ERK2 degraders

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; and R6, R7, and R8 are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy. As evidenced by this application, these compounds and compositions are suitable for, among other things, treating cancer.

Description

Atty. Dkt. No.: 115872-3155 (SK2024-037-03) ERK2 DEGRADERS CROSS-REFERENCE TO RELEATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Appl. No. 63 / 661,465, filed June 18, 2024 and U.S. Provisional Appl. No.63 / 662,103, filed June 20, 2024, the contents of each of which are incorporated herein by reference in their entireties for any and all purposes. FIELD

[0002] The present technology is directed to compounds, compositions, and methods related to degraders of extracellular signal-regulated kinase and uses thereof. SUMMARY

[0003] In an aspect, the present technology provides a compound or a pharmaceutically acceptable salt thereof according to Formula Iwherein R1is 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; and R6, R7, and R8are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy. 1 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0004] 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).

[0005] In a related aspect, a medicament for treating a cancer in a subject is provided that includes a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be colon cancer.

[0006] 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. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be colon cancer.

[0007] 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 subject suffering from a cancer, where the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be colon cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIGS.1A and 1B are representative western blot analyses of HCT116 cells treated with 1 µM of the indicated compounds for 24 hours.

[0009] FIG.2 shows the pharmacokinetics of various compounds 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-1 mice. Data is shown as the mean ± standard deviation. FIG.2A shows the pharmacokinetics of Target 7 of the present technology. FIG.2B shows the pharmacokinetics of Target 26 of the present technology. FIG.2C shows the pharmacokinetics of Target 43-P1 of the present technology. 2 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) DETAILED DESCRIPTION

[0010] The following terms are used throughout as defined below.

[0011] 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.

[0012] 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 be understood 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.%.”

[0013] 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.”

[0014] 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. 3 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0015] 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 (i.e., F, Cl, Br, and I); hydroxyls; 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 (i.e., SF5), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like.

[0016] 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.

[0017] 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, sec- butyl, 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. 4 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0018] 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 mono- substituted 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.

[0019] 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. In 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.

[0020] 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. 5 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0021] 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.

[0022] 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.

[0023] 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, from 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 tri- substituted with substituents such as those listed above.

[0024] 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 6 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0025] 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.

[0026] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non- aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom 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, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]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, 7 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, 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 mono- substituted 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.

[0027] 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. Heteroaryl 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 (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, 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.

[0028] 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 8 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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-methyl, pyridin-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.

[0029] 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.

[0030] 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, and so 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.

[0031] 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. 9 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0032] 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.

[0033] 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.

[0034] The term “carboxylate” as used herein refers to a -COOH group.

[0035] 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.

[0036] 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)-(C1-5 alkyl) and the group is termed "carbonylamino," and in others the amide is –NHC(O)-alkyl and the group is termed "alkanoylamino."

[0037] The term “nitrile” or “cyano” as used herein refers to the –CN group.

[0038] Urethane groups include N- and O-urethane groups, i.e., -NR73C(O)OR74and -OC(O)NR73R74groups, respectively. R73and R74are independently a substituted or 10 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R73may also be H.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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. 11 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0045] 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.

[0046] 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.

[0047] 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-.

[0048] 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.

[0049] 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.

[0050] The term “nitro” as used herein refers to an –NO2group.

[0051] The term “trifluoromethyl” as used herein refers to –CF3.

[0052] The term “trifluoromethoxy” as used herein refers to –OCF3.

[0053] The term “azido” refers to –N3.

[0054] 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.

[0055] The term “isocyano” refers to –NC.

[0056] The term “isothiocyano” refers to –NCS.

[0057] The term “pentafluorosulfanyl” refers to –SF5. 12 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0058] 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.

[0059] 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, methanesulfonic acid, 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. 13 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0060] 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.”

[0061] “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:.

[0062] As another example, guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other:.

[0063] 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. 14 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0064] 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.

[0065] 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.

[0066] 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.

[0067] The Present Technology

[0068] In an aspect, the present technology provides a compound or a pharmaceutically acceptable salt thereof according to Formula Iwherein 15 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) R1is 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; and R6, R7, and R8are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy.

[0069] 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.

[0070] 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 IA16 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0071] In any embodiment herein, R1may be

[0072] In any embodiment herein, R2may be methyl or Cl.

[0073] In any embodiment herein, R3may be methyl,17 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0074] In any embodiment herein, R4may be H or methyl. In any embodiment herein, Z1may be CH or N. In any embodiment herein, Z2may be CH or N. In any embodiment herein, Z3may be CH or N.

[0075] 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 cancer. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be 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. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, 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. 18 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0076] “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 as from 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.

[0077] 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. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be 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 19 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0078] 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 instant compositions 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.

[0079] 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.

[0080] 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 20 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0081] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn 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), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[0082] 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.

[0083] 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.

[0084] 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 21 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0085] 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, for example, 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.

[0086] 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.

[0087] 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.

[0088] 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 22 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0089] 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.

[0090] 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. The compounds 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.

[0091] 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.

[0092] 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. 23 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0093] 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. The cancer may express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be colon cancer.

[0094] 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.

[0095] 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 24 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) compound to the target of interest, the target may be isolated, purified and further characterized such as by determining the amino acid sequence.

[0096] 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.

[0097] 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 the subject 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 express a RAS pathway mutation such as KRAS-G13D. For example, the cancer may be colon cancer.

[0098] 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, 25 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0099] 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.

[0100] 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 to more 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. EXAMPLES Example 1: Materials, Reagents, and General Methods

[0101] Reagents and Cell Lines. Cell lines were purchased from ATCC. Antibodies were purchased from Cell Signaling, Abcam, 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 26 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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.

[0102] NMR Assays.1H NMR spectra were recorded at 400 MHz 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), (J=coupling constant in 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 400 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.

[0103] Chromatography Assays. Reactions were monitored by TLC using EMD silica gel 60 F254(250 µm) glass-backed plates (visualized by UV fluorescence quenching and stained with basic KMnO4solution) and by liquid chromatography-tandem mass spectrometry (LC-MS). Analysis by reverse-phase LC-MS was performed as noted or otherwise on a Waters system (Acquity Premier UPLC-MS), with a C18 column (2.1 mm × 100 mm, 1.7 µm particle size) with a multiwavelength 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 27 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 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 µm irregular particle size) were employed for normal- phase (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 × 100 mm, 5 µm particle size) with a multiwavelength 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 / injection). Example 2: Synthesis of Target 1

[0104] Synthesis and Characterization of Compound 1-1.To a solution of 4-bromo-2-fluoro-5-methylpyridine (Compound a, 2.00 g, 10.5 mmol, 1 equiv.) and propan-2-amine (Compound 1, 1.68 g, 28.4 mmol, 2.44 mL, 2.7 equiv.) in DMSO (20.0 mL) was added N,N-diisopropylethylamine (DIEA, 4.08 g, 31.6 mmol, 5.50 mL, 3 equiv.). The mixture was heated to 140 °C and stirred at 140 °C for 24 h. LC-MS showed Compound a was consumed and the desired m / z (retention time (RT) = 0.383 min) was detected. HPLC showed the product (RT = 0.926 min) was detected. The mixture was cooled to 25 °C and poured into H2O (100 mL) slowly and extracted three times with 100 mL ethyl acetate. The organic layers were combined and washed three times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18250 mm × 70 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 20 min), then it was concentrated to remove most of acetonitrile and adjusted pH to 7 with NaHCO3, and extracted three times with 200 mL ethyl acetate. The organic layers were combined and washed three times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product. The product 4-bromo-N-isopropyl- 5-methyl-pyridin-2-amine (Compound 1-1, 1.60 g, 6.98 mmol, 66.4% yield, 100% purity) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.60 (s, 1H), 4.29 (br d, J = 6.4 Hz, 1H), 3.84 - 3.77 (m, 1H), 2.22 (s, 3H), 1.22 (d, J = 6.4 Hz, 6H). 28 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0105] Synthesis and Characterization of Compound 1-2.A mixture of Compound 1-1 (1.50 g, 6.55 mmol, 1 equiv.), methyl 1-(p-tolylsulfonyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-2-carboxylate (Compound b, 3.18 g, 7.86 mmol, 1.2 equiv.), K3PO4 (4.17 g, 19.6 mmol, 3 equiv.), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, 479 mg, 655 µmol, 0.1 equiv.) in dioxane (15.0 mL) and H2O (3.00 mL) was degassed and purged with N2three times at 25 °C, and then the mixture was heated to 90 °C and stirred at 90 °C for 12 h under N2 atmosphere. LC-MS showed Compound 1-1 was consumed and the desired m / z (RT = 0.487 min) was detected. HPLC showed the product (RT = 1.507 mins) was detected. The reaction mixture was cooled to 25 °C and poured into H2O (30.0 mL), and the aqueous phase was extracted three times with 30.0 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 1 / 1, CH2Cl2 / MeOH = 10 / 1, Rf = 0.50), then the fraction was concentrated. The product methyl 4-[2- (isopropylamino)-5-methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 1-2, 2.80 g, 6.24 mmol, 95.2% yield, 95.2% purity) was obtained as a brown solid. LC-MS: m / z = 428.1 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.00 - 7.90 (m, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 2.0 Hz, 1H), 6.35 (s, 1H), 4.31 (br d, J = 8.0 Hz, 1H), 3.93 - 3.85 (m, 1H), 3.78 (s, 3H), 2.45 (s, 3H), 2.26 (s, 3H), 1.25 - 1.24 (m, 6H).

[0106] Synthesis and Characterization of Compound 1-3.29 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 1-2 (2.70 g, 6.01 mmol, 1 equiv.) in tetrahydrofuran (THF, 15.0 mL) and H2O (15.0 mL) was added NaOH (1.20 g, 30.1 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C stirred at 80 °C for 12 h. LC-MS showed Compound 1-2 was consumed and the desired m / z (RT = 0.357 min) was detected. The mixture was cooled to 25 °C and concentrated to remove most of THF. The pH was adjusted to 3 - 4 with 1 M HCl. The mixture was then filtered, and the filter cake was concentrated to get crude product. The crude product was used in the next step without further purification. The product 4-[2- (isopropylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 1-3, 1.30 g, crude) was obtained as a brown solid. LC-MS: m / z = 260.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.7 - 12.3 (m, 1H), 12.1 (br s, 1H), 7.77 (s, 1H), 7.26 (br s, 1H), 6.97 (br s, 1H), 6.55 (s, 1H), 6.37 - 6.14 (m, 1H), 4.00 - 3.90 (m, 1H), 2.19 (s, 3H), 1.14 (br d, J = 6.0 Hz, 6H).

[0107] Synthesis and Characterization of Compound 1-4.To a solution of Compound 1-3 (100 mg, 386 μmol, 1 equiv.) in N-methylpyrrolidone (NMP, 1.00 mL) was added (1S)-2-azido-1-(3-chlorophenyl)ethanamine (Compound 1-5, 108 mg, 463 μmol, 1.2 equiv., HCl), hydroxybenzotriazole (HOBt, 62.5 mg, 463 μmol, 1.2 equiv.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 148 mg, 771 μmol, 2 equiv.) and DIEA (99.7 mg, 771 μmol, 134 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. Thin layer chromatography (TLC) (petroleum ether / ethyl acetate = 0 / 1) indicated Compound 1-3 (Rf= 0.39) was consumed and one new spot (Rf= 0.20) was detected. The mixture was filtered with the injector. The filtrate was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 42%-72% acetonitrile over 9 min), then it was lyophilized. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2-(isopropylamino)-5- methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 1-4, 72.0 mg, 164 μmol, 42.6% yield, 100% purity) was obtained as a white solid. LC-MS: m / z = 438.2 [M+H]+.1H NMR: 30 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (400 MHz, DMSO-d6) δ 11.8 (br d, J = 1.2 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.43 - 7.36 (m, 3H), 7.18 (br d, J = 19.6 Hz, 2H), 6.47 (s, 1H), 5.94 - 5.92 (m, 1H), 5.32 - 5.27 (m, 1H), 3.98 - 3.92 (m, 1H), 3.72 - 3.66 (m, 2H), 2.20 (s, 3H), 1.12 (d, J = 6.4 Hz, 6H).

[0108] Synthesis and Characterization of Target 1.To a solution of Compound 1-4 (65.0 mg, 148 μmol, 1 equiv.) in THF (0.90 mL) and H2O (0.10 mL) was added triphenylphosphine (PPh3, 58.4 mg, 223 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 1-4 was consumed and the desired m / z (RT = 0.410 min) was detected. The mixture was concentrated to remove most of THF and filtered with the injector. The filtrate was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 28%-58% acetonitrile over 9 min), then it was lyophilized. The product N-[(1S)-2- amino-1-(3-chlorophenyl)ethyl]-4-[2-(isopropylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 1, 21.4 mg, 47.8 μmol, 32.2% yield, 98.4% purity) was obtained as a white solid. LC-MS: m / z = 412.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.74 - 11.72 (m, 1H), 8.36 (br d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.42 - 7.29 (m, 4H), 7.21 - 7.13 (m, 2H), 6.47 (s, 1H), 5.89 (d, J = 8.4 Hz, 1H), 4.98 - 4.93 (m, 1H), 3.98 - 3.93 (m, 1H), 2.89 (br d, J = 6.8 Hz, 2H), 2.21 (s, 3H), 1.13 (d, J = 6.4 Hz, 6H).

[0109] Synthesis and Characterization of Compound 1-7.31 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of tert-butyl N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]carbamate (Compound 1-6, 2.95 g, 10.9 mmol, 1 equiv.) in dichloromethane (DCM (CH2Cl2), 30.0 mL) was added triethylamine (TEA, 1.65 g, 16.3 mmol, 2.27 mL, 1.5 equiv.) and methanesulfonyl chloride (MsCl, 1.85 g, 16.2 mmol, 1.25 mL, 1.49 equiv.) at 0 °C. The mixture was stirred at 20 °C for 1.5 h. LC-MS showed Compound 1-6 was consumed and the desired m / z (RT = 0.508 min) was detected. The mixture was poured into iced NH4Cl (30.0 mL), then the aqueous phase was extracted three times with 20.0 mL CH2Cl2. The organic layers were combined and washed one time with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. The product (2S)-2-(tert- butoxycarbonylamino)-2-(3-chlorophenyl)ethyl]methanesulfonate (Compound 1-7, 3.80 g, crude) was obtained as a yellow solid. LC-MS: m / z = 249.9 [M-100+H]+.

[0110] Synthesis and Characterization of Compound 1-8.To a solution of Compound 1-7 (3.80 g, 10.9 mmol, 1 equiv.) in dimethylformamide (DMF, 40.0 mL) was added NaN3 (1.40 g, 21.5 mmol, 1.98 equiv.) at 25 °C. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated Compound 1-7 (Rf = 0.20) was consumed and one new spot (Rf = 0.69) was detected. The mixture was cooled to 25 °C and poured into iced NaHCO3 (100 mL), then the aqueous phase was extracted three times with 100 mL ethyl acetate. The organic layers were combined and washed four times with 100 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, petroleum ether / ethyl acetate = 3 / 1 Rf= 0.69), then the fraction was concentrated. The product tert-butyl N- [(1S)-2-azido-1-(3-chlorophenyl)ethyl]carbamate (Compound 1-8, 2.67 g, 9.00 mmol, 82.8% yield, 100% purity) was obtained as a yellow solid. LC-MS: m / z = 197.0 [M-100+H]+.1H NMR: (400 MHz, DMSO-d6) δ 7.69 (br d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.40 - 7.31 (m, 3H), 4.83 - 4.69 (m, 1H), 3.55 - 3.40 (m, 2H), 1.38 (s, 9H). 32 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0111] Synthesis and Characterization of Compound 1-5.A mixture of Compound 1-8 (2.67 g, 9.00 mmol, 1 equiv.) in HCl / dioxane (2.00 M, 53.4 mL, 11.9 equiv.) was stirred at 25 °C for 12 h. LC-MS showed Compound 1-8 was consumed and the desired m / z (RT = 0.358 min) was detected. The mixture was concentrated. The crude product was used in the next step without further purification. The product Compound 1-5 (2.00 g, 8.41 mmol, 93.5% yield, 98.0% purity, HCl) was obtained as a white solid. LC-MS: m / z = 197.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.89 (br s, 2H), 7.71 (s, 1H), 7.55 - 7.53 (m, 1H), 7.49 - 7.48 (m, 2H), 4.54 (t, J = 6.4 Hz, 1H), 3.93 - 3.81 (m, 2H). Example 3: Synthesis of Target 2

[0112] Synthesis and Characterization of Compound 2-1.To a solution of Compound a (2.00 g, 10.5 mmol, 1 equiv.) and tetrahydropyran-4-amine (Compound 2, 1.28 g, 12.6 mmol, 1.2 equiv.) in DMSO (20.0 mL) was added DIEA (4.08 g, 31.6 mmol, 5.50 mL, 3 equiv.) at 25 °C. The mixture was heated to 140 °C and stirred at 140 °C for 12 h. LC-MS showed 15.7% Compound a (RT = 0.471 min) remained and the desired m / z (RT = 0.342 min) was detected. The mixture was cooled to 25 °C and poured into H2O (100 mL) slowly and extracted three times with 100 mL ethyl acetate. The organic layers were combined and washed three times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18250 mm × 70 mm, 10 µm; 33 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) mobile phase: [water (FA)-acetonitrile]; gradient: 10%-40% acetonitrile over 20 min), concentrated to remove most of acetonitrile and adjusted pH to 7 with NaHCO3, and extracted three times with 200 mL ethyl acetate. The organic layers were combined and washed two times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product. The product 4-bromo-5-methyl-N-tetrahydropyran-4- yl-pyridin-2-amine (Compound 2-1, 1.40 g, 5.13 mmol, 48.8% yield, 99.4% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.88 (s, 1H), 6.63 (s, 1H), 4.38 (br d, J = 7.2 Hz, 1H), 4.02 - 3.98 (m, 2H), 3.85 - 3.70 (m, 1H), 3.57 - 3.51 (m, 2H), 2.22 (s, 3H), 2.02 (br dd, J = 12.8, 1.6 Hz, 2H), 1.58 - 1.44 (m, 2H).

