1.6 1.6 1.6 69 3.3 0.5 2 0.5 0.5 0.5 19.6 NA 1 616.1 NA 1 0.5 0.5 0.5 70 3.2 0.4 2 0.4 0.4 0.4 142.1 NA 1 1778.0 NA 1 0.4 0.4 0.4 71 15.7 0.6 2 0.6 0.6 0.6 1063.0 NA 1 10000.0 NA 1 0.6 0.6 0.6 72 2.2 1.0 3 1.0 1.0 1.0 20.7 9.1 2 673.3 517.2 2 1.0 1.0 1.073 2.1 0.7 3 0.7 0.7 0.7 15.2 0.1 2 1033.8 691.8 2 0.7 0.7 0.7 74 2.6 0.9 2 0.9 0.9 0.9 27.9 NA 1 694.4 NA 1 0.9 0.9 0.9 75 23.8 4.9 2 4.9 4.9 4.9 301.6 NA 1 3934.0 NA 1 4.9 4.9 4.9 76 3.9 0.9 2 0.9 0.9 0.9 51.7 NA 1 885.2 NA 1 0.9 0.9 0.9 77 3.9 0.6 2 0.6 0.6 0.6 64.9 9.1 2 1938.0 35.4 2 0.6 0.6 0.6 78 1.6 NA 1 NA NA NA 144.6 NA 1 2910.0 NA 1 NA NA NA 79 17.6 NA 1 NA NA NA 880.6 NA 1 10000.0 NA 1 NA NA NA 151 28.7 5.0 2 - - - - - - - - - - - - 152 3.7 1.4 2 - - - - - - - - - - - - 153 6.0 1.8 2 - - - - - - - - - - - - 154 2.5 0.4 2 - - - - - - - - - - - - 155 5.0 1.4 2 - - - - - - - - - - - - 156 16.1 7.0 2 - - - - - - - - - - - - 157 8.0 2.0 2 - - - - - - - - - - - - 158 18.2 10.4 2 - - - - - - - - - - - - 159 7.9 3.7 2 - - - - - - - - - - - - 160 6.0 3.3 2 - - - - - - - - - - - - 161 72.7 55.1 2 - - - - - - - - - - - - 162 1.5 0.3 2 - - - - - - - - - - - -MSK-20525Example 53: Cell Proliferation Assays

[0172] HCT116 cells were seeded in 96-well tissue culture treated plates (Corning, 3917; seeding density = 0.01×106) and cultured at 37 °C for 24 hours. On the second day, medium was aspirated and fresh medium was added into the plates (100 pL / well). Stocks of the compounds that were 10-fold diluted in DMSO (stock concentrations = 1 mM, 100 pM, 10 pM, 1 pM, 100 nM, 10 nM, 1 nM, 100 pM) were subsequently added into the wells (1 pL / well, 1% DMSO / well; final concentrations = 10 pM, 1 pM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, 1 pM). The cells were cultured at 37 °C for an additional 72 hours. Cell viability was quantified by measuring ATP levels in the cells using CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7572) according to the manufacturer’s instructions. Data was processed by Prism. Results for the selected compounds are shown in Table 3 below, where N indicates the number of independent biological replicates.