[0113] Synthesis and Characterization of Compound 2-2.A mixture of Compound 2-1 (1.30 g, 4.77 mmol, 1 equiv.), Compound b (2.32 g, 5.72 mmol, 1.2 equiv.), K3PO4(3.03 g, 14.3 mmol, 3 equiv.), Pd(dppf)Cl2(349 mg, 476 μmol, 0.1 equiv.) in dioxane (13.0 mL) and H2O (2.60 mL) was degassed and purged with N2three times at 25 °C, and then the mixture was heated to 90 °C and stirred at 90 °C for 12 h under N2 atmosphere. LC-MS showed Compound 2-1 was consumed and the desired m / z (RT = 0.475 min) was detected. HPLC showed the product (RT = 1.439 mins) was detected. The reaction mixture was cooled to 25 °C and poured into H2O (30.0 mL), and the aqueous phase was extracted three times with 30.0 mL ethyl acetate. The organic layers were combined and washed two times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 1 / 1, CH2Cl2 / MeOH = 10 / 1, Rf= 0.50), then the fraction was concentrated. The product methyl 4-[5- methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 2-2, 2.24 g, 4.46 mmol, 93.6% yield, 93.5% purity) was obtained as a brown solid. LC-MS: m / z = 470.2 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 2.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 1.6 Hz, 1H), 6.46 (s, 1H), 34 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 5.31 (s, 1H), 4.06 - 3.98 (m, 2H), 3.90 - 3.82 (m, 1H), 3.79 (s, 3H), 3.62 - 3.53 (m, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 2.09 - 2.02 (m, 2H), 1.66 - 1.55 (m, 2H).

[0114] Synthesis and Characterization of Compound 2-3.To a solution of Compound 2-2 (2.14 g, 4.26 mmol, 1 equiv.) in THF (12.0 mL) and H2O (12.0 mL) was added NaOH (852 mg, 21.3 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C stirred at 80 °C for 12 h. LC-MS showed Compound 2-2 was consumed and the desired m / z (RT = 0.344 min) was detected. The mixture was cooled to 25 °C and concentrated to remove most of THF, then adjusted to pH 3-4 with 1 M HCl, filtered, and the filter cake was concentrated to get crude product. The crude product was used in the next step without further purification. The product 4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4- pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 2-3, 1.10 g, crude) was obtained as a brown solid. LC-MS: m / z = 302.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.6 - 12.4 (m, 1H), 12.2 (br s, 1H), 7.77 (s, 1H), 7.39 (br s, 1H), 7.05 (br s, 1H), 6.80 (br s, 1H), 3.92 - 3.83 (m, 3H), 3.45 - 3.38 (m, 2H), 2.25 (s, 3H), 1.91 - 1.85 (m, 2H), 1.50 - 1.39 (m, 2H).

[0115] Synthesis and Characterization of Compound 2-4.To a solution of Compound 2-3 (200 mg, 663 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 1-5 (206 mg, 796 μmol, 1.2 equiv., HCl), HOBt (108 mg, 796 μmol, 1.2 equiv.), EDCI (254 mg, 1.33 mmol, 2 equiv.), and DIEA (172 mg, 1.33 mmol, 231 μL, 2 equiv.) at 0 35 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 2-3 was consumed and the desired m / z (RT = 0.635 min) was detected. The mixture was poured into H2O (10.0 mL), then the aqueous phase was extracted three times with 10.0 mL ethyl acetate. The organic layers were combined and washed one time with 10.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[5- methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 2- 4, 318 mg, crude) was obtained as brown oil. LC-MS: m / z = 480.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.66 (br d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.55 (s, 1H), 7.40 - 7.29 (m, 3H), 7.23 - 7.12 (m, 2H), 6.51 (s, 1H), 6.12 (d, J = 7.6 Hz, 1H), 5.42 - 5.16 (m, 1H), 3.91 - 3.81 (m, 3H), 3.74 - 3.62 (m, 2H), 3.43 - 3.38 (m, 2H), 1.99 (s, 3H), 1.86 - 1.84 (m, 2H), 1.44 - 1.35 (m, 2H).

[0116] Synthesis and Characterization of Target 2.To a solution of Compound 2-4 (318 mg, 596 μmol, 1 equiv.) in THF (2.70 mL) and H2O (0.30 mL) was added PPh3 (235 mg, 894 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 2-4 was consumed and the desired m / z (RT = 0.378 min) was detected. The mixture was concentrated to remove most of THF and filtered with the injector. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 9 min), then it was lyophilized. The product N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]- 4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 2, 97.6 mg, 192 μmol, 32.2% yield, 98.2% purity, FA) was obtained as an off-white solid. LC- MS: m / z = 454.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.93 (br d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.52 - 7.32 (m, 4H), 7.18 (br d, J = 18.0 Hz, 2H), 6.50 (s, 1H), 6.12 36 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (br d, J = 8.0 Hz, 1H), 5.29 - 5.13 (m, 1H), 3.95 - 3.73 (m, 3H), 3.46 - 3.31 (m, 2H), 3.21 - 3.03 (m, 2H), 2.20 (s, 3H), 1.94 - 1.78 (m, 2H), 1.51 - 1.28 (m, 2H). Example 4: Synthesis of Target 3

[0117] Synthesis and Characterization of Compound 3-1.To a solution of Compound a (2.00 g, 10.5 mmol, 1 equiv.) and 1-methylpiperidin-4-amine (Compound 3, 1.44 g, 12.6 mmol, 1.2 equiv.) in DMSO (20.0 mL) was added DIEA (4.08 g, 31.6 mmol, 5.50 mL, 3 equiv.) at 25 °C. The mixture was heated to 120 °C and stirred at 120 °C for 12 h. LC-MS showed Compound a (RT = 0.494 min) remained and the desired m / z (RT = 0.276 min) was detected. The reaction mixture was cooled to 25 °C and poured into H2O (200 mL), and the aqueous phase was extracted three times with 10.0 mL ethyl acetate. The organic layers were combined and washed two times with 200 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18250 mm × 70 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 20 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give 4-bromo-5-methyl-N-(1-methyl-4- piperidyl)pyridin-2-amine (Compound 3-1, 900 mg, 3.17 mmol, 30.0% yield, 100% purity) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.60 (s, 1H), 4.29 (d, J = 8.4 Hz, 1H), 3.63 - 3.45 (m, 1H), 2.81 (d, J = 11.2 Hz, 2H), 2.32 (s, 3H), 2.25 - 2.13 (m, 5H), 2.08 - 1.99 (m, 2H), 1.62 - 1.45 (m, 2H).

[0118] Synthesis and Characterization of Compound 3-2.37 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) A mixture of Compound 3-1 (800 mg, 2.81 mmol, 1 equiv.), Compound b (1.37 g, 3.38 mmol, 1.2 equiv.), K3PO4 (1.79 g, 8.44 mmol, 3 equiv.) and Pd(dppf)Cl2 (206 mg, 282 μmol, 0.1 equiv.) in dioxane (8.00 mL) and H2O (1.60 mL) at 25 °C was degassed and purged with N2 three times, and then the mixture was heated to 90 °C and stirred at 90 °C for 6 h under N2 atmosphere. LC-MS showed Compound 3-1 was consumed and the desired m / z (RT = 0.427 min) was detected. HPLC showed Compound 3-1 was consumed and desired peak (RT = 3.088 mins) was detected. The mixture was cooled down to 25 °C, then poured into 50.0 mL H2O, then extracted three times with 50.0 mL ethyl acetate. The combined organic layers were washed two times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated to give the product. The residue was purified by triturated with petroleum ether: ethyl acetate = 5: 1 (15.0 mL) at 25 °C for 1 h. Next, the purified residue was filtered, and the filter cake was concentrated to give methyl 4-[5-methyl-2-[(1-methyl-4-piperidyl)amino]-4-pyridyl]-1- (p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 3-2, 2.40 g, crude) as a brown solid. LC- MS: m / z = 483.2 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 7.98 - 7.90 (m, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 2.0 Hz, 1H), 6.36 (s, 1H), 4.35 - 4.21 (m, 1H), 3.78 (s, 3H), 3.71 - 3.59 (m, 1H), 2.94 - 2.74 (m, 2H), 2.45 (s, 3H), 2.33 (s, 3H), 2.30 - 2.15 (m, 5H), 2.13 - 2.04 (m, 2H), 1.64 - 1.51 (m, 2H).

[0119] Synthesis and Characterization of Compound 3-3.To a solution of Compound 3-2 (1.64 g, 2.87 mmol, 1 equiv.) in THF (8.00 mL) and H2O (8.00 mL) was added LiOH•H2O (602 mg, 14.3 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 3-2 (RT = 0.886 min) remained and the desired m / z (RT = 0.734 min) was detected. The mixture was concentrated to remove most of THF, then adjusted pH to 5 with 1 M HCl, filtered, and the filter cake was concentrated to get crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (HCl)- acetonitrile]; gradient: 5%-35% acetonitrile over 10 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give 4-[5-methyl-2-[(1-methyl-4-piperidyl)amino]-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2- 38 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) carboxylic acid (Compound 3-3, 660 mg, 1.40 mmol, 50.0% yield, 99.4% purity) as a white solid. LC-MS: m / z = 469.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 9.31 - 8.66 (m, 1H), 8.28 - 8.16 (m, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.91 - 7.82 (m, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.42 - 7.30 (m, 1H), 7.15 (s, 1H), 4.38 - 3.98 (m, 1H), 3.49 (br d, J = 12.0 Hz, 2H), 3.43 - 3.29 (m, 1H), 3.21 - 2.96 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.42 (s, 3H), 2.35 - 2.29 (m, 3H), 2.17 (br d, J = 13.6 Hz, 2H), 2.00 - 1.82 (m, 2H).

[0120] Synthesis and Characterization of Compound 3-4.To a solution of Compound 3-3 (460 mg, 976 μmol, 1 equiv.) in THF (2.50 mL) and H2O (2.50 mL) was added NaOH (195 mg, 4.88 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 80 °C for 12 h. LC-MS showed Compound 3-3 (RT = 1.346 mins) remained and the desired m / z (RT = 0.847 min) was detected. The mixture was cooled down to 25 °C. The mixture was concentrated to remove THF, then the mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 0%-27% acetonitrile over 12 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give 4-[5-methyl-2-[(1-methyl- 4-piperidyl)amino]-4-pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 3-4, 280 mg, 891 μmol, 91.2% yield, 100% purity) as a yellow solid. LC-MS: m / z = 315.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 7.72 (s, 1H), 6.93 (s, 1H), 6.62 (s, 1H), 6.48 (s, 1H), 5.90 (d, J = 8.0 Hz, 1H), 3.68 - 3.54 (m, 1H), 2.72 (d, J = 11.2 Hz, 2H), 2.17 (d, J = 6.0 Hz, 6H), 1.99 (t, J = 11.2 Hz, 2H), 1.86 (d, J = 10.4 Hz, 2H), 1.48 - 1.32 (m, 2H).

[0121] Synthesis and Characterization of Compound 3-5. 39 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound 3-4 (120 mg, 382 μmol, 1 equiv.) and Compound 1-5 (107 mg, 458 μmol, 1.2 equiv., HCl) in NMP (1.00 mL) was added HOBt (61.9 mg, 458 μmol, 1.2 equiv.), EDCI (146 mg, 763 μmol, 2 equiv.) and DIEA (98.7 mg, 763 μmol, 133 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 3- 4 was consumed and the desired m / z (RT = 0.682 min) was detected. The mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18150 mm × 40 mm, 10 µm; mobile phase: [water (NH4HCO3)- acetonitrile]; gradient: 28%-58% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[5-methyl-2-[(1-methyl-4- piperidyl)amino]-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 3-5, 90.0 mg, 183 μmol, 47.8% yield, 100% purity) as a yellow solid. LC-MS: m / z = 493.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.46 - 7.32 (m, 3H), 7.24 - 7.05 (m, 2H), 6.49 (s, 1H), 6.01 (d, J = 7.6 Hz, 1H), 5.32 - 5.25 (m, 1H), 3.74 - 3.56 (m, 3H), 2.77 - 2.65 (m, 2H), 2.18 (d, J = 18.8 Hz, 6H), 2.03 - 1.92 (m, 2H), 1.90 - 1.80 (m, 2H), 1.48 - 1.33 (m, 2H).

[0122] Synthesis and Characterization of Target 3.40 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Compound 3-5 (80.0 mg, 162 μmol, 1 equiv.), triphenylphosphine (63.8 mg, 243 μmol, 1.5 equiv.) in THF (1.80 mL) and H2O (0.20 mL) at 25 °C, then the mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 3-5 was consumed and the desired m / z (RT = 0.578 min) was detected. The mixture was concentrated to remove most of THF, then the mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: YMC-Actus Triart C18150 mm × 39 mm, 7 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 0%-30% acetonitrile over 9 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N- [(1S)-2-amino-1-(3-chlorophenyl)ethyl]-4-[5-methyl-2-[(1-methyl-4-piperidyl)amino]-4- pyridyl]-1H-pyrrole-2-carboxamide (Target 3, 81.6 mg, 134 μmol, 82.4% yield, 99.2% purity, 3FA) as a light yellow solid. LC-MS: m / z = 467.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 9.10 (d, J = 8.0 Hz, 1H), 8.30 (s, 3H), 7.79 (s, 1H), 7.48 (s, 1H), 7.43 - 7.34 (m, 3H), 7.17 (br d, J = 12.8 Hz, 2H), 6.49 (s, 1H), 6.19 - 6.06 (m, 1H), 5.30 - 5.21 (m, 1H), 3.74 (s, 1H), 3.24 - 3.13 (m, 2H), 2.96 (d, J = 11.6 Hz, 2H), 2.45 - 2.35 (m, 5H), 2.20 (s, 3H), 1.94 (d, J = 10.4 Hz, 2H), 1.59 - 1.46 (m, 2H). Example 5: Synthesis of Target 4

[0123] Synthesis and Characterization of Compound 4-1.To a solution of Compound a (1.50 g, 7.89 mmol, 1 equiv.) and 1-isopropylpiperidin-4- amine (Compound 4, 1.35 g, 9.47 mmol, 1.2 equiv.) in DMSO (15.0 mL) was added DIEA (3.06 g, 23.7 mmol, 4.13 mL, 3 equiv.) at 25 °C. The mixture was heated to 120 °C and stirred at 120 °C for 12 h. LC-MS (EW52666-21-P1A1) indicated Compound a (RT = 0.493 min) remained and the desired m / z (RT = 0.324 min) was detected. The reaction mixture was cooled to 25 °C and poured into H2O (200 mL), and the aqueous phase was extracted three times with 10.0 mL ethyl acetate. The organic layers were combined and washed two times with 200 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced 41 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) pressure to give a crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 0%-20% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The mixture was adjusted to pH 8 with saturated NaHCO3 solution. The mixture was extracted two times with 100 mL ethyl acetate. The combined organic layers were dried over Na2SO4and concentrated to give 4-bromo-N-(1-isopropyl-4- piperidyl)-5-methyl-pyridin-2-amine (Compound 4-1, 740 mg, 2.34 mmol, 29.6% yield, 98.9% purity) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.60 (s, 1H), 4.32 (d, J = 7.6 Hz, 1H), 3.64 - 3.39 (m, 1H), 2.94 - 2.66 (m, 3H), 2.33 (t, J = 11.2 Hz, 2H), 2.21 (s, 3H), 2.10 - 1.99 (m, 2H), 1.65 - 1.40 (m, 2H), 1.06 (d, J = 6.4 Hz, 6H).

[0124] Synthesis and Characterization of Compound 4-2.A mixture of Compound 4-1 (740 mg, 2.34 mmol, 1 equiv.), Compound b (1.14 g, 2.81 mmol, 1.2 equiv.), K3PO4(1.49 g, 7.03 mmol, 3 equiv.) and Pd(dppf)Cl2(172 mg, 234 μmol, 0.1 equiv.) in dioxane (10.0 mL) and H2O (2.00 mL) at 25 °C was degassed and purged with N2 three times, and then the mixture was heated to 90 °C and stirred at 90 °C for 6 h under N2 atmosphere. LC-MS demonstrated Compound 4-1 was consumed and the desired m / z (RT = 0.437 min) was detected. The mixture was cooled down to 25 °C, then poured into H2O (50.0 mL), then extracted three times with 50 mL ethyl acetate. The combined organic layers were washed two times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated to give the product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 8%-38% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The mixture was adjusted to pH 8 with saturated NaHCO3solution. The mixture was extracted two times with 100 mL ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give methyl 4-[2-[(1-isopropyl-4- piperidyl)amino]-5-methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 4-2, 980 mg, 1.90 mmol, 81.2% yield, 99.2% purity) as a white solid. LC-MS: m / z = 511.3 42 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.05 - 7.92 (m, 3H), 7.84 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 2.0 Hz, 1H), 6.54 (s, 1H), 6.10 (d, J = 7.6 Hz, 1H), 3.71 (s, 3H), 3.68 - 3.57 (m, 1H), 2.81 - 2.65 (m, 3H), 2.42 (s, 3H), 2.27 - 2.14 (m, 5H), 1.87 (d, J = 10.0 Hz, 2H), 1.42 - 1.28 (m, 2H), 0.96 (d, J = 6.4 Hz, 6H).

[0125] Synthesis and Characterization of Compound 4-3.To a solution of Compound 4-2 (880 mg, 1.71 mmol, 1 equiv.) in THF (5.00 mL) and H2O (5.00 mL) was added LiOH•H2O (359 mg, 8.55 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS (EW52666-32-P1A) showed Compound 4-2 (RT = 0.954 min) remained and the desired m / z (RT = 0.779 min) was detected. The reaction mixture was concentrated under reduced pressure to give 4-[2-[(1-isopropyl-4-piperidyl)amino]-5-methyl- 4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylic acid (Compound 4-3, 850 mg, crude) as a yellow solid. LC-MS: m / z = 497.3 [M+H]+.

[0126] Synthesis and Characterization of Compound 4-4.To a solution of Compound 4-3 (850 mg, 1.71 mmol, 1 equiv.) in THF (5.00 mL) and H2O (5.00 mL) was added NaOH (342 mg, 8.56 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 80 °C for 12 h. LC-MS showed Compound 4-3 (RT = 1.532 mins) remained and the desired m / z (RT = 0.973 min) was detected. The mixture was cooled down to 25 °C. The mixture was concentrated to remove THF, then the mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 0%-30% 43 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) acetonitrile over 12 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give 4-[2-[(1-isopropyl-4- piperidyl)amino]-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 4-4, 480 mg, 1.39 mmol, 81.3% yield, 99.3% purity) as a yellow solid. LC-MS: m / z = 343.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.5 (s, 1H), 7.73 (s, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.48 (s, 1H), 5.92 (d, J = 7.6 Hz, 1H), 3.69 - 3.54 (m, 1H), 2.85 - 2.68 (m, 3H), 2.29 - 2.14 (m, 5H), 1.89 (d, J = 10.0 Hz, 2H), 1.45 - 1.32 (m, 2H), 0.98 (d, J = 6.4 Hz, 6H).

[0127] Synthesis and Characterization of Compound 4-5.A mixture of Compound 4-4 (140 mg, 409 μmol, 1 equiv.) and Compound 1-5 (114 mg, 490 μmol, 1.2 equiv., HCl) in NMP (1.00 mL) was added HOBt (66.3 mg, 491 μmol, 1.2 equiv.), EDCI (157 mg, 818 μmol, 2 equiv.) and DIEA (106 mg, 818 μmol, 142 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 4-4 was consumed and the desired m / z (RT = 0.794 min) was detected. The mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18150 mm × 40 mm, 10 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 30%-60% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N- [(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2-[(1-isopropyl-4-piperidyl)amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Compound 4-5, 90.0 mg, 173 μmol, 42.3% yield, 100% purity) as a yellow solid. LC-MS: m / z = 521.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.55 (s, 1H), 7.43 - 7.34 (m, 3H), 7.18 (d, J = 20 Hz, 2H), 6.49 (s, 1H), 6.03 - 5.95 (m, 1H), 5.34 - 5.25 (m, 1H), 3.75 - 3.53 (m, 3H), 2.80 - 2.65 (m, 3H), 2.24 - 2.15 (m, 5H), 1.93 - 1.82 (m, 2H), 1.43 - 1.27 (m, 2H), 0.96 (d, J = 6.4 Hz, 6H). 44 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0128] Synthesis and Characterization of Target 4.A mixture of Compound 4-5 (90.0 mg, 173 μmol, 1 equiv.), PPh3(68.0 mg, 259 μmol, 1.5 equiv.) in THF (1.80 mL) and H2O (0.20 mL) at 25 °C, then the mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 4-5 was consumed and the desired m / z (RT = 0.579 min) was detected. The mixture was concentrated to remove most of the THF, then the mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: YMC-Actus Triart C18150 mm × 30 mm, 7 µm; mobile phase: [water (FA)- acetonitrile]; gradient: 0%-30% acetonitrile over 9 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]-4-[2-[(1-isopropyl-4-piperidyl)amino]-5- methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 4, 106 mg, 164 μmol, 94.9% yield, 98.2% purity, 3FA) as a yellow solid. LC-MS: m / z = 495.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 9.10 (d, J = 8.4 Hz, 1H), 8.31 (s, 3H), 7.79 (s, 1H), 7.47 (s, 1H), 7.42 - 7.34 (m, 3H), 7.17 (d, J = 15.6 Hz, 2H), 6.50 (s, 1H), 6.16 (d, J = 6.0 Hz, 1H), 5.27 - 5.19 (m, 1H), 3.77 (d, J = 3.2 Hz, 1H), 3.22 - 3.11 (m, 2H), 3.08 - 2.97 (m, 3H), 2.61 (t, J = 10.8 Hz, 2H), 2.21 (s, 3H), 1.99 (d, J = 10.4 Hz, 2H), 1.60 - 1.49 (m, 2H), 1.10 (d, J = 6.4 Hz, 6H). Example 6: Synthesis of Target 5

[0129] Synthesis and Characterization of Compound 5-1. 45 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of 2,4-dibromo-5-methylpyridine (Compound a-1, 1.32 g, 5.26 mmol, 1 equiv.) and 1-(4-amino-1-piperidyl)ethanone (Compound 5, 898 mg, 6.31 mmol, 1.2 equiv.) in dioxane (13.2 mL) was added t-BuONa (1.01 g, 10.5 mmol, 2 equiv.), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 482 mg, 526 μmol, 0.1 equiv.) and Xantphos (609 mg, 1.05 mmol, 0.2 equiv.) at 25 °C under N2. The mixture was degassed and purged with N2three times. The mixture was heated to 100 °C and stirred at 100 °C for 4 h under N2. LC-MS showed Compound a-1 was consumed and the desired m / z (RT = 0.858 min) was detected. The mixture was cooled to 25 °C and poured into water (20.0 mL) at 25 °C then extracted three times with 50 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 15%-45% acetonitrile over 15 min). The eluent was concentrated under reduced pressure at 45 °C and extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-[4-[(4-bromo-5-methyl-2-pyridyl)amino]-1- piperidyl]ethanone (Compound 5-1, 922 mg, 2.95 mmol, 56.1% yield) as a white solid. LC- MS: m / z = 314.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 6.74 (s, 1H), 6.49 (d, J = 7.6 Hz, 1H), 4.19 (br d, J = 13.2 Hz, 1H), 3.94 - 3.82 (m, 1H), 3.75 (br d, J = 13.6 Hz, 1H), 3.23 - 3.05 (m, 1H), 2.85 - 2.72 (m, 1H), 2.12 (s, 3H), 2.04 - 1.97 (m, 3H), 1.94 - 1.81 (m, 2H), 1.37 - 1.14 (m, 2H).

[0130] Synthesis and Characterization of Compound 5-2. 46 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 5-1 (461 mg, 1.48 mmol, 1 equiv.) in dioxane (4.61 mL) and H2O (0.922 mL) was added Compound b (718 mg, 1.77 mmol, 1.2 equiv.), K3PO4(940 mg, 4.43 mmol, 3 equiv.) and Pd(dppf)Cl2 (108 mg, 148 μmol, 0.1 equiv.) at 25 °C under N2. The mixture was degassed and purged with N2three times. The mixture was heated to 90 °C and stirred at 90 °C for 6 h under N2. LC-MS showed Compound 5-1 was consumed and the desired m / z (RT = 1.031 mins) was detected. The mixture was cooled to 20 °C, the two batches was combined and poured into water (100 mL) at 20 °C and extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (3.00 mL) at 25 °C for 30 mins. The suspension was filtered, and the filter cake was concentrated to give methyl 4-[2-[(1-acetyl-4- piperidyl)amino]-5-methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 5-2, 1.30 g, crude) as a gray solid. LC-MS: m / z = 511.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.01 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 2.0 Hz, 1H), 6.56 (s, 1H), 6.23 (d, J = 7.6 Hz, 1H), 4.20 (br d, J = 12.8 Hz, 1H), 3.98 - 3.85 (m, 1H), 3.76 (br d, J = 14.4 Hz, 1H), 3.71 (s, 3H), 3.17 (br t, J = 11.2 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.42 (s, 3H), 2.19 (s, 3H), 2.00 (s, 3H), 1.97 - 1.79 (m, 2H), 1.42 - 1.15 (m, 2H).

[0131] Synthesis and Characterization of Compound 5-3.47 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 5-2 (1.30 g, 2.55 mmol, 1 equiv.) in THF (13.0 mL) and H2O (13.0 mL) was added LiOH•H2O (534 mg, 12.7 mmol, 5 equiv.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 5-2 was consumed completely and the desired m / z (RT = 1.302 mins) was detected. The reaction mixture was cooled to 25 °C and concentrated, then adjusted to pH 4. No solid precipitated out of the reaction solution, and the aqueous phase was lyophilized to give 4-[2-[(1-acetyl-4- piperidyl)amino]-5-methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylic acid (Compound 5-3, 1.30 g, crude) as a brown solid and used in the next step without further purification. LC-MS: m / z = 497.3 [M+H]+.

[0132] Synthesis and Characterization of Compound 5-4.To a solution of Compound 5-3 (1.30 g, 2.62 mmol, 1 equiv.) in THF (26.0 mL) was added TBAF (1.00 M, 7.85 mL, 3 equiv.) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 36 h. LC-MS showed 56.3% of Compound 5-3 (RT = 1.215 mins) remained and 18.1% of desired m / z (RT = 0.848 min) was detected. The mixture was cooled to 25 °C then TBAF (1.00 M, 15.7 mL, 6 equiv.) was added. The mixture was heated to 80 °C and stirred at 80 °C for 48 h. LC-MS showed 10.6% of Compound 5-3 (RT = 1.260 mins) remained and 46.9% of desired m / z (RT = 0.825 min) was detected. The mixture was cooled to 25 °C then TBAF (1.00 M, 15.7 mL, 6 equiv.) was added. The mixture was heated to 80 °C and stirred at 80 °C for 24 h. LC-MS showed Compound 5-3 was consumed completely and the desired m / z (RT = 0.844 min) was detected. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, CH2Cl2 / MeOH = 1 / 0 to 5 / 1, CH2Cl2 / MeOH = 5 / 1, Rf = 0.01) and the fraction was concentrated to give 4-[2-[(1-acetyl-4-piperidyl)amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 5-4, 860 mg, crude) as a yellow solid. LC-MS: m / z = 343.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6). δ 11.3 (br s, 1H), 7.73 (s, 1H), 6.89 (br s, 1H), 6.65 - 6.40 (m, 2H), 6.01 (br d, J = 8.0 Hz, 1H), 4.21 (br d, J = 12.4 Hz, 48 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 1H), 3.93 - 3.85 (m, 1H), 3.77 (br d, J = 13.6 Hz, 1H), 3.37 - 3.23 (m, 1H), 2.78 (br t, J = 11.2 Hz, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.97 - 1.82 (m, 2H), 1.28 - 1.15 (m, 2H).

[0133] Synthesis and Characterization of Compound 5-5.To a solution of Compound 5-4 (300 mg, 876 μmol, 1 equiv.) in NMP (6.00 mL) was added Compound 1-5 (245 mg, 1.05 mmol, 1.2 equiv., HCl), HOBt (142 mg, 1.05 mmol, 1.2 equiv.), EDCI (336 mg, 1.75 mmol, 2 equiv.), and DIEA (226 mg, 1.75 mmol, 305 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 5-4 was consumed completely and the desired m / z (RT = 1.000 mins) was detected. The reaction mixture was poured into water (30.0 mL) and a solid precipitated out of the mixture. The suspension was filtered, washed three times with 3.00 mL water, and dried to give 4-[2-[(1- acetyl-4-piperidyl)amino]-5-methyl-4-pyridyl]-N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-1H- pyrrole-2-carboxamide (Compound 5-5, 230 mg, 441 μmol, 50.4% yield) as a yellow solid, which was used in the next step without further purification. LC-MS: m / z = 521.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.43 - 7.34 (m, 3H), 7.21 (s, 1H), 7.19 - 7.13 (m, 1H), 6.52 (s, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.39 - 5.21 (m, 1H), 4.20 (br d, J = 12.8 Hz, 1H), 3.98 - 3.84 (m, 1H), 3.81 - 3.72 (m, 1H), 3.71 - 3.61 (m, 2H), 3.21 - 3.12 (m, 1H), 2.85 - 2.76 (m, 1H), 2.23 - 2.19 (m, 3H), 2.00 (s, 3H), 1.94 - 1.86 (m, 2H), 1.38 - 1.20 (m, 2H).

[0134] Synthesis and Characterization of Target 5. 49 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 5-5 (230 mg, 441 μmol, 1 equiv.) in THF (10.4 mL) and H2O (1.15 mL) was added PPh3 (174 mg, 662 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed that Compound 5-5 was consumed completely, and the desired m / z (RT = 0.750 min) was detected. The reaction mixture was concentrated to give the residue. The residue was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18150 mm × 40 mm, 10 µm; mobile phase: [water ( NH4HCO3)-acetonitrile]; gradient: 12%-42% acetonitrile over 52 min). The eluent was concentrated under reduced pressure at 40 °C and lyophilized to give 4-[2-[(1-acetyl-4-piperidyl)amino]-5-methyl-4-pyridyl]-N- [(1S)-2-amino-1-(3-chlorophenyl)ethyl]-1H-pyrrole-2-carboxamide (Target 5, 60.0 mg, 118.3 μmol, 26.8% yield, 97.5% purity) as a white solid. LC-MS: m / z = 495.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (br s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 7.39 - 7.27 (m, 3H), 7.23 (s, 1H), 7.14 (s, 1H), 6.53 (s, 1H), 6.12 (d, J = 8.0 Hz, 1H), 4.92 (q, J = 7.2 Hz, 1H), 4.20 (br d, J = 12.8 Hz, 1H), 4.00 - 3.84 (m, 1H), 3.81 - 3.71 (m, 1H), 3.22 - 3.12 (m, 1H), 2.86 (d, J = 6.8 Hz, 2H), 2.83 - 2.75 (m, 1H), 2.22 (s, 3H), 2.00 (s, 3H), 1.95 - 1.84 (m, 2H), 1.83 - 1.45 (m, 2H), 1.36 - 1.19 (m, 2H). Example 7: Synthesis of Target 6

[0135] Synthesis and Characterization of Compound 6-1. 50 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of 3-(diethylamino)propanoic acid (Compound 6-1a, 2.49 g, 13.7 mmol, 1.1 equiv., HCl) in CH2Cl2 (25.0 mL) was added DIEA (3.23 g, 25.0 mmol, 4.35 mL, 2 equiv.), EDCI (3.59 g, 18.7 mmol, 1.5 equiv.) and 4-dimethylaminopyridine (DMAP, 153 mg, 1.25 mmol, 0.1 equiv.) at 25 °C. Then tert-butyl N-(4-piperidyl) carbamate (Compound 6, 2.50 g, 12.5 mmol, 1 equiv.) was added to the mixture at 25 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed 1.8% of Compound 6-1 (RT = 0.426 min) remained and the desired m / z(RT = 0.478 min) was detected. The reaction mixture was poured into H2O (50.0 mL) and extracted two times with 50.0 mL CH2Cl2. The organic layers were combined and washed one time with 80.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition: column: Welch Ultimate XB-SiOH 250 mm × 70 mm, 10 µm; mobile phase: [Hexane-EtOH]; gradient: 1%-40% acetonitrile over 15 mins). The eluent was concentrated under reduced pressure to give tert-butyl N-[1-[3-(diethylamino)propanoyl]-4- piperidyl]carbamate (Compound 6-1, 3.00 g, 9.16 mmol, 73.4% yield) as yellow oil. LC- MS: m / z = 328.2 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 4.52 - 4.45 (m, 2H), 3.85 - 3.82 (m, 1H), 3.71 - 3.66 (m, 1H), 3.15 - 3.01 (m, 1H), 2.82 - 2.71 (m, 3H), 2.58 - 2.48 (m, 6H), 2.05 - 2.02 (m, 1H), 1.96 - 1.93 (m, 1H), 1.45 (s, 9H), 1.34 - 1.27 (m, 2H), 1.04 (t, J = 7.2 Hz, 6H).

[0136] Synthesis and Characterization of Compound 6-2. 51 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 6-1 (3.00 g, 9.16 mmol, 1 equiv.) was added HCl / dioxane (2.00 M, 30.0 mL, 6.55 equiv.) at 15 °C. The mixture was stirred at 15 °C for 12 h. LC-MS showed Compound 6-1 (RT = 0.488 min) remained and the desired m / z was detected. The product peak is in the front. The reaction mixture concentrated under reduced pressure. The residue was dissolved in H2O (40.0 mL) and adjusted to pH 8 with saturated NaHCO3solution. The aqueous phase was extracted three times with 30.0 mL CH2Cl2 / MeOH = 10 / 1. The organic phase was discarded, and the aqueous phase was lyophilized to give the crude product (3.00 g). The crude product (3.00 g) was washed one time with 100 mL acetonitrile, CH2Cl2 / MeOH = 10 / 1 (60.0 mL). The eluent was concentrated under reduced pressure to give 1-(4-amino-1-piperidyl)-3-(diethylamino)propan-1-one (Compound 6-2, 2.00 g, 8.80 mmol, 96.0% yield) as a white solid.1H NMR: (400 MHz, deuterated methanol (MeOD)) δ 4.58 - 4.55 (m, 1H), 4.04 - 4.01 (m, 1H), 3.31 - 3.23 (m, 1H), 3.22 - 3.15 (m, 3H), 3.02 - 2.97 (m, 4H), 2.87 - 2.71 (m, 3H), 2.07 - 2.02 (m, 2H), 1.60 - 1.51 (m, 1H), 1.47 - 1.40 (m, 1H), 1.24 (t, J = 7.2 Hz, 6H).

[0137] Synthesis and Characterization of Compound 6-3.52 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 6-2 (1.59 g, 7.01 mmol, 1.1 equiv.) and Compound a-1 (1.60 g, 6.38 mmol, 1 equiv.) in dioxane (16.0 mL) was added t-BuONa (1.23 g, 12.8 mmol, 2 equiv.), Pd2(dba)3(584 mg, 638 μmol, 0.1 equiv.) and Xantphos (738 mg, 1.28 mmol, 0.2 equiv.) at 20 °C under N2. The mixture was heated to 100 °C and stirred at 100 °C for 4 h under N2. LC-MS showed Compound 6-2 was consumed completely and the desired m / z (RT = 0.426 min) was detected. The reaction mixture was cooled to 25 °C. The mixture was poured into H2O (50.0 mL) and ethyl acetate (40.0 mL). The mixture was filtered to give the filtrate. The organic phase was separated, and the aqueous phase was extracted two times with 40.0 mL ethyl acetate. The organic layers were combined and washed one time with 100 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give 1-[4-[(4-bromo-5-methyl-2-pyridyl)amino]-1-piperidyl]-3- (diethylamino)propan-1-one (Compound 6-3, 1.00 g, 2.26 mmol, 35.4% yield, 89.8% purity) as pink oil. LC-MS: m / z =399.1 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.65 (s, 1H), 5.03 - 4.97 (m, 1H), 4.42 (d, J = 12.8 Hz, 1H), 3.89 - 3.78 (m, 2H), 3.33 - 3.20 (m, 3H), 3.12 - 3.06 (m, 4H), 3.01 - 2.89 (m, 3H), 2.22 (s, 3H), 2.12 - 2.01 (m, 2H), 1.50 - 1.37 (m, 2H), 1.32 (t, J = 7.2 Hz, 6H).