[0173] As shown in Table 3 below, the anti-proliferative activity of the present technology was demonstrated based upon inhibition of growth of the KRAS-G13D mutant cell line HCT116. The growth and viability of HCT116 is dependent on ERK2 as well as other proteins predominantly in the RAS / ERK and PI3K pathways. The inhibition of HCT116 viability with compounds of the present technology supports the use of these agents as anti-cancer therapeutics.Table 3. EC50values of the indicated compoundsERK inhibitor Average ECso (nM) Standard Deviation (nM) N BVD-523 94.6 5.4 254 8.6 0.5 2 55-P1 188.6 94.8 2 55-P2 2421.5 470.2 2 57 38.4 18.7 2 60 27.3 NA 1 61 3.4 NA 1 62 3.4 NA 1 63-P1 13.4 NA 1 63-P2 0.1 NA 1 64 19.7 NA 1 65 12.4 NA 1MSK-2052566 15.9 NA 1 67 135.8 NA 1 68 7.9 NA 1 69 8.6 NA 1 70 42.1 NA 1 71 184.5 NA 1 72 2.7 NA 1 73 2.0 NA 1 74 1.0 NA 1 75 13.9 NA 1 76 4.5 NA 1 77 4.8 NA 1 78 6.1 NA 1 79 42.0 NA 1 151 190.3 20.7 2 152 37.9 9.9 2 153 86.2 54.1 2 154 61.2 28.2 2 155 67.9 31.3 2 156 280.2 157.1 2 157 37.5 8.9 2 158 43.5 6.2 2 159 22.1 12.4 2 160 93.2 44.3 2 161 121.2 7.4 2 162 5.0 1.4 2Example 54: Western Blots

[0174] HCT116 cells were seeded in 6-well tissue culture treated plates (CELLTREAT Scientific Products, 229106; seeding density = 1 xlO6) and cultured at 37 °C for 24 hours. On the second day, medium was aspirated, and fresh medium was added into the plates (2 mL / well). DMSO or 1 mM DMSO stocks of the compounds were subsequently added into the wells (2 pL / well, 0.1% DMSO / well; final concentrations = 1 pM). The cells were cultured at 37 °C for an additional 24 hours. On the third day, cells in each well were washed by PBS, trypsinized, and transferred into 1.5 mL Eppendorf tubes. The cell pellets were thenMSK-20525washed by PBS and boiled in 2x XT Sample Buffer (Bio-Rad, 1610791) at 95 °C three times for ten minutes each. The cell pellets were vigorously vortexed in-between each ten-minute boil. The crude cell lysates were separated by electrophoresis on 12% Criterion™ XT BisTris Protein Gels (Bio-Rad, 3450119). Proteins were then transferred from gels to PVDF membranes (Thermo Scientific, 88518). The membranes were incubated in 5% milk in 0.1% Tween-20 / PBS at room temperature for 2 hours, incubated with the indicated primary antibodies (Cell Signaling Technology, P-ERK1 / 2, 4370; ERK1 / 2, 4695; ERK1, 4372;ERK2, 9108; P-p90RSK 1 / 2 / 3, 8753; p90RSKl / 2 / 3, 9355; GAPDH, 2118) diluted in 0.1% Tween-20 / PBS at 4 °C overnight, and incubated with HRP-linked anti -rabbit antibody (Cell Signaling Technology, 7074) diluted in 0.1% Tween-20 / PBS at room temperature for 2 hours. The membranes were washed by 0.1% Tween-20 / PBS after each incubation. Clarity Western ECL Substrate (Bio-Rad, 1705060) was applied to the membranes and signal bands were detected by iBright 1500 (Invitrogen).

[0175] HCT-116 cells (KRAS-G13D) were treated with 1 pM of each compound for 24 hours. The total and phosphorylated forms of several markers as indicative of RAS and ERK pathway activity modulation were measured by western blot, including the release of negative-feedback signaling (p-MEKl / 2, p-ERKl / 2), ERK1 / 2 substrate phosphorylation (p-RSK1 / 2 / 3), and small molecule-induced degradation of target proteins (ERK1 / 2, ERK1, or ERK2).