[0138] Synthesis and Characterization of Compound 6-4.A mixture of Compound 6-3 (1.10 g, 2.45 mmol, 1 equiv.), methyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Compound c, 738 mg, 2.94 mmol, 1.2 equiv.), K3PO4(1.56 g, 7.34 mmol, 3 equiv.), Pd(dppf)Cl2(179 mg, 245 μmol, 0.1 equiv.) in dioxane (22.0 mL) and H2O (4.40 mL) at 25 °C was degassed and purged with N2 for three 53 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) times, and then the mixture was heated to 90 °C stirred at 90 °C for 1.5 h under N2 atmosphere. LC-MS showed Compound 6-3 was consumed completely and the desired m / z (RT = 0.364 min) was detected. The reaction mixture was cooled to 25 °C. The mixture was poured into H2O (100 mL) and ethyl acetate (100 mL). The mixture was filtered to give the filtrate. The organic phase was separated, and the aqueous phase was extracted two times with 100 mL ethyl acetate. The organic layers were combined, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 2%-32% acetonitrile over 22 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give methyl 4-[2-[[1-[3-(diethylamino)propanoyl]-4-piperidyl]amino]-5- methyl-4-pyridyl]-1H-pyrrole-2-carboxylate (Compound 6-4, 900 mg, 1.80 mmol, 73.4% yield, 97.3% purity, FA) as an off-white. LC-MS: m / z = 442.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 7.79 (s, 1H), 7.27 (s, 1H), 7.00 (s, 1H), 6.52 (s, 1H), 6.06 (d, J = 6.8 Hz, 1H), 4.22 (d, J = 12.8 Hz, 1H), 3.97 - 3.76 (m, 5H), 3.18 (t, J = 11.6 Hz, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.89 - 2.73 (m, 5H), 2.69 - 2.59 (m, 2H), 2.01 - 1.84 (m, 2H), 1.39 - 1.19 (m, 2H), 1.09 - 1.05 (m, 6H).

[0139] Synthesis and Characterization of Compound 6-5.To a solution of Compound 6-4 (1.00 g, 2.20 mmol, 1 equiv.) in THF (10.0 mL) and H2O (2.00 mL) was added LiOH•H2O (462 mg, 11.0 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 60 h. LC-MS showed Compound 6-4 (RT = 0.935 min) remained. Then H2O (1.00 mL) was added to the mixture at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 6-4 (RT = 0.920 min) remained. Then H2O (1.00 mL) was 54 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) added to the mixture at 25 °C. The mixture was stirred at 25 °C for 5 h. LC-MS showed Compound 6-4 (RT = 0.941 min) remained. The mixture was stirred at 25 °C for 12 h. LC- MS showed Compound 6-4 (RT = 0.962 min) remained and the desired m / z (RT = 803 min) was detected. The reaction mixture was concentrated to remove THF, and the aqueous phase was adjusted to pH 5 using 1 M HCl. The aqueous phase was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)- acetonitrile]; gradient: 1%-25% acetonitrile over 15 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give 4-[2-[[1-[3-(diethylamino)propanoyl]-4-piperidyl]amino]-5-methyl-4-pyridyl]-1H- pyrrole-2-carboxylic acid (Compound 6-5, 650 mg, 1.51 mmol, 68.7% yield, 99.6% purity) as an off-white solid. LC-MS: m / z = 442.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.20 (dd, J = 4.8, 2.8 Hz, 1H), 6.92 (t, J = 2.0 Hz, 1H), 6.51 (s, 1H), 6.14 (d, J = 7.6 Hz, 1H), 4.23 (d, J = 13.6 Hz, 1H), 3.96 - 3.88 (m, 1H), 3.83 (d, J = 13.6 Hz, 1H), 3.17 (t, J = 11.6 Hz, 1H), 3.04 (t, J = 7.2 Hz, 2H), 2.95 - 2.81 (m, 5H), 2.75 - 2.64 (m, 2H), 2.18 (s, 3H), 1.92 (dd, J = 17.2, 2.8 Hz, 2H), 1.39 - 1.39 (m, 2H), 1.11 (t, J = 6.8 Hz, 6H).

[0140] Synthesis and Characterization of Compound 6-6.To a solution of Compound 6-5 (200 mg, 466 μmol, 1 equiv.) and Compound 1-5 (130 mg, 559 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added HOBt (75.6 mg, 559 μmol, 1.2 equiv.), EDCI (179 mg, 932 μmol, 2 equiv.) and DIEA (241 mg, 1.86 mmol, 325 μL, 4 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed 1.7% of 55 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Compound 6-5 (RT = 0.837 min) remained and the desired m / z (RT = 1.337 mins) was detected. The reaction mixture was poured into H2O (40.0 mL) and extracted five times with 30.0 mL ethyl acetate. The organic layers were combined, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2-azido-1-(3- chlorophenyl)ethyl]-4-[2-[[1-[3-(diethylamino)propanoyl]-4-piperidyl]amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Compound 6-6, 900 mg, crude) as yellow oil. LC-MS: m / z = 606.5 [M+H]+.

[0141] Synthesis and Characterization of Target 6.To a solution of Compound 6-6 (850 mg, 800 μmol, 1 equiv.) in THF (9.00 mL) and H2O (1.00 mL) was added PPh3(315 mg, 1.20 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 6-6 was consumed completely and the desired m / z (RT = 0.462 min) was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was dissolved in acetonitrile and filtered to give the filtrate. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: %-30% acetonitrile over 9 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give a product. The product was added H2O (30.0 mL). The aqueous phase was adjusted to pH 8 using NH3•H2O and extracted three times with 30.0 mL ethyl acetate. The organic layers were combined, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product. The product was added H2O (25.0 mL) and lyophilized to give N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]- 4-[2-[[1-[3-(diethylamino)propanoyl]-4-piperidyl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 6, 123 mg, 202 μmol, 26.6% yield, 95.1% purity) as an off-white solid. 56 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) LC-MS: m / z = 580.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.42 (s, 1H), 7.39 (s, 3H), 7.23 (s, 1H), 7.14 (s, 1H), 6.52 (s, 1H), 6.12 (d, J = 8.0 Hz, 1H), 4.99 - 4.94 (m, 1H) 4.22 (d, J = 12.4 Hz, 1H), 3.99 - 3.77 (m, 2H), 3.17 (t, J = 11.6 Hz, 1H), 2.97 - 2.85 (m, 2H), 2.80 (t, J = 11.2 Hz, 1H), 2.67 - 2.60 (m, 2H), 2.49 - 2.39 (m, 6H), 2.21 (s, 3H), 1.96 - 1.86 (m, 2H), 1.38 - 1.20 (m, 2H), 0.95 (t, J = 7.2 Hz, 6H). Example 8: Synthesis of Target 7

[0142] Synthesis and Characterization of Compound 7-1.A mixture of Compound a-1 (570 mg, 2.27 mmol, 1 equiv.), (3S,4S)-3- fluorotetrahydropyran-4-amine) (Compound 7, 424 mg, 2.73 mmol, 1.2 equiv., HCl), t- BuONa (437 mg, 4.54 mmol, 2 equiv.), Pd2(dba)3 (208 mg, 227 μmol, 0.1 equiv.) and Xantphos (263 mg, 454 μmol, 0.2 equiv.) in dioxane (6.00 mL) was degassed and purged with N2 three times at 20 °C, and then the mixture was heated to 100 °C and stirred at 100 °C for 4 h under N2 atmosphere. LC-MS showed Compound a-1 was consumed and the desired m / z (RT = 0.357 min) was detected. The mixture was cooled to 25 °C and filtered with the injector. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 8%-38% acetonitrile over 15 min), then it was lyophilized. The product 4-bromo-N-[(3S,4S)-3- fluorotetrahydropyran-4-yl]-5-methyl-pyridin-2-amine (Compound 7-1, 350 mg, 1.21 mmol, 53.3% yield, 100% purity) was obtained as a white solid. LC-MS: m / z = 291.0 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.71 (s, 1H), 4.77 - 4.65 (m, 2H), 4.23 - 4.16 (m, 2H), 4.07 - 4.03 (m, 1H), 3.68 - 3.55 (m, 2H), 2.23 (s, 3H), 1.98 - 1.87 (m, 2H).

[0143] Synthesis and Characterization of Compound 7-2. 57 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound 7-1 (350 mg, 1.21 mmol, 1 equiv.), Compound b (589 mg, 1.45 mmol, 1.2 equiv.), K3PO4(771 mg, 3.63 mmol, 3 equiv.), Pd(dppf)Cl2(88.6 mg, 121 μmol, 0.1 equiv.) in dioxane (3.50 mL) and H2O (0.70 mL) was degassed and purged with N2three times at 25 °C, and then the mixture was heated to 90 °C and stirred at 90 °C for 12 h under N2 atmosphere. LC-MS showed 12.3% of Compound 7-1 (RT = 0.348 min) remained and the desired m / z (RT = 0.461min) was detected. The mixture was cooled to 25 °C and poured into H2O (20.0 mL), then the aqueous phase was extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed one time with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)- acetonitrile]; gradient: 20%-50% acetonitrile over 15 min). Then the mixture was adjusted pH to 8 with NaHCO3, concentrated to remove most of acetonitrile, and extracted three times with 10.0 mL ethyl acetate. The organic layers were combined and washed one time with 100 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The product methyl 4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1-(p- tolylsulfonyl)pyrrole-2-carboxylate (Compound 7-2, 530 mg, 1.09 mmol, 89.8% yield, 100% purity) was obtained as a brown solid. LC-MS: m / z = 488.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.01 - 7.96 (m, 3H), 7.86 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 2.0 Hz, 1H), 6.72 (s, 1H), 6.33 (d, J = 8.4 Hz, 1H), 4.79 - 4.67 (m, 1H), 4.21 - 4.14 (m, 1H), 3.98 (br t, J = 12.0 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.72 (s, 3H), 3.64 - 3.48 (m, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 1.79 - 1.73 (m, 1H), 1.66 - 1.59 (m, 1H).

[0144] Synthesis and Characterization of Compound 7-3. 58 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 7-2 (500 mg, 1.03 mmol, 1 equiv.) in H2O (5.00 mL) and THF (5.00 mL) was added LiOH•H2O (215 mg, 5.13 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 7-2 was consumed and the desired m / z (RT = 0.431 min) was detected. The mixture was concentrated to give crude product. The crude product was used in the next step without further purification. The product 4-[2- [[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1-(p- tolylsulfonyl)pyrrole-2-carboxylic acid (Compound 7-3, 485 mg, crude) was obtained as a brown solid. LC-MS: m / z = 474.1 [M+H]+.

[0145] Synthesis and Characterization of Compound 7-4.To a solution of Compound 7-3 (485 mg, 1.02 mmol, 1 equiv.) in THF (5.00 mL) and H2O (5.00 mL) was added NaOH (205 mg, 5.12 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 h. LC-MS showed Compound 7-3 was consumed and the desired m / z (RT = 0.566 min) was detected. The mixture was cooled to 25 °C and concentrated to remove most of THF, then adjusted to pH to 3-4 with 1 M HCl, filtered, and the filter cake was concentrated to get crude product. The crude product was used in the next step without further purification. The product 4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4- yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 7-4, 280 mg, crude) was obtained as a brown solid. LC-MS: m / z = 320.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.5 - 12.4 (m, 1H), 12.1 (br s, 1H), 7.79 (s, 1H), 7.23 (s, 1H), 6.95 (s, 1H), 6.68 59 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (s, 1H), 6.33 - 6.28 (m, 1H), 4.79 - 4.67 (m, 1H), 4.28 - 4.08 (m, 1H), 3.98 (br t, J = 12.4 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.65 - 3.45 (m, 2H), 2.19 (s, 3H), 1.87 - 1.61 (m, 2H).

[0146] Synthesis and Characterization of Compound 7-5.To a solution of Compound 7-4 (140 mg, 358 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound 1-5 (111 mg, 430 μmol, 1.2 equiv., HCl), HOBt (58.1 mg, 430 μmol, 1.2 equiv.), EDCI (137 mg, 716 μmol, 2 equiv.), and DIEA (92.6 mg, 716 μmol, 125 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 7-4 was consumed and the desired m / z (RT = 0.543min) was detected. The mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed one time with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used to next without purification. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2-[[(3S,4S)-3- fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 7-5, 218 mg, crude) was obtained as brown oil. LC-MS: m / z = 498.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.79 - 8.55 (m, 1H), 7.79 (s, 1H), 7.58 - 7.50 (m, 1H), 7.38 - 7.32 (m, 2H), 7.25 - 7.12 (m, 2H), 6.66 (s, 1H), 6.30 (br d, J = 8.4 Hz, 1H), 5.37 - 5.22 (m, 1H), 4.81 - 4.64 (m, 1H), 4.25 - 4.08 (m, 1H), 4.05 - 3.99 (m, 2H), 3.91 - 3.83 (m, 1H), 3.70 - 3.60 (m, 2H), 3.54 - 3.44 (m, 2H), 2.15 - 2.09 (m, 2H), 1.99 (s, 3H).

[0147] Synthesis and Characterization of Target 7. 60 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 7-5 (218 mg, 398 μmol, 1 equiv.) in THF (2.70 mL) and H2O (0.30 mL) was added PPh3(156 mg, 596 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 7-5 was consumed and the desired m / z (RT = 0.379 min) was detected. The mixture was concentrated to remove most of THF and filtered with the injector. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 9 min), then it was lyophilized. The product N-[(1S)-2-amino-1-(3- chlorophenyl)ethyl]-4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Target 7, 72.6 mg, 139 μmol, 34.9% yield, 99.1% purity, FA) was obtained as an off-white solid. LC-MS: m / z = 472.2 [M+H]+.1H NMR: EW52655-38-P1A2 (400 MHz, DMSO-d6) δ 11.9 - 11.7 (m, 1H), 8.85 - 8.57 (m, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 7.42 - 7.32 (m, 4H), 7.21 - 7.12 (m, 2H), 6.66 (s, 1H), 6.27 (d, J = 4.0 Hz, 1H), 5.17 - 5.05 (m, 1H), 4.86 - 4.63 (m, 1H), 4.27 - 4.13 (m, 1H), 4.02 - 3.98 (m, 1H), 3.89 - 3.86 (m, 1H), 3.62 (br d, J = 13.2 Hz, 1H), 3.55 - 3.47 (m, 2H), 3.07 - 3.01 (m, 2H), 2.22 (s, 3H), 1.85 - 1.73 (m, 1H), 1.69 - 1.62 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ - 204.018. Example 9: Synthesis of Target 8

[0148] Synthesis and Characterization of Compound 8-1..61 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) A mixture of Compound a-1 (570 mg, 2.27 mmol, 1 equiv.), (3R,4R)-3- fluorotetrahydropyran-4-amine (Compound 8, 424 mg, 2.73 mmol, 1.2 equiv., HCl), t- BuONa (437 mg, 4.54 mmol, 2 equiv.), Pd2(dba)3(208 mg, 227 μmol, 0.1 equiv.) and Xantphos (263 mg, 454 μmol, 0.2 equiv.) in dioxane (6.00 mL) was degassed and purged with N2 three times at 20 °C, and then the mixture was heated to 100 °C and stirred at 100 °C for 4 h under N2atmosphere. LC-MS showed Compound a-1 was consumed and the desired m / z (RT = 0.341min) was detected. The mixture was cooled to 25 °C and filtered with the injector. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 12%-42% acetonitrile over 15 min), then it was lyophilized. The product 4-bromo-N-[(3R,4R)-3- fluorotetrahydropyran-4-yl]-5-methyl-pyridin-2-amine (Compound 8-1, 400 mg, 1.38 mmol, 60.9% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.70 (s, 1H), 4.96 - 4.56 (m, 2H), 4.28 - 3.99 (m, 3H), 3.78 - 3.52 (m, 2H), 2.23 (s, 3H), 2.00 - 1.82 (m, 2H).

[0149] Synthesis and Characterization of Compound 8-2.A mixture of Compound 8-1 (410 mg, 1.42 mmol, 1 equiv.), Compound b (690 mg, 1.70 mmol, 1.2 equiv.), K3PO4(903 mg, 4.25 mmol, 3 equiv.), Pd(dppf)Cl2(104 mg, 142 μmol, 0.1 equiv.) in dioxane (5.00 mL) and H2O (1.00 mL) at 25 °C was degassed and purged with N2 three times, and then the mixture was heated to 90 °C stirred at 90 °C for 6 h under N2 atmosphere. LC-MS showed Compound 8-1 was consumed completely and the desired m / z (RT = 0.466 min) was detected. The mixture was cooled to 25 °C and poured into water (20.0 mL) then extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 20%-50% acetonitrile over 22 min) and the eluent was concentrated under 45 °C to remove acetonitrile. The aqueous phase was adjusted to a pH of 62 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) about 7-8 by saturated NaHCO3 solution then extracted three times with 10.0 mL ethyl acetate. The organic layers were combined and washed three times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 4-[2- [[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1-(p- tolylsulfonyl)pyrrole-2-carboxylate (Compound 8-2, 600 mg, 1.23 mmol, 86.8% yield) as a yellow solid. LC-MS: m / z = 488.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.87 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 1.6 Hz, 1H), 6.75 (s, 1H), 6.57 - 6.30 (m, 1H), 4.88 - 4.58 (m, 1H), 4.27 - 4.10 (m, 1H), 4.02 - 3.94 (m, 1H), 3.89 (br d, J = 7.6 Hz, 1H), 3.72 (s, 3H), 3.56 - 3.44 (m, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 1.82 - 1.74 (m, 1H), 1.71 - 1.61 (m, 1H).

[0150] Synthesis and Characterization of Compound 8-3.To a solution of Compound 8-2 (600 mg, 1.23 mmol, 1 equiv.) in THF (12.0 mL) and H2O (12.0 mL) was added NaOH (246 mg, 6.15 mmol, 5 equiv.) at 25 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 12 h. LC-MS showed Compound 8-2 was consumed and the desired m / z (RT = 0.811 min) was detected. The reaction mixture was cooled to 25 °C and concentrated to remove THF. The aqueous phase was adjusted pH 4-5 using 1 M HCl. Solid precipitated out of the reaction solution, the solid was filtered, and the filter cake was dried to give 4-[2-[[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 8-3, 400 mg, crude) as a gray solid and used in the next step without further purification. LC-MS: m / z = 320.2 [M+H]+.1H NMR: EW52658-7-P1A (400 MHz, DMSO-d6) δ 12.0 (br s, 1H), 7.78 (s, 1H), 7.31 - 7.14 (m, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 6.20 (br d, J = 8.4 Hz, 1H), 4.95 - 4.58 (m, 1H), 4.28 - 4.08 (m, 1H), 3.98 (br t, J = 12.0 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.56 - 3.44 (m, 2H), 2.19 (s, 3H), 1.79 - 1.75 (m, 1H), 1.70 - 1.61 (m, 1H).

[0151] Synthesis and Characterization of Compound 8-4. 63 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 8-3 (150 mg, 470 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound 1-5 (131 mg, 564 μmol, 1.2 equiv., HCl), HOBt (76.2 mg, 564 μmol, 1.2 equiv.), EDCI (180 mg, 939 μmol, 2 equiv.), and DIEA (121 mg, 939 μmol, 164 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 8-3 was consumed and the desired m / z (RT = 0.448 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2-azido-1-(3- chlorophenyl)ethyl]-4-[2-[[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Compound 8-4, 233 mg, crude) as yellow oil and used in the next step without further purification. LC-MS: m / z = 498.1 [M+H]+.

[0152] Synthesis and Characterization of Target 8.To a solution of Compound 8-4 (233 mg, 468 μmol, 1 equiv.) in THF (4.20 mL) and H2O (0.46 mL) was added PPh3 (184 mg, 702 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 8-4 was consumed and the desired m / z (RT = 0.378 min) was detected. The reaction mixture was concentrated to give the residue. The residue was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18150 mm × 64 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 40 mm, 10 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 20%-50% acetonitrile over 52 min). The eluent was concentrated under reduced pressure at 40 °C and lyophilized to give N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]-4-[2-[[(3R,4R)-3- fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 8, 88.2 mg, 185 μmol, 39.5% yield, 98.9% purity) as a gray solid. LC-MS: m / z = 472.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 7.37 - 7.27 (m, 3H), 7.23 (s, 1H), 7.13 (s, 1H), 6.72 - 6.63 (m, 1H), 6.25 (d, J = 8.0 Hz, 1H), 5.01 - 4.86 (m, 1H), 4.82 - 4.58 (m, 1H), 4.31 - 4.08 (m, 1H), 3.98 (br t, J = 12.4 Hz, 1H), 3.89 (br dd, J = 11.2, 3.6 Hz, 1H), 3.65 - 3.45 (m, 2H), 2.90 - 2.82 (m, 2H), 2.22 (s, 3H), 1.78 (dt, J = 12.4, 8.4 Hz, 1H), 1.70 - 1.63 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ -204.053. Example 10: Synthesis of Target 9

[0153] Synthesis and Characterization of Compound 9-1.To a solution of Compound 1-3 (200 mg, 771 μmol, 1 equiv.) in NMP (2.00 mL) was added tert-butyl N-[(2S)-2-aminopropyl]carbamate (Compound e, 161 mg, 925 μmol, 1.2 equiv.), HOBt (125 mg, 925 μmol, 1.2 equiv.), EDCI (296 mg, 1.54 mmol, 2 equiv.), and DIEA (199 mg, 1.54 mmol, 269 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 1-3 was consumed and the desired m / z (RT = 0.424 min) was detected. The mixture was filtered with the injector. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 12%-42% acetonitrile over 15 min), then it was lyophilized. The product tert-butyl N-[(2S)-2-[[4-[2-(isopropylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2- carbonyl]amino]propyl]carbamate (Compound 9-1, 300 mg, 636 μmol, 82.5% yield, 97.9% purity, FA) was obtained as a white solid. LC-MS: m / z = 416.1 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 9.81 - 9.78 (m, 1H), 7.60 (s, 1H), 7.40 (br d, J = 5.6 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 6.88 (s, 1H), 6.58 (s, 1H), 5.02 - 5.01 (m, 1H), 4.15 (s, 1H), 3.78 - 3.72 (m, 1H), 65 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 3.35 - 3.26 (m, 3H), 2.28 (s, 3H), 1.41 (s, 9H), 1.32 (d, J = 6.0 Hz, 6H), 1.27 (d, J = 6.4 Hz, 3H).

[0154] Synthesis and Characterization of Target 9.To a solution of Compound 9-1 (270 mg, 636 μmol, 1.0 equiv., FA) in dioxane (3.00 mL) was added HCl / dioxane (2.00 M, 5.87 mL, 18.4 equiv.). The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 9-1 was consumed and the desired m / z (RT = 0.537 min) was detected. The mixture was concentrated. The crude product was purified by prep- HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 18%-48% acetonitrile over 11 min), then it was lyophilized. The product N-[(1S)-2-amino-1-methyl-ethyl]-4-[2-(isopropylamino)-5-methyl- 4-pyridyl]-1H-pyrrole-2-carboxamide (Target 9, 50.1 mg, 159 μmol, 34.6% yield, 100% purity) was obtained as a white solid. LC-MS: m / z = 316.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.69 - 11.67 (m, 1H), 7.77 - 7.72 (m, 2H), 7.09 (s, 2H), 6.44 (s, 1H), 5.86 (d, J = 8.0 Hz, 1H), 3.96 - 3.88 (m, 2H), 2.65 - 2.54 (m, 2H), 2.19 (s, 3H), 1.13 - 1.06 (m, 9H). Example 11: Synthesis of Target 10

[0155] Synthesis and Characterization of Compound 10-1.To a solution of Compound 2-3 (250 mg, 829 μmol, 1 equiv.) in NMP (2.50 mL) was added Compound e (173 mg, 995 μmol, 1.2 equiv.), HOBt (134 mg, 995 μmol, 1.2 equiv.), EDCI (318 mg, 1.66 mmol, 2 equiv.) and DIEA (214 mg, 1.66 mmol, 289 μL, 2 equiv.) at 0 °C. 66 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 2-3 was consumed and the desired m / z (RT = 0.409 min) was detected. The mixture was filtered with the injector. The filtrate was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 10%-40% acetonitrile over 15 min), then it was lyophilized. The product tert-butyl N-[(2S)-2-[[4-[5-methyl-2- (tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carbonyl]amino]propyl]carbamate (Compound 10-1, 265 mg, 526 μmol, 63.4% yield, 100% purity, FA) was obtained as a white solid. LC-MS: m / z = 458.2 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 9.86 - 9.79 (m, 1H), 7.60 (s, 1H), 7.40 (br d, J = 5.6 Hz, 1H), 7.18 (br d, J = 0.8 Hz, 1H), 6.88 (s, 1H), 6.58 (s, 1H), 5.02 - 5.00 (m, 1H), 4.20 - 4.11 (m, 1H), 3.77 - 3.66 (m, 1H), 3.35 - 3.26 (m, 3H), 2.28 (s, 3H), 1.41 (s, 9H), 1.32 (br d, J = 6.0 Hz, 6H), 1.27 (d, J = 6.4 Hz, 3H).

[0156] Synthesis and Characterization of Target 10.To a solution of Compound 10-1 (235 mg, 467 μmol, 1.0 equiv., FA) in dioxane (2.50 mL) was added HCl / dioxane (2.00 M, 4.54 mL, 19.4 equiv.). The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 10-1 was consumed and the desired m / z (RT = 0.482 min) was detected. The mixture was concentrated. The crude product was purified by prep- HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 10%-40% acetonitrile over 11 min), then it was lyophilized. The product N-[(1S)-2-amino-1-methyl-ethyl]-4-[5-methyl-2-(tetrahydropyran- 4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 10, 45.8 mg, 127 μmol, 77.1% yield, 98.9% purity) was obtained as an off-white solid. LC-MS: m / z = 358.2 [M+H]+.1H NMR: EW52655-19-P1A3 (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.49 (br d, J = 7.2 Hz, 1H), 7.08 - 7.03 (m, 2H), 6.51 (s, 1H), 5.75 (br d, J = 7.6 Hz, 1H), 3.92 - 3.85 (m, 4H), 3.46 - 3.40 (m, 2H), 2.66 - 2.63 (m, 2H), 2.21 (s, 3H), 1.89 (br dd, J = 11.6, 2.0 Hz, 2H), 1.47 - 1.43 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H). 67 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Example 12: Synthesis of Target 11

[0157] Synthesis and Characterization of Compound 11-1.A mixture of Compound 3-4 (120 mg, 382 μmol, 1 equiv.) and Compound e (79.8 mg, 458 μmol, 1.2 equiv.) in NMP (1.00 mL) was added HOBt (61.9 mg, 458 μmol, 1.2 equiv.), EDCI (146 mg, 763 μmol, 2 equiv.) and DIEA (98.7 mg, 763 μmol, 133 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 3-4 was consumed and the desired m / z (RT = 0.593 min) was detected. The mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18 150 mm × 40 mm, 10 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 16%- 46% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give tert-butyl N- [(2S)-2-[[4-[5-methyl-2-[(1-methyl-4-piperidyl)amino]-4-pyridyl]-1H-pyrrole-2- carbonyl]amino]propyl]carbamate (Compound 11-1, 70.0 mg, 149 μmol, 38.9% yield, 100% purity) as a white solid. LC-MS: m / z = 471.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 7.82 - 7.73 (m, 2H), 7.12 - 6.98 (m, 2H), 6.88 (t, J = 5.2 Hz, 1H), 6.46 (s, 1H), 5.95 (d, J = 8.0 Hz, 1H), 4.12 - 3.93 (m, 1H), 3.67 - 3.52 (m, 1H), 3.04 (t, J = 6.0 Hz, 2H), 2.75 - 2.64 (m, 2H), 2.17 (d, J = 12.4 Hz, 6H), 2.02 - 1.92 (m, 2H), 1.89 - 1.80 (m, 2H), 1.43 - 1.33 (m, 11H), 1.08 (d, J = 6.8 Hz, 3H).

[0158] Synthesis and Characterization of Target 11.68 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 11-1 (70.0 mg, 149 μmol, 1 equiv.) in dioxane (1.00 mL) was added HCl / dioxane (1.00 mL, 2.00 M) at 25 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 11-1 was consumed and the desired m / z (RT = 0.367 min) was detected. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (HCl)-acetonitrile]; gradient: 0%-20% acetonitrile over 18 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-methyl-ethyl]-4-[5- methyl-2-[(1-methyl-4-piperidyl)amino]-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 11, 59.0 mg, 121 μmol, 81.6% yield, 98.8% purity, 3HCl) as an off-white solid. LC-MS: m / z = 371.2 [M+H]+.1H NMR: (400 MHz, MeOD) δ 7.73 (s, 1H), 7.63 - 7.46 (m, 2H), 7.41 - 7.14 (m, 1H), 4.44 - 4.29 (m, 1H), 4.22 - 3.98 (m, 1H), 3.67 - 3.33 (m, 4H), 3.28 (s, 1H), 3.19 - 3.07 (m, 2H), 3.01 - 2.90 (m, 3H), 2.49 - 2.40 (m, 3H), 2.38 - 2.21 (m, 2H), 2.19 - 1.86 (m, 2H), 1.37 (d, J = 6.8 Hz, 3H). Example 13: Synthesis of Target 12

[0159] Synthesis and Characterization of Compound 12-1.A mixture of Compound 4-4 (140 mg, 409 μmol, 1 equiv.) and Compound e (85.5 mg, 491 μmol, 1.2 equiv.) in NMP (1.00 mL) was added HOBt (66.3 mg, 491 μmol, 1.2 equiv.), EDCI (157 mg, 818 μmol, 2 equiv.) and DIEA (106 mg, 818 μmol, 142 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 4-4 (RT = 0.322 min) remained and the desired m / z (RT = 0.656 min) was detected. The mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18150 mm × 40 mm, 10 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 16%-46% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give tert- 69 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) butyl N-[(2S)-2-[[4-[2-[(1-isopropyl-4-piperidyl)amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carbonyl]amino]propyl]carbamate (Compound 12-1, 90.0 mg, 181 μmol, 44.1% yield, 100% purity) as a yellow solid. LC-MS: m / z = 499.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 7.84 - 7.71 (m, 2H), 7.14 - 7.00 (m, 2H), 6.88 (t, J = 5.6 Hz, 1H), 6.46 (s, 1H), 5.93 (d, J = 7.6 Hz, 1H), 4.12 - 3.93 (m, 1H), 3.69 - 3.53 (m, 1H), 3.13 - 2.95 (m, 2H), 2.82 - 2.60 (m, 3H), 2.25 - 2.10 (m, 5H), 1.87 (d, J = 10.8 Hz, 2H), 1.43 - 1.29 (m, 11H), 1.08 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.4 Hz, 6H).

[0160] Synthesis and Characterization of Target 12.To a solution of Compound 12-1 (80.0 mg, 160 μmol, 1 equiv.) in dioxane (1.00 mL) was added HCl / dioxane (1.00 mL, 2.00 M) at 25 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 12-1 (RT = 0.416 min) remained and the desired m / z (RT = 0.310 min) was detected. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (HCl)-acetonitrile]; gradient: 0%-20% acetonitrile over 18 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1- methyl-ethyl]-4-[2-[(1-isopropyl-4-piperidyl)amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 12, 51.6 mg, 100 μmol, 62.8% yield, 99.1% purity, 3HCl) as an off- white solid. LC-MS: m / z = 399.3 [M+H]+.1H NMR: (400 MHz, MeOD) δ 7.74 (s, 1H), 7.63 - 7.48 (m, 2H), 7.44 - 7.16 (m, 1H), 4.40 - 4.07 (m, 2H), 3.65 - 3.34 (m, 5H), 3.20 - 3.06 (m, 2H), 2.45 - 2.32 (m, 5H), 2.22 - 1.93 (m, 2H), 1.47 - 1.35 (m, 9H). Example 14: Synthesis of Target 13

[0161] Synthesis and Characterization of Compound 13-1. 70 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 5-3 (480 mg, 1.40 mmol, 1 equiv.) in NMP (4.80 mL) was added Compound e (293 mg, 1.68 mmol, 1.2 equiv.), HOBt (227 mg, 1.68 mmol, 1.2 equiv.), EDCI (537 mg, 2.80 mmol, 2 equiv.) and DIEA (362 mg, 2.80 mmol, 488 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 5-3 was consumed completely and the desired m / z (RT = 0.836 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted six times with 20.0 mL ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (TFA)-acetonitrile]; gradient: 0%-18% acetonitrile over 10 min). The eluent was concentrated under reduced pressure at 40 °C and lyophilized to give tert-butyl N-[(2S)-2-[[4-[2-[(1-acetyl-4-piperidyl)amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carbonyl]amino]propyl]carbamate (Compound 13-1, 100 mg, 201 μmol, 76.9% yield) as a white solid. LC-MS: m / z = 499.5 [M+H]+.

[0162] Synthesis and Characterization of Target 13.To a solution of Compound 13-1 (100 mg, 201 μmol, 1 equiv.) in dioxane (10.0 mL) was added HCl / dioxane (2.00 M, 1.00 mL, 9.97 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 13-1 was consumed completely and the desired m / z (RT = 0.537 min) was detected. The reaction mixture was concentrated then adjusted to pH 8 using NH3•H2O and concentrated to give the residue. The residue was purified by prep- 71 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 20%-50% acetonitrile over 11 min). The eluent was concentrated under reduced pressure at 40 °C and lyophilized to give 4-[2-[(1-acetyl-4- piperidyl)amino]-5-methyl-4-pyridyl]-N-[(1S)-2-amino-1-methyl-ethyl]-1H-pyrrole-2- carboxamide (Target 13, 20.8 mg, 52.0 μmol, 25.9% yield, 99.6% purity) as a white solid. LC-MS: m / z = 399.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.64 - 7.32 (m, 1H), 7.06 (br d, J = 18.8 Hz, 2H), 6.52 (s, 1H), 5.78 (br d, J = 7.2 Hz, 1H), 4.34 - 3.66 (m, 4H), 2.71 - 2.59 (m, 2H), 2.21 (s, 3H), 2.00 (s, 3H), 1.97 - 1.84 (m, 2H), 1.42 - 1.24 (m, 2H), 1.14 (br d, J = 6.8 Hz, 3H). Example 15: Synthesis of Target 14

[0163] Synthesis and Characterization of Compound 14-1.To a solution of Compound 6-5 (400 mg, 932 μmol, 1 equiv.) in NMP (4.00 mL) was added Compound e (195 mg, 1.12 mmol, 1.2 equiv.), HOBt (151 mg, 1.12 mmol, 1.2 equiv.), EDCI (357 mg, 1.86 mmol, 2 equiv.) and DIEA (361 mg, 2.80 mmol, 487 μL, 3 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 6-5 was consumed completely and the desired m / z (RT = 1.127 mins) was detected. The reaction mixture was poured into H2O (40.0 mL) and extracted five times with 30.0 mL ethyl acetate. The organic layers were combined, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 2%-32% acetonitrile over 22 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give tert-butyl N-[(2S)- 72 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 2-[[4-[2-[[1-[3-(diethylamino)propanoyl]-4-piperidyl]amino]-5-methyl-4-pyridyl]-1H- pyrrole-2-carbonyl]amino]propyl]carbamate (Compound 14-1, 330 mg, 538 μmol, 57.7% yield, 95.1% purity) as a yellow solid. LC-MS: m / z = 584.5 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 7.96 - 7.67 (m, 2H), 7.15 - 7.07 (m, 1H), 7.04 (s, 1H), 6.89 (t, J = 6.0 Hz, 1H), 6.49 (s, 1H), 6.12 (d, J = 7.6 Hz, 1H), 4.22 (d, J = 13.2 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.94 - 3.88 (m, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.17 (t, J = 11.2 Hz, 1H), 3.04 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 11.2 Hz, 1H), 2.78 - 2.69 (m, 4H), 2.65 - 2.56 (m, 2H), 2.20 (s, 3H), 2.00 - 1.80 (m, 2H), 1.36 (s, 9H), 1.26 - 1.16 (m, 1H), 1.09 - 1.03 (m, 7H).