[0176] As shown in Tables 4-10b below, several compounds reported herein demonstrate features of ERK1 or ERK2 target engagement in cells. This data evidences chemo-type specificity among compounds such that only certain ERK inhibitors also possess ERK2 degradation activity and thus may be described as functioning via the mechanism of small molecule-induced ERK2 degradation.Table 4. Quantification of western blot signals for indicated thiazole compounds for p-P90RSK1 / 2 / 3 (%)ERK Inhibitor Mean (%) Standard Deviation (%} N DMSO 100 0 9 BVD-523 11 5 954 1 NA 1 55-P1 3 NA 1MSK-2052555-P2 91 NA 1 57 1 NA 1 60 1.6 NA 1 61 0.1 NA 1 62 0.1 NA 1 63-P1 0.1 NA 1 63-P2 0.4 NA 1 64 4.5 NA 1 65 2.4 NA 1 66 1.2 NA 1 67 29.8 NA 1 68 0.2 NA 1 69 0.9 NA 1 70 2.4 NA 1 71 13.7 NA 1 72 0.3 NA 1 73 0.2 NA 1 74 0.1 NA 1 75 0.1 NA 1 76 1.3 NA 1 77 0.1 NA 1 78 0.2 NA 1 790.1 NA 1Table 5. Quantification of western blot signals for indicated thiazole compounds for p- ERK1 / 2 (%)ERK Inhibitor Mean (%) Standard Deviation (%} N DMSO 100 0 8 BVD-523 333 408 854 99 NA 1 55-P1 73 NA 1 55-P2 131 NA 1 57 104 NA 1 60 34.7 NA 1 61 28.0 NA 1 62 23.5 NA 1MSK-2052563-P1 33.0 NA 1 63-P2 30.2 NA 1 64 40.0 NA 1 65 38.9 NA 1 66 34.0 NA 1 67 82.3 NA 1 68 24.0 NA 1 69 20.4 NA 1 70 27.6 NA 1 71 37.2 NA 1 72 59.2 NA 1 73 118.4 NA 1 74 14.6 NA 1 75 24.6 NA 1 76 28.4 NA 1 77 23.6...

Claims

MSK-20525What is claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, according to Formula IR1(I)whereinR1is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;R2is H, alkyl, halo, amino, amide, hydroxyl, or O-R5;R3is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;R4is H or alkyl;R5is alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;Z1is CH, N, or C-R6;Z2is CH, N, or C-R7;Z3is CH, N, or C-R8;R6, R7, and R8are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy;andX1is NH or O.

2. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IA)3. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound,MSK-20525or a pharmaceutically acceptable salt thereof, according to Formula (IB)4. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-3, wherein R1is alkyl or heterocyclyl.

5. The compound, or pharmaceutically acceptable salt thereof, of claim 4, wherein R1is unsubstituted heterocyclyl.

6. The compound, or pharmaceutically acceptable salt thereof, of claim 4, wherein R1is substituted heterocyclyl.

7. The compound, or pharmaceutically acceptable salt thereof, of claim 5 or 6, wherein the heterocyclyl is a four to six-membered heterocyclyl.

8. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 5-7, wherein the heterocyclyl is an oxygen or nitrogen-containing heterocyclyl.

9. The compound, or pharmaceutically acceptable salt thereof, of claim 4, wherein R1is alkyl10. The compound, or pharmaceutically acceptable salt thereof, of claim 9, wherein R1is Ci-C4 alkyl.

11. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-3,wherein R1isMSK-2052512. The compound, or pharmaceutically acceptable salt thereof, of claim 11, wherein R1is13. The compound, or pharmaceutically acceptable salt thereof, of claim 12, wherein R1is14. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-5, wherein the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IA-1) or (IB-1)(IB-1).MSK-2052515. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-14, wherein R2is alkyl or halo.

16. The compound, or pharmaceutically acceptable salt thereof, of claim 15, wherein R2is alkyl.

17. The compound, or pharmaceutically acceptable salt thereof, of claim 15 or 16, wherein R2is methyl.

18. The compound, or pharmaceutically acceptable salt thereof, of claim 15, wherein R2is halo.

19. The compound, or pharmaceutically acceptable salt thereof, of claim 18, wherein R2is Cl.

20. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-19, wherein R3is alkyl or aryl.

21. The compound, or pharmaceutically acceptable salt thereof, of claim 20, wherein R3is aryl.

22. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 14-21, wherein the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IA-2) or (IB-2)wherein each R9is independently selected from halo, alkyl, and alkoxy; andm is 0-5.MSK-2052523. The compound, or pharmaceutically acceptable salt thereof, of claim 22, wherein m is 0-2.

24. The compound, or pharmaceutically acceptable salt thereof, of claim 23 or 23, wherein m is 0.

25. The compound, or pharmaceutically acceptable salt thereof, of claim 22 or 23, wherein m is 1 or 2.

26. The compound, or pharmaceutically acceptable salt thereof, of claim 25, wherein m is 1 and R9is in the meta position.

27. The compound, or pharmaceutically acceptable salt thereof, of claim 25, wherein m is 2 and both R9are in the meta positions.

28. The compound, or pharmaceutically acceptable salt thereof, of claim 26 or 27, wherein R9is alkyl.

29. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 26-28, wherein R9is C1-C3 alkyl.

30. The compound, or pharmaceutically acceptable salt thereof, of claim 26 or 27, wherein R9is halo.

31. The compound, or pharmaceutically acceptable salt thereof, of claim 30, wherein R9is F, Cl, or Br.

32. The compound, or pharmaceutically acceptable salt thereof, of claim 26 or 27, wherein R9is alkoxy.

33. The compound, or pharmaceutically acceptable salt thereof, of claim 32, wherein R9is methoxy.MSK-2052534. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-20,35. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 14-22, wherein the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IA-3) or (IB-3)(IB-3).MSK-2052536. The compound, or pharmaceutically acceptable salt thereof, of claim 35, wherein the compound, or a pharmaceutically acceptable salt thereof, according to Formula I is a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IA-4) or (IB-4)37. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-36, wherein R4is H or methyl.

38. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-37, wherein R4is H.

39. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-38, wherein Z1is CH or N.

40. The compound, or pharmaceutically acceptable salt thereof, of claim 39, wherein Z1is CH.

41. The compound, or pharmaceutically acceptable salt thereof, of claim 39, wherein Z1is N.

42. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-41, wherein Z2and Z3are each CH.

43. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-41, wherein Z2is N and Z3is CH.

44. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound is selected from:MSK-20525MSK-20525MSK-20525MSK-20525MSK-20525MSK-20525MSK-20525or pharmaceutically acceptable salt thereof of any one thereof.

45. The compound, or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound is selected from:MSK-20525pharmaceutically acceptable salt thereof of any one thereof.

46. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, 11,ClNHNH219, 34, 37, or 39, wherein the compound isMSK-2052547. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 3, 11,MSK-20525or pharmaceutically acceptable salt thereof of any onethereof.MSK-2052548. A composition comprising a compound of any one of claims 1-47 and a pharmaceutically acceptable carrier.

49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-47, wherein the compound is present in an amount effective to treat a cancer.

50. The pharmaceutical composition of claim 49, wherein the cancer expresses a RAS pathway mutation, optionally wherein the RAS pathway mutation is KRAS-G13D.

51. A method of treating a subject suffering from a cancer, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-47.

52. The method of claim 51, wherein the cancer expresses a RAS pathway mutation, optionally wherein the RAS pathway mutation is KRAS-G13D.

53. The method of claim 51 or 52, wherein the cancer is selected from lung cancer, pancreatic cancer, ovarian cancer, myeloma, leukemia, liver melanoma, and colon cancer.

54. The method of any one of claims 51-53, wherein the cancer is colon cancer.

55. A medicament for treating a cancer in a subject, the medicament comprising a compound of any one of claims 1 -47.

56. The medicament of claim 55, wherein the medicament further comprises a pharmaceutically acceptable carrier.

57. The medicament of claim 55, wherein the medicament comprises an effective amount of the compound for treating the cancer.

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