[0164] Synthesis and Characterization of Target 14.To a solution of Compound 14-1 (150 mg, 244 μmol, 1 equiv.) in dioxane (1.50 mL) was added HCl / dioxane (2.00 M, 1.43 mL, 11.7 equiv.). The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 14-1 was consumed completely and the desired m / z (RT = 0.391 min) was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Agela DuraShell C18150 mm × 25 mm, 5 µm; mobile phase: [water (HCl)-acetonitrile]; gradient: 0%-25% acetonitrile over 20 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give N-[(1S)-2-amino-1-methyl-ethyl]-4-[2-[[1-[3- (diethylamino)propanoyl]-4-piperidyl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 14, 66.0 mg, 111 μmol, 52.0% yield, 99.8% purity, 3HCl) as an off- white solid. LC-MS: m / z = 484.3 [M+H]+.1H NMR: (400 MHz, MeOD) δ 7.69 (s, 1H), 7.50 (d, J = 4.4 Hz, 2H), 7.16 (s, 1H), 4.51 (d, J = 13.2 Hz, 1H), 4.43 - 4.31 (m, 1H), 4.06 - 73 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 3.88 (m, 2H), 3.41 (s, 3H), 3.30 - 3.25 (m, 4H), 3.18 - 3.09 (m, 2H), 3.07 - 2.95 (m, 3H), 2.40 (s, 3H), 2.20 - 2.05 (m, 2H), 1.71 - 1.51 (m, 2H), 1.34 (d, J = 2.0 Hz, 9H). Example 16: Synthesis of Target 15

[0165] Synthesis and Characterization of Compound 15-1.To a solution of Compound 7-4 (140 mg, 358 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound e (74.9 mg, 430 μmol, 1.2 equiv.), HOBt (58.1 mg, 430 μmol, 1.2 equiv.), EDCI (137 mg, 716 μmol, 2 equiv.), and DIEA (92.6 mg, 716 μmol, 125 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 7-4 was consumed and the desired m / z (RT = 0.617 min) was detected. The mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed one time with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The filtrate was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 20%-50% acetonitrile over 12 min), then it was lyophilized. The product tert-butyl N-[(2S)-2-[[4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H- pyrrole-2-carbonyl]amino]propyl]carbamate (Compound 15-1, 90.0 mg, 189 μmol, 52.8% yield, 100% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.75 - 11.74 (m, 1H), 7.87 - 7.75 (m, 2H), 7.14 - 7.01 (m, 2H), 6.90 (br t, J = 6.4 Hz, 1H), 6.63 (s, 1H), 6.22 (d, J = 8.8 Hz, 1H), 4.82 - 4.63 (m, 1H), 4.24 - 4.08 (m, 1H), 4.07 - 3.94 (m, 2H), 3.88 (br d, J = 8.0 Hz , 1H), 3.67 - 3.42 (m, 2H), 3.04 (br t, J = 6.0 Hz, 2H), 2.20 (s, 3H), 1.83 - 1.71 (m, 1H), 1.68 - 1.60 (m, 1H), 1.42 - 1.30 (m, 9H), 1.13 - 1.03 (m, 3H).19F NMR: (400 MHz, DMSO-d6) δ -204.024.

[0166] Synthesis and Characterization of Target 15. 74 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 15-1 (80.0 mg, 168 μmol, 1 equiv.) in dioxane (2.00 mL) was added HCl / dioxane (2.00 M, 4.00 mL, 47.6 equiv.). The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 15-1 was consumed and the desired m / z (RT = 0.472 min) was detected. The mixture was concentrated to give the crude product. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 12%-42% acetonitrile over 12 min), then it was lyophilized. The product N-[(1S)-2-amino-1-methyl-ethyl]-4-[2-[[(3S,4S)-3- fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 15, 50.2 mg, 134 μmol, 79.4% yield, 99.9% purity) was obtained as a white solid. LC-MS: m / z = 376.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.48 (br d, J = 7.6 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.65 (s, 1H), 5.85 (br d, J = 8.4 Hz, 1H), 4.86 - 4.64 (m, 1H), 4.27 - 4.10 (m, 1H), 4.05 - 3.85 (m, 3H), 3.66 - 3.46 (m, 2H), 2.72 - 2.58 (m, 2H), 2.22 (s, 3H), 1.85 - 1.77 (m, 1H), 1.74 - 1.67 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H).19F NMR: (400 MHz, DMSO- d6) δ -203.988. Example 17: Synthesis of Target 16

[0167] Synthesis and Characterization of Compound 16-1.To a solution of Compound 8-3 (150 mg, 470 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound e (98.2 mg, 564 μmol, 1.2 equiv.), HOBt (76.2 mg, 564 μmol, 1.2 equiv.), EDCI (180 mg, 939 μmol, 2 equiv.), and DIEA (121 mg, 939 μmol, 164 μL, 2 equiv.) at 0 °C. The 75 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 8-3 was consumed and the desired m / z (RT = 0.400 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl N-[(2S)-2-[[4-[2-[[(3R,4R)-3- fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carbonyl]amino]propyl]carbamate (Compound 16-1, 223 mg, crude) as yellow oil. Compound 16-1 was used in the next step without further purification. LC-MS: m / z = 476.2 [M+H]+.A solution of Compound 16-1 (200 mg, 421 μmol, 1 equiv.) in HCl / dioxane (2.00 M, 4.00 mL, 19 equiv.) was stirred at 25 °C for 2 h. LC-MS showed Compound 16-1 was consumed and the desired m / z (RT = 1.121 mins) was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)- acetonitrile]; gradient: 20%-50% acetonitrile over 11 min). The eluent was concentrated under reduced pressure at 40 °C and lyophilized to give N-[(1S)-2-amino-1-methyl-ethyl]-4- [2-[[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 16, 45.6 mg, 119 μmol, 28.4% yield, 98.2% purity) as an off-white solid. LC-MS: m / z = 376.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 7.79 (s, 1H), 7.75 (br d, J = 8.0 Hz, 1H), 7.10 (s, 2H), 6.64 (s, 1H), 6.21 (d, J = 8.0 Hz, 1H), 4.87 - 4.58 (m, 1H), 4.29 - 4.07 (m, 1H), 3.98 (br t, J = 12.4 Hz, 1H), 3.93 - 3.82 (m, 2H), 3.70 - 3.43 (m, 2H), 2.70 - 2.56 (m, 2H), 2.21 (s, 3H), 1.90 - 1.49 (m, 4H), 1.11 (d, J = 6.8 Hz, 3H).19F NMR: (400 MHz, DMSO-d6) δ -204.035. Example 18: Synthesis of Target 17

[0169] Synthesis and Characterization of Compound 17-1. 76 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of 4-[2-[[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H- pyrrole-2-carboxylic acid (Compound 19-4, 100 mg, 298 μmol, 1 equiv.) and Compound e (62.3 mg, 357 μmol, 1.2 equiv.) in NMP (1.00 mL) was added HOBt (48.3 mg, 357 μmol, 1.2 equiv.), EDCI (114 mg, 596 μmol, 2 equiv.) and DIEA (77.0 mg, 596 μmol, 104 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 19-4 was consumed and the desired m / z (RT = 0.565 min) was detected. The reaction mixture was poured into H2O (20.0 mL), and the aqueous phase was extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed two times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 20%-50% acetonitrile over 12 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give tert- butyl N-[(2S)-2-[[4-[2-[[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]- 1H-pyrrole-2-carbonyl]amino]propyl]carbamate (Compound 17-1, 50.0 mg, 105 μmol, 35.3% yield, 100% purity) as a white solid. LC-MS: m / z = 476.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 7.84 - 7.74 (m, 2H), 7.16 - 7.02 (m, 2H), 6.88 (t, J = 5.6 Hz, 1H), 6.56 (s, 1H), 6.38 (d, J = 7.6 Hz, 1H), 4.58 - 4.36 (m, 1H), 4.22 - 4.09 (m, 1H), 4.08 - 3.86 (m, 2H), 3.83 - 3.71 (m, 1H), 3.57 - 3.41 (m, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H), 2.13 - 1.98 (m, 1H), 1.54 - 1.43 (m, 1H), 1.36 (s, 9H), 1.09 (d, J = 6.4 Hz, 3H).

[0170] Synthesis and Characterization of Target 17.77 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 17-1 (50.0 mg, 105 μmol, 1 equiv.) in dioxane (1.00 mL) was added HCl / dioxane (1.00 mL, 2.00 M) at 25 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 17-1 was consumed and the desired m / z (RT = 0.333 min) was detected. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 15%-45% acetonitrile over 11 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-methyl-ethyl]-4-[2- [[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 17, 37.1 mg, 98.6 μmol, 93.7% yield, 99.5% purity) as an off-white solid. LC-MS: m / z = 376.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.63 - 7.35 (m, 1H), 7.12 - 7.00 (m, 2H), 6.59 (s, 1H), 6.09 (d, J = 7.2 Hz, 1H), 4.61 - 4.37 (m, 1H), 4.23 - 4.08 (m, 1H), 4.01 - 3.87 (m, 2H), 3.84 - 3.74 (m, 1H), 3.57 - 3.44 (m, 2H), 2.22 (s, 3H), 2.15 - 2.05 (m, 1H), 1.59 - 1.48 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H).19F NMR: (400 MHz, DMSO-d6) δ -189.894. Example 19: Synthesis of Target 18

[0171] Synthesis and Characterization of Compound 18-2.To a solution of (3R,4S)-3-fluorotetrahydropyran-4-amine (Compound 18-1, 413 mg, 2.65 mmol, 1.2 equiv., HCl) and Compound a-1 (555 mg, 2.21 mmol, 1 equiv.) in dioxane (6.00 mL) was added t-BuONa (425 mg, 4.42 mmol, 2 equiv.), Pd2(dba)3 (203 mg, 221 μmol, 0.1 equiv.) and Xantphos (256 mg, 442 μmol, 0.2 equiv.) at 20 °C under N2. The mixture was heated to 100 °C and stirred at 100 °C for 4 h. LC-MS showed Compound 18-1 was consumed completely and the desired m / z (RT = 0.382 min) was detected. The reaction mixture was cooled to 25 °C. The mixture was poured into H2O (40.0 mL) and extracted two times with 30.0 mL ethyl acetate. The organic layers were combined and washed one time 78 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) with 60.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 15 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give 4-bromo-N-[(3R,4S)-3- fluorotetrahydropyran-4-yl]-5-methyl-pyridin-2-amine (Compound 18-2, 385 mg, 1.33 mmol, 60.2% yield, 100% purity) as a brown solid.1H NMR: (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.80 (s, 1H), 5.56 (s, 1H), 4.52 - 4.36 (m, 1H), 4.14 - 4.06 (m, 1H), 3.93 - 3.89 (m, 2H), 3.60 - 3.48 (m, 2H), 2.30 - 2.21 (m, 4H), 1.71 - 1.61 (m, 1H).19F NMR: (400 MHz, CDCl3) δ -192.301.

[0172] Synthesis and Characterization of Compound 18-3.A mixture of Compound 18-2 (385 mg, 1.33 mmol, 1 equiv.), Compound b (648 mg, 1.60 mmol, 1.2 equiv.), K3PO4(848 mg, 3.99 mmol, 3 equiv.), and Pd(dppf)Cl2(97.4 mg, 133 μmol, 0.1 equiv.) in dioxane (5.00 mL) and H2O (1.00 mL) at 25 °C was degassed and purged with N2three times. The mixture was heated to 90 °C stirred at 90 °C for 6 h under N2atmosphere. LC-MS showed Compound 18-2 was consumed completely and the desired m / z (RT = 0.472 min) was detected. The reaction mixture was cooled to 25 °C. The mixture was poured into H2O (50.0 mL) and ethyl acetate (40.0 mL). The mixture was filtered to give the filtrate. The organic phase was separated, and the aqueous phase was extracted two times with 40.0 mL ethyl acetate. The organic layers were combined and washed one time with 100 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate to petroleum ether / ethyl acetate / CH2Cl2= 30 / 1 to 10 / 1 / 30, petroleum ether / ethyl acetate = 0 / 1, Rf = 0.50). The fraction was concentrated under reduced pressure to give methyl 4-[2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5- methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 18-3, 630 mg, 1.18 79 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) mmol, 88.9% yield, 91.7% purity) as brown solid. LC-MS: m / z =488.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.03 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.88 (s, 1H) 7.50 (d, J = 8.4 Hz, 2H) 7.31 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.55 - 4.34 (m, 1H), 4.21 - 4.15 (m, 1H), 3.97 - 3.89 (m, 1H), 3.79 - 3.71 (m, 4H), 3.55 - 3.43 (m, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 2.08 - 2.04 (m, 1H), 1.53 - 1.45 (m, 1H).19F NMR: EW52614-5- P1A (400 MHz, DMSO-d6) δ -190.226.

[0173] Synthesis and Characterization of Compound 18-6.To a solution of Compound 18-3 (800 mg, 1.64 mmol, 1 equiv.) in THF (8.00 mL) and H2O (8.00 mL) was added LiOH•H2O (344 mg, 8.20 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 18-3 was consumed completely and the desired m / z (RT = 1.345 mins) was detected. The reaction was concentrated under vacuum at 40 °C to give 4-[2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4- pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylic acid (Compound 18-6, 776 mg, crude) as brown oil. LC-MS: m / z = 474.3 [M+H]+.

[0174] Synthesis and Characterization of Compound 18-4.To a solution of Compound 18-6 (776 mg, 1.64 mmol, 1 equiv.) in THF (8.00 mL) and H2O (8.00 mL) was added NaOH (393 mg, 9.83 mmol, 6 equiv.) at 25 °C. The mixture was 80 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) stirred at 80 °C for 20 h. LC-MS showed 0.5% of Compound 18-6 (RT = 1.369 mins) remained and the desired m / z (RT = 0.862 min) was detected. The reaction mixture was concentrated under reduced pressure to remove THF and adjusted to pH 6 using 1 M HCl. The mixture was filtered, and the filter cake was collected and dried under reduced pressure to give 4-[2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole- 2-carboxylic acid (Compound 18-4, 450 mg, 1.41 mmol, 85.6% yield) as an off-white solid. LC-MS: m / z =320.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.0 (s, 1H), 7.80 (s, 1H), 7.22 (s, 1H), 6.94 (s, 1H), 6.57 (s, 1H), 6.37 (d, J = 7.6 Hz, 1H), 4.55 - 4.35 (m, 1H), 4.21 - 4.09 (m, 1H), 3.99 - 3.89 (m, 1H), 3.81 - 3.73 (m, 1H), 3.56 - 3.42 (m, 3H), 2.19 (s, 3H), 2.04 (d, J = 4.4 Hz, 1H), 1.55 - 1.40 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ -190.114.

[0175] Synthesis and Characterization of Compound 18-5.To a solution of Compound 18-4 (150 mg, 470 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound e (98.2 mg, 564 μmol, 1.2 equiv.), HOBt (76.2 mg, 564 μmol, 1.2 equiv.), EDCI (180 mg, 939 μmol, 2 equiv.) and DIEA (121 mg, 939 μmol, 164 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 18-4 was consumed completely and the desired m / z (RT = 0.530 min) was detected. The mixture was poured into H2O (10.0 mL) and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed one time with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (FA)- acetonitrile]; gradient: 12%-42% acetonitrile over 9 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give tert-butyl N-[(2S)-2-[[4-[2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl- 4-pyridyl]-1H-pyrrole-2-carbonyl]amino]propyl]carbamate (Compound 18-5, 134 mg, 271 μmol, 57.8% yield, 96.3% purity) as a white solid. LC-MS: m / z = 476.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.7 (s, 1H), 7.83 - 7.76 (m, 2H), 7.14 - 7.14 (m, 1H), 7.06 (s, 1H), 81 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 6.89 (t, J = 5.6 Hz, 1H), 6.56 (s, 1H), 6.39 (d, J = 7.6 Hz, 1H), 4.55 - 4.36 (m, 1H), 4.19 - 4.10 (m, 1H), 4.09 - 3.99 (m, 1H), 3.98 - 3.88 (m, 1H), 3.81 - 3.74 (m, 1H), 3.56 - 3.48 (m, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.20 (s, 3H), 2.06 (dd, J = 9.2, 4.4 Hz, 1H), 1.49 (td, J = 8.8, 4.4 Hz, 1H), 1.36 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H).19F NMR: (400 MHz, DMSO-d6) δ -190.066.

[0176] Synthesis and Characterization of Target 18.To a solution of Compound 18-5 (134 mg, 271 μmol, 1 equiv.) in dioxane (3.00 mL) was added HCl / dioxane (2.00 M, 5.78 mL, 42.6 equiv.). The mixture was stirred at 25 °C for 3 h. LC-MS showed Compound 18-5 was consumed completely and the desired m / z (RT = 0.668 min) was detected. The reaction mixture was adjusted to pH 8 using NH3•H2O and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)- acetonitrile]; gradient: 0%-25% acetonitrile over 11 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, the residual aqueous was lyophilized to give N-(2-amino-1-methyl-ethyl)-4-[2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5- methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 18, 57.2 mg, 151 μmol, 55.7% yield, 99.3% purity) as a white solid. LC-MS: m / z = 376.2 [M+H]+.1H NMR: (400 MHz, MeOD) δ 7.77 (s, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 6.63 (s, 1H), 4.54 - 4.33 (m, 1H), 4.21 - 3.98 (m, 3H), 3.93 - 3.82 (m, 1H), 3.61 - 3.46 (m, 2H), 2.95 - 2.69 (m, 2H), 2.31 - 2.24 (m, 3H), 2.22 - 2.12 (m, 1H), 1.65 - 1.52 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H).19F NMR: (400 MHz, MeOD) δ -193.839. Example 20: Synthesis of Target 19

[0177] Synthesis and Characterization of Compound 19-1. 82 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound a-1 (650 mg, 2.59 mmol, 1 equiv.), (3S,4R)-3- fluorotetrahydropyran-4-amine (Compound 9, 483 mg, 3.11 mmol, 1.2 equiv., HCl), t- BuONa (498 mg, 5.18 mmol, 2 equiv.), Pd2(dba)3 (237 mg, 259 μmol, 0.1 equiv.), and Xantphos (300 mg, 518 μmol, 0.2 equiv.) in dioxane (7.00 mL) was degassed and purged with N2 three times at 25 °C. The mixture was heated to 100 °C and stirred at 100 °C for 4 h under N2 atmosphere. LC-MS showed Compound a-1 was consumed and the desired m / z (RT = 0.376 min) was detected. The mixture was cooled to 25 °C and filtered with the injector. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18 150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 10%-40% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give 4-bromo-N-[(3S,4R)-3- fluorotetrahydropyran-4-yl]-5-methyl-pyridin-2-amine (Compound 19-1, 420 mg, 1.45 mmol, 56.0% yield, 100% purity) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.74 (s, 1H), 6.91 (s, 1H), 4.59 - 4.32 (m, 1H), 4.20 - 4.02 (m, 1H), 4.00 - 3.88 (m, 1H), 3.82 - 3.67 (m, 1H), 3.61 - 3.44 (m, 2H), 2.29 - 2.15 (m, 4H), 1.83 - 1.67 (m, 1H).19F NMR: (400 MHz, CDCl3) δ -191.640.

[0178] Synthesis and Characterization of Compound 19-2.A mixture of Compound 19-1 (370 mg, 1.28 mmol, 1 equiv.), Compound b (622 mg, 1.54 mmol, 1.2 equiv.), K3PO4 (815 mg, 3.84 mmol, 3 equiv.) and Pd(dppf)Cl2 (93.6 mg, 128 μmol, 0.1 equiv.) in dioxane (4.00 mL) and H2O (0.80 mL) at 25 °C was degassed and purged 83 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) with N2 three times. The mixture was heated to 90 °C and stirred at 90 °C for 6 h under N2 atmosphere. LC-MS showed Compound 19-1 was consumed and the desired m / z (RT = 0.478 min) was detected. The mixture was cooled to 25 °C, poured into H2O (50.0 mL), then extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed two times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated to give the product. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 20%-50% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The mixture was adjusted to pH 8 using saturated NaHCO3solution. The mixture was extracted two times with 100 mL ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give methyl 4-[2-[[(3S,4R)-3- fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2- carboxylate (Compound 19-2, 460 mg, 943 μmol, 73.7% yield, 100% purity) as a white solid. LC-MS: m / z = 488.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.03 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.88 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 2.0 Hz, 1H), 6.64 (s, 1H), 6.51 (d, J = 8.0 Hz, 1H), 4.58 - 4.34 (m, 1H), 4.25 - 4.11 (m, 1H), 3.99 - 3.87 (m, 1H), 3.83 - 3.75 (m, 1H), 3.72 (s, 3H), 3.55 - 3.45 (m, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 2.14 - 2.02 (m, 1H), 1.59 - 1.40 (m, 1H).

[0179] Synthesis and Characterization of Compound 19-3.To a solution of Compound 19-2 (390 mg, 800 μmol, 1 equiv.) in THF (2.00 mL) and H2O (2.00 mL) was added LiOH•H2O (168 mg, 4.00 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS (EW52666-36-P1B) showed Compound 19-2 was consumed and the desired m / z (RT = 0.936 min) was detected. The reaction mixture was concentrated under reduced pressure to give 4-[2-[[(3S,4R)-3-fluorotetrahydropyran-4- yl]amino]-5-methyl-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylic acid (Compound 19- 3, 380 mg, crude) as a yellow solid. LC-MS: m / z = 474.3 [M+H]+.

[0180] Synthesis and Characterization of Compound 19-4. 84 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 19-3 (380 mg, 803 μmol, 1 equiv.) in THF (2.00 mL) and H2O (2.00 mL) was added NaOH (161 mg, 4.01 mmol, 5 equiv.) at 25 °C. The mixture was stirred at 80 °C for 12 h. LC-MS showed Compound 19-3 was consumed and the desired m / z (RT = 0.867 min) was detected. The mixture was cooled to 25 °C. The mixture was concentrated to remove most of THF, then adjusted pH to 5 with 1 M HCl, filtered, and the filter cake was concentrated to give Compound 19-4 (220 mg, 655 μmol, 81.9% yield, 95.1% purity) as a yellow solid. LC-MS: m / z = 320.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.5 - 12.4 (m, 1H), 12.1 (s, 1H), 7.80 (s, 1H), 7.26 (s, 1H), 6.97 (s, 1H), 6.78 - 6.43 (m, 2H), 4.59 - 4.35 (m, 1H), 4.27 - 4.08 (m, 1H), 4.02 - 3.88 (m, 1H), 3.86 - 3.71 (m, 1H), 3.54 - 3.42 (m, 2H), 2.20 (s, 3H), 2.08 - 2.00 (m, 1H), 1.57 - 1.42 (m, 1H).

[0181] Synthesis and Characterization of Compound 19-5.To a mixture of Compound 19-4 (100 mg, 298 μmol, 1 equiv.) and Compound 1-5 (83.3 mg, 357 μmol, 1.2 equiv., HCl) in NMP (1.00 mL) was added HOBt (48.3 mg, 357 μmol, 1.2 equiv.), EDCI (114 mg, 596 μmol, 2 equiv.) and DIEA (80.0 mg, 596 μmol, 104 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 19-4 was consumed and the desired m / z (RT = 0.648 min) was detected. The reaction mixture was poured into H2O (20.0 mL), and the aqueous phase was extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed two times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give N- 85 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) [(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2-[[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]- 5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 19-5, 150 mg, 254 μmol, 85.2% yield, 84.3% purity) as yellow oil. LC-MS: m / z = 498.2 [M+H]+.

[0182] Synthesis and Characterization of Target 19.A mixture of Compound 19-5 (150 mg, 254 μmol, 1 equiv.) and PPh3 (99.9 mg, 381 μmol, 1.5 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was stirred at 25 °C for 12 h. LC-MS showed Compound 19-5 was consumed and the desired m / z (RT = 0.579 min) was detected. The mixture was concentrated to remove most of THF, then the mixture was filtered with the injector. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18 150 mm × 25 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 9 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3- chlorophenyl)ethyl]-4-[2-[[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Target 19, 54.3 mg, 95.6 μmol, 37.6% yield, 99.1% purity, 2FA) as an off-white solid. LC-MS: m / z = 472.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.30 (s, 2H), 7.81 (s, 1H), 7.46 (s, 1H), 7.41 - 7.32 (m, 3H), 7.19 (d, J = 18.8 Hz, 2H), 6.59 (s, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.22 - 5.12 (m, 1H), 4.57 - 4.36 (m, 1H), 4.24 - 4.08 (m, 1H), 3.99 - 3.86 (m, 1H), 3.83 - 3.72 (m, 1H), 3.55 - 3.43 (m, 2H), 3.15 - 3.05 (m, 2H), 2.22 (s, 3H), 2.10 - 2.00 (m, 1H), 1.58 - 1.39 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ -190.090. Example 21: Synthesis of Target 20

[0183] Synthesis and Characterization of Compound 20-1. 86 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 18-4 (150 mg, 469 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound 1-5 (131 mg, 564 μmol, 1.2 equiv., HCl), HOBt (76.2 mg, 564 μmol, 1.2 equiv.), EDCI (180 mg, 939 μmol, 2 equiv.) and DIEA (121 mg, 939 μmol, 164 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 18-4 was consumed completely and the desired m / z (RT = 0.590 min) was detected. The mixture was poured into H2O (10.0 mL) and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed one time with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used into the next step. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2- [[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4-pyridyl]-1H-pyrrole-2- carboxamide (Compound 20-1, 400 mg, crude) was obtained as yellow oil. LC-MS: m / z = 498.1 [M+H]+.

[0184] Synthesis and Characterization of Target 20.To a solution of Compound 20-1 (400 mg, 649 μmol, 1 equiv.) in THF (3.60 mL) and H2O (0.40 mL) was added PPh3(256 mg, 975 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 20-1 was consumed completely and the desired m / z (RT = 0.481 min) was detected. The reaction mixture was concentrated under vacuum to remove THF. The residue was purified by prep-HPLC (neutral condition: column: Waters XBridge® Prep OBD C18150 mm × 40 mm, 10 µm; mobile phase: [water 87 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (NH4HCO3)-acetonitrile]; gradient: 20%-50% acetonitrile over 52 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, and the residual aqueous was lyophilized to give a product. The product N-[(1S)-2-amino-1-(3- chlorophenyl)ethyl]-4-[2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Target 20, 92.6 mg, 193 μmol, 29.8% yield, 98.6% purity) was obtained as a white solid. LC-MS: m / z = 472.2 [M+H]+.1H NMR: EW52614- 25-P1A (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.24 (m, 5H), 7.15 (s, 1H), 6.60 (s, 1H), 6.42 (d, J = 7.6 Hz, 1H), 5.01 - 4.86 (m, 1H), 4.55 - 4.36 (m, 1H), 4.21 - 4.10 (m, 1H), 3.93 (ddd, J = 18.0, 12.0, 3.6 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.55 - 3.46 (m, 2H), 2.90 - 2.80 (m, 2H), 2.22 (s, 3H), 2.10 - 2.04 (m, 1H), 1.52 - 1.45 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ -190.007. Example 22: Synthesis of Target 22

[0185] Synthesis and Characterization of Compound 22A-2To the mixture of (2S)-2-amino-2-(3-chloro-5-fluorophenyl)ethanol (Compound 22A-1, 950 mg, 5.01 mmol, 1 equiv.) in CH2Cl2 (10.0 mL) was added Boc2O (1.31 g, 6.01 mmol, 1.38 mL, 1.2 equiv.) and TEA (1.52 g, 15.0 mmol, 2.09 mL, 3 equiv.) at 0 °C. The mixture was stirred at 20 °C for 10 h. LC-MS showed that Compound 22A-1 was consumed completely, and the desired product (RT = 0.535 min) was detected. The mixture was poured into H2O (25.0 mL) and extracted two times with 30.0 mL ethyl acetate. The organic layers were combined and washed two times with 30.0 mL brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1, product: petroleum ether / ethyl acetate = 2 / 1, Rf= 0.50) and concentrated. The product tert-butyl N-[(1S)-1-(3-chloro-5-fluorophenyl)-2- hydroxyethyl]carbamate (Compound 22A-2, 1.20 g, 4.13 mmol, 82.4% yield, 99.7% purity) was obtained as a white solid. LC-MS: m / z = 234.0 (M+H-56)+.1H NMR: (400 88 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) MHz,CDCl3) δ 7.11 (s, 1H), 7.01 (td, J = 8.4, 2.0 Hz, 1H), 6.95 (br d, J = 9.2 Hz, 1H), 5.38 (br s, 1H), 4.73 (br s, 1H), 3.97 - 3.66 (m, 2H), 2.47 - 2.06 (m, 1H), 1.44 (br s, 9H).

[0186] Synthesis and Characterization of Compound 22A-3To the mixture of Compound 22A-2 (500 mg, 1.73 mmol, 1 equiv.) in CH2Cl2 (5.00 mL) was added TEA (261 mg, 2.59 mmol, 360 μL, 1.5 equiv.) and MsCl (0.250 g, 2.18 mmol, 168 μL, 1.26 equiv.) at 0 °C. The mixture was stirred at 20 °C for 1 h. LC-MS showed the Compound 22A-2 was consumed completely and desired product (RT = 0.575 min) was detected. The mixture was poured into H2O (25.0 mL) and extracted two times with 30.0 mL ethyl acetate. The organic layers were combined and washed two times with 30.0 mL brine, dried over Na2SO4, filtered, and concentrated. The product [(2S)-2-(tert- butoxycarbonylamino)-2-(3-chloro-5-fluorophenyl)ethyl]methanesulfonate (Compound 22A-3, 634 mg, crude) was obtained as a yellow solid. LC-MS: m / z = 268.0 (M+H-100)+.

[0187] Synthesis and Characterization of Compound 22A-4To the mixture of Compound 22A-3 (630 mg, 1.71 mmol, 1 equiv.) in DMF (7.00 mL) was added NaN3(0.200 g, 3.08 mmol, 1.8 equiv.) at 20 °C under N2. The mixture was stirred at 50 °C for 24 h. LC-MS showed the Compound 22A-3 was consumed completely and desired product (RT = 0.612 min) was detected. The mixture was cooled to 25 °C and poured into iced NaHCO3 (50.0 mL), then the aqueous phase was extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed four times with 50.0 mL brine, 89 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1, product: petroleum ether / ethyl acetate = 3 / 1, Rf= 0.60) and the solvent was concentrated at 35 °C. The product tert-butyl N-[(1S)-2-azido-1-(3-chloro-5- fluorophenyl)ethyl]carbamate (Compound 22A-4, 350 mg, 1.11 mmol, 64.8% yield, 99.9% purity) was obtained as a white solid.1H NMR: (400 MHz,CDCl3) δ 7.11 (s, 1H), 7.05 (td, J = 8.0, 2.0 Hz, 1H), 6.95 (br d, J = 8.8 Hz, 1H), 5.11 (br s, 1H), 4.84 (br s, 1H), 3.77 - 3.48 (m, 2H), 1.45 (s, 9H).

[0188] Synthesis and Characterization of Compound 22ATo a mixture of Compound 22A-4 (100 mg, 317 μmol, 1 equiv.) in dioxane (1.00 mL) was added HCl / dioxane (2.00 M, 2.00 mL, 12.5 equiv.) at 20 °C. The mixture was stirred at 20 °C for 1 h. LC-MS showed that Compound 22A-4 was consumed completely, and the desired product (RT = 0.383 min) was detected. The mixture was concentrated. The product (1S)-2-azido-1-(3-chloro-5-fluorophenyl)ethanamine (Compound 22A, 80.0 mg, crude, HCl) was obtained as a white solid.1H NMR: (400 MHz, MeOD) δ 7.40 (s, 1H), 7.36 (td, J = 8.4, 2.0 Hz, 1H), 7.29 - 7.23 (m, 1H), 4.58 (dd, J = 7.6, 4.8 Hz, 1H), 4.01 - 3.91 (m, 1H), 3.85 - 3.77 (m, 1H).

[0189] Synthesis and Characterization of Compound 22-590 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a mixture of Compound 2-3 (75.0 mg, 248 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 22A (74.9 mg, 298 μmol, 1.2 equiv., HCl), HOBt (40.3 mg, 298 μmol, 1.2 equiv.), EDCI (95.4 mg, 497 μmol, 2 equiv.), and DIEA (128 mg, 995 μmol, 173 μL, 4 equiv.) at 0 °C. The mixture was stirred at 25 °C for 10 h. LC-MS showed that Compound 22-4 was consumed completely, and the desired product (RT = 1.073 mins) was detected. The mixture was poured into H2O (35.0 mL) and extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed two times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated. The product N-[(1S)-2-azido-1-(3-chloro-5- fluorophenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2- carboxamide (Compound 22-5, 125 mg, crude) was obtained as a gray oil. LC-MS: m / z = 498.3 [M+H]+.

[0190] Synthesis and Characterization of Target 22To a mixture of Compound 22-5 (120 mg, 240 μmol, 1 equiv.) in the THF (2.00 mL) and H2O (0.200 mL) was added PPh3 (94.8 mg, 361 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 5 h. LC-MS showed that Compound 2-5 was consumed completely, and desired product (RT = 0.579 min) was detected. The mixture was concentrated. The mixture was dissolved with acetonitrile. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water ( NH4HCO3)-acetonitrile]; gradient: 25%-55% acetonitrile over 9 min), then it was lyophilized. The product N-[(1S)-2- amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4- pyridyl]-1H-pyrrole-2-carboxamide (Target 22, 35.3 mg, 71.1 μmol, 29.5% yield, 95.0% purity) was obtained as the light yellow solid. LC-MS: m / z = 472.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.52 (br d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.36 - 7.30 (m, 2H), 7.27 - 7.19 (m, 2H), 7.16 (br s, 1H), 6.51 (s, 1H), 6.11 (br d, J = 7.6 Hz, 1H), 5.12 - 91 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 5.04 (m, 1H), 3.94 - 3.79 (m, 3H), 3.43 - 3.37 (m, 2H), 3.08 - 2.94 (m, 2H), 2.21 (s, 3H), 1.86 (br d, J = 12.4 Hz, 2H), 1.45 - 1.35 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -110.713. Example 23: Synthesis of Target 23

[0191] Synthesis and Characterization of Compound 23-2.To a solution of (2S)-2-amino-2-(3-bromo-5-fluorophenyl)ethanol (Compound 23-1, 2.00 g, 7.39 mmol, 1.0 equiv., HCl) and TEA (2.24 g, 22.1 mmol, 3.09 mL, 3 equiv.) in CH2Cl2(20.0 mL) was added Boc2O (1.94 g, 8.87 mmol, 2.04 mL, 1.2 equiv.) in CH2Cl2 (20.0 mL) at 0 °C. After addition, the mixture was warmed to 20 °C and stirred at 20 °C for 12 h. LC-MS showed Compound 23-1 was consumed and the desired m / z (RT = 0.508 min) was detected. The reaction mixture was poured into H2O (200 mL) slowly and extracted two times with 150 mL ethyl acetate. The organic layers were combined and washed three times with 200 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.39). The fraction was concentrated under vacuum to give tert-butyl N-[(1S)-1-(3-bromo-5- fluorophenyl)-2-hydroxyethyl]carbamate (Compound 23-2, 2.00 g, 5.97 mmol, 80.7% yield, 99.8% purity) as white solid. LC-MS: m / z = 236.0 (M+H-100)+.1H NMR: (400 MHz, CDCl3) δ 7.27 - 7.26 (m, 1H), 7.18 (td, J = 8.0, 2.0 Hz, 1H), 7.00 (br d, J = 9.2 Hz, 1H), 5.31 (br d, J = 7.2 Hz, 1H), 4.85 - 4.62 (m, 1H), 3.93 - 3.76 (m, 2H), 2.00 - 1.74 (m, 1H), 1.45 (br s, 9H).

[0192] Synthesis and Characterization of Compound 23-3 . 92 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 23-2 (500 mg, 1.50 mmol, 1 equiv.) in CH2Cl2 (5.00 mL) was added TEA (227 mg, 2.24 mmol, 312 μL, 1.5 equiv.) and MsCl (220 mg, 1.92 mmol, 148 μL, 1.28 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. LC-MS showed Compound 23-2 was consumed and the desired m / z (RT = 0.535 min) was detected. The mixture was poured into iced NH4Cl (30.0 mL), then the aqueous phase was extracted two times with 20.0 mL CH2Cl2. The organic layers were combined and washed two times with 30.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give [(2S)-2-(3-bromo-5-fluorophenyl)-2-(tert-butoxycarbonylamino)ethyl]methanesulfonate (Compound 23-3, 616 mg, 1.49 mmol, 99.8% yield) as an off-white solid. LC-MS: m / z = 313.9 (M+H-100)+.

[0193] Synthesis and Characterization of Compound 23-4.To a solution of Compound 23-3 (616 mg, 1.49 mmol, 1 equiv.) in DMF (6.00 mL) was added NaN3(200 mg, 3.08 mmol, 2.06 equiv.) at 20 °C. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. LC-MS showed Compound 23-3 was consumed and the desired m / z (RT = 1.445 mins) was detected. The mixture was cooled to 25 °C and poured into iced NaHCO3(80.0 mL), then the aqueous phase was extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed four times with 80.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 15 / 1, petroleum ether / ethyl acetate = 5 / 1, Rf = 0.50), then the 93 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) fraction was concentrated to give tert-butyl N-[(1S)-2-azido-1-(3-bromo-5- fluorophenyl)ethyl]carbamate (Compound 23-4, 420 mg, 1.17 mmol, 78.1% yield, 99.9% purity) as colorless oil. LC-MS: m / z = 261.1 (M+H-100)+.1H NMR: (400 MHz, CDCl3) δ 7.26 (br s, 1H), 7.20 (td, J = 8.0, 2.0 Hz, 1H), 6.99 (br d, J = 9.2 Hz, 1H), 5.25 - 4.97 (m, 1H), 4.93 - 4.71 (m, 1H), 3.74 - 3.53 (m, 2H), 1.45 (br s, 9H).19F NMR: (400 MHz, CDCl3) δ - 109.688.

[0194] Synthesis and Characterization of Compound 23-5.A solution of Compound 23-4 (200 mg, 556 μmol, 1 equiv.) in HCl / dioxane (4.00 mL) was stirred at 25 °C for 12 h. LC-MS showed Compound 23-4 was consumed and the desired m / z (RT = 0.375 min) was detected. The reaction mixture was concentrated under reduced pressure to give (1S)-2-azido-1-(3-bromo-5-fluorophenyl)ethanamine (Compound 23-5, 150 mg, 507 μmol, 91.2% yield, HCl) as an off-white solid. LC-MS: m / z = 259.0 [M+H]+.

[0195] Synthesis and Characterization of Compound 23-6.To a mixture of Compound 22-4 (85.0 mg, 282 μmol, 1 equiv.) and Compound 23-5 (100 mg, 338 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added HOBt (45.7 mg, 338 μmol, 1.2 equiv.) and EDCI (108 mg, 564 μmol, 105 μL, 2 equiv.). Then DIEA (145 mg, 1.13 mmol, 196 μL, 4 equiv.) was added at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C 94 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) for 8 h. LC-MS showed Compound 22-4 was consumed and the desired m / z (RT = 1.081 mins) was detected. The mixture was poured into H2O (50.0 mL), then the aqueous phase was extracted three times with 30.0 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give N-[(1S)-2-azido-1-(3-bromo-5- fluorophenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2- carboxamide (Compound 23-6, 200 mg, crude) as brown oil. LC-MS: m / z = 542.2 [M+H]+.

[0196] Synthesis and Characterization of Target 23.To a mixture of Compound 23-6 (200 mg, 368 μmol, 1 equiv.) in THF (3.60 mL) and H2O (0.400 mL) was added PPh3(145 mg, 553 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 23-6 was consumed and the desired m / z (RT = 0.818 min) was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 20%-50% acetonitrile over 10 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3-bromo-5- fluorophenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 23, 30.2 mg, 58.4 μmol, yield over two steps: 20.8%, 99.7% purity, 100% enantiomerically enriched) as an off-white solid. LC-MS: m / z = 516.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.75 (br s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.45 - 7.37 (m, 2H), 7.27 - 7.19 (m, 2H), 7.14 (s, 1H), 6.52 (s, 1H), 6.11 (d, J = 7.6 Hz, 1H), 4.93 (q, J = 7.2 Hz, 1H), 3.92 - 3.81 (m, 3H), 3.43 - 3.37 (m, 2H), 2.86 (d, J = 6.8 Hz, 2H), 2.21 (s, 3H), 1.97 - 1.54 (m, 4H), 1.45 - 1.35 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -110.886. Example 24: Synthesis of Target 24 95 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0197] Synthesis and Characterization of Compound 24-2.To a mixture of 5-chloropyridine-3-carbaldehyde (Compound 24-1, 5.00 g, 35.3 mmol, 1 equiv.) in MeOH (50.0 mL) was added (2S)-2-amino-2-phenyl-ethanol (Compound 24-1A, 5.33 g, 38.8 mmol, 1.1 equiv.), MgI2 (982 mg, 3.53 mmol, 221 μL, 0.1 equiv.) at 20 °C for 15 mins, then the mixture was added trimethylsilyl cyanide (TMSCN, 4.37 g, 44.0 mmol, 5.51 mL, 1.25 equiv.) and stirred at 20 °C for 1 h. LC-MS showed Compound 24-1 was consumed and one peak (RT = 0.479 min) with desired m / z was detected. The mixture was poured into H2O (200 mL) and extracted two times with 200 mL ethyl acetate. The organic layers were combined and washed one time with 200 mL brine, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18250 mm × 70 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 20%-50% acetonitrile over 20 min) and the eluent was concentrated to give (2S)-2-(5-chloro- 3-pyridyl)-2-[[(1S)-2-hydroxy-1-phenylethyl]amino]acetonitrile (Compound 24-2, 5.00 g, 17.3 mmol, 49.1% yield) as yellow oil. LC-MS: m / z = 288.0 [M+H]+.

[0198] Synthesis and Characterization of Compound 24-3.To a mixture of Compound 24-2 (5.00 g, 17.3 mmol, 1 equiv.) in MeOH (50.0 mL) was added HCl / dioxane (2.00 M, 50.0 mL, 5.75 equiv.) at 20 °C, then the mixture was heated to 80 °C and stirred at 80 °C for 2 h. TLC (petroleum ether: ethyl acetate = 2 / 1) showed 96 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Compound 24-2 (Rf = 0.50) was consumed and one main spot (Rf = 0.68) was detected. The mixture was cooled to 20 °C and concentrated to give methyl 2-(5-chloro-3-pyridyl)-2-[[(1S)- 2-hydroxy-1-phenylethyl]amino]acetate (Compound 24-3, 5.00 g, 15.5 mmol, 89.7% yield) as a yellow solid.

[0199] Synthesis and Characterization of Compound 24-4.To a mixture of Compound 24-3 (5.00 g, 15.5 mmol, 1 equiv.) in MeOH (50.0 mL) was added CH2Cl2 (50.0 mL) and triacetoxyplumbyl acetate (7.60 g, 17.1 mmol, 1.1 equiv.). The mixture was stirred at 20 °C for 0.5 h. TLC (petroleum ether: ethyl acetate = 2 / 1) showed Compound 24-3 (Rf= 0.68) was consumed and one main spot (Rf= 0.78) was detected. The mixture was filtered, and the filtrate was collected and concentrated to give methyl 2-(5- chloro-3-pyridyl)-2-[(Z)-(2-hydroxy-1-phenylethylidene)amino]acetate (Compound 24-4, 5.00 g, crude) as yellow oil.

[0200] Synthesis and Characterization of Compound 24-5.To a mixture of Compound 24-4 (5.00 g, 15.6 mmol, 1 equiv.) in THF (50.0 mL) was added HCl (1.00 M, 25.0 mL, 1.59 equiv.) at 20 °C and stirred at 20 °C for 2 h. LC-MS showed Compound 24-4 was consumed and one peak (RT = 0.395 min) with the desired m / z was detected. The mixture was concentrated to get a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna™ C18250 mm × 70 mm, 10 µm; mobile phase: [water 97 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (HCl)-acetonitrile]; gradient: 0%-20% acetonitrile over 8 min) and the eluent was concentrated to give methyl 2-amino-2-(5-chloro-3-pyridyl)acetate (Compound 24-5, 2.00 g, 8.44 mmol, 64.0% yield over two steps, HCl) as a yellow solid. LC-MS: m / z = 201.0 [M+H]+.

[0201] Synthesis and Characterization of Compound 24-6.To a mixture of Compound 24-5 (2.00 g, 8.44 mmol, 1.0 equiv., HCl) in CH2Cl2(20.0 mL) was added TEA (2.56 g, 25.3 mmol, 3.52 mL, 3 equiv.) and Boc2O (1.84 g, 8.44 mmol, 1.94 mL, 1 equiv.). The mixture was stirred at 20 °C for 2 h. LC-MS showed Compound 24-5 (RT = 0.300 min) remained and one peak (RT = 0.507 min) with the desired m / z was detected. The mixture was poured into H2O (50.0 mL) and extracted two times with 50.0 mL CH2Cl2. The organic layers were combined and washed one time with 50.0 mL brine and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 6 / 1, petroleum ether : ethyl acetate = 2 / 1, Rf = 0.36) and the fraction was concentrated to give methyl 2-(tert- butoxycarbonylamino)-2-(5-chloro-3-pyridyl)acetate (Compound 24-6, 1.60 g, 5.32 mmol, 63.0% yield) as colorless oil. LC-MS: m / z = 301.0 [M+H]+.

[0202] Synthesis and Characterization of Compound 24-7.To a mixture of Compound 24-6 (1.50 g, 4.99 mmol, 1 equiv.) in THF (30.0 mL) was added diisobutylaluminium hydride (DIBAL-H, 1.00 M, 14.9 mL, 3 equiv.) at -30 °C under N2, 98 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) then the mixture was warmed to 20 °C and stirred at 20 °C for 2 h. LC-MS showed Compound 24-6 was consumed and one peak (RT = 0.871 min) with the desired m / z was detected. The mixture was poured into H2O (100 mL) and 0.5M HCl was added until pH 5 was obtained. The mixture was extracted two times with 100 mL ethyl acetate. The organic layers were combined and washed one time with 100 mL brine then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250 mm × 70 mm, 10 µm; mobile phase: [Hexane-EtOH]; gradient: 1%- 40% EtOH over 14 min) and the eluent was concentrated to give tert-butyl N-[1-(5-chloro-3- pyridyl)-2-hydroxyethyl]carbamate (Compound 24-7, 300 mg, 1.10 mmol, 22.05% yield) as yellow oil. LC-MS: m / z = 273.0 [M+H]+.

[0203] Synthesis and Characterization of Compound 24-8.To a mixture of Compound 24-7 (300 mg, 1.10 mmol, 1 equiv.) in CH2Cl2(6.00 mL) was added TEA (333 mg, 3.30 mmol, 459 μL, 3 equiv.) and MsCl (0.320 g, 2.79 mmol, 216 μL, 2.54 equiv.) at 0 °C, then the mixture was stirred at 0 °C for 1 h. LC-MS showed Compound 24-7 was consumed and one peak (RT = 0.466 min) with the desired m / z was detected. The mixture was poured into H2O (50 mL), then the aqueous phase was extracted two times with 50.0 mL CH2Cl2. The organic layers were combined and washed one time with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give [2-(tert-butoxycarbonylamino)-2-(5-chloro-3-pyridyl)ethyl]methanesulfonate (Compound 24-8, 300 mg, 855 μmol, 77.7% yield) as yellow oil. LC-MS: m / z = 351.0 [M+H]+.

[0204] Synthesis and Characterization of Compound 24-9. 99 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a mixture of Compound 24-8 (300 mg, 855 μmol, 1 equiv.) in DMF (6.00 mL) was added NaN3(0.130 g, 2.00 mmol, 2.34 equiv.) at 20 °C, then the mixture was heated to 50 °C and stirred at 50 °C for 12 h. LC-MS showed Compound 24-8 was consumed and one peak (RT = 0.496 min) with the desired m / z was detected. The mixture was cooled to 25 °C and poured into iced saturated NaHCO3 solution (50.0 mL), then the aqueous phase was extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed four times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1, petroleum ether: ethyl acetate = 2 / 1, Rf= 0.32) and the fraction was concentrated to give tert-butyl N-[2-azido-1-(5-chloro-3- pyridyl)ethyl]carbamate (Compound 24-9, 300 mg, crude) as yellow oil. LC-MS: m / z = 298.1 [M+H]+.

[0205] Synthesis and Characterization of Compound 24-10.To a mixture of Compound 24-9 (300 mg, 1.01 mmol, 1 equiv.) in dioxane (3.00 mL) was added HCl / dioxane (2.00 M, 3.00 mL, 5.95 equiv.). The mixture was stirred at 20 °C for 2 h. LC-MS showed Compound 24-9 was consumed and one peak (RT = 0.275 min) with the desired m / z was detected. The mixture was concentrated to give 2-azido-1-(5-chloro-3- pyridyl)ethanamine (Compound 24-10, 150 mg, 640 μmol, 75.1% yield over two steps, HCl) as a yellow solid. LC-MS: m / z = 198.0 [M+H]+.

[0206] Synthesis and Characterization of Compound 24-11. 100 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a mixture of Compound 24-10 (150 mg, 640 μmol, 1.0 equiv., HCl) in NMP (3.00 mL) was added Compound 2-3 (193 mg, 640 μmol, 1 equiv.), DIEA (331 mg, 2.56 mmol, 446 μL, 4 equiv.), HOBt (103 mg, 768 μmol, 1.2 equiv.), and EDCI (245 mg, 1.28 mmol, 2 equiv.). The mixture was stirred at 20 °C for 2 h. LC-MS showed Compound 2-3 was consumed and one peak (RT = 0.897 min) with the desired m / z was detected. The mixture was poured into H2O (30.0 mL) and extracted three times with ethyl 30.0 mL acetate. The organic layers were combined and washed three times with 30.0 mL brine, then concentrated under reduced pressure to give N-[2-azido-1-(5-chloro-3-pyridyl)ethyl]-4-[5-methyl-2- (tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 24-11, 300 mg, crude) as yellow oil. LC-MS: m / z = 481.1 [M+H]+.

[0207] Synthesis and Characterization of Compound 24-12.To a mixture of Compound 24-11 (300 mg, 623 μmol, 1 equiv.) in THF (5.00 mL) was added H2O (0.500 mL) and PPh3 (245 mg, 935 μmol, 1.5 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed Compound 24-11 was consumed and one peak (RT = 0.638 min) with the desired m / z was detected. The mixture was concentrated to get a residue. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH3•H2O)-acetonitrile]; gradient: 12%-42% acetonitrile over 12 min). 101 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) The eluent was concentrated to give N-[2-amino-1-(5-chloro-3-pyridyl)ethyl]-4-[5-methyl-2- (tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 24-12, 60.0 mg, 131 μmol, 20.5% yield over two steps) as a yellow solid. LC-MS: m / z = 455.2 [M+H]+.

[0208] Synthesis and Characterization of Targets 24-P1 and 24-P2.Compound 24-12 (60.0 mg) was purified by prep-SFC (column: (s,s) WHELK-O1 (250 mm × 30 mm, 10 µm); mobile phase: [CO2-acetonitrile / i-PrOH(0.1% NH3•H2O)]; B%:55%, isocratic elution mode), giving two peaks. The eluent was concentrated to get two residues. The first residue was purified by prep-SFC (column: REGIS(S,S)WHELK-O1 (250 mm × 25 mm, 10 µm); mobile phase: [CO2-acetonitrile / i-PrOH(0.1% NH3•H2O)]; B%:55%, isocratic elution mode). The eluent was concentrated and lyophilized to give N-[(1S)-2-amino-1-(5- chloro-3-pyridyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 24-P1, 14.1 mg, 29.5 μmol, 22.4% yield, 95.3% purity) as an off-white solid. The second residue was purified by prep-SFC (column: (s,s) WHELK-O1 (250 mm × 30 mm, 10 µm); mobile phase: [CO2-EtOH (0.1% NH3•H2O)]; gradient: 50%-55% EtOH over 4.8 min). The eluent was concentrated and lyophilized to give N-[(1R)-2-amino-1-(5- chloro-3-pyridyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2- carboxamide (Target 24-P2, 13.6 mg, 29.1 μmol, 22.1% yield, 97.0% purity) as an off-white solid. LC-MS of Target 24-P1: m / z = 455.2 [M+H]+.1H NMR of Target 24-P1: (400 MHz, MeOD) δ 8.54 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.93 (m, 1H), 7.76 (s, 1H), 7.21 (m, 2H), 6.58 (s, 1H), 5.21 - 5.17 (m, 1H), 3.99 - 3.95 (m, 2H), 3.86 - 3.83 (m, 1H), 3.58 - 3.52 (m, 2H), 3.17 - 3.14 (m, 2H), 2.28 (s, 3H), 2.00 - 1.95 (m, 2H), 1.55 - 1.50 (m, 2H). LC-MS of Target 24-P2: m / z = 455.2 [M+H]+.1H NMR of Target 24-P2: (400 MHz, MeOD) δ 8.54 - 8.49 (m, 2H), 7.93 (m, 1H), 7.76 (s, 1H), 7.21 (m, 2H), 6.58 (s, 1H), 5.21 - 5.18 (m, 1H), 3.99 - 3.95 (m, 2H), 3.87 - 3.84 (m, 1H), 3.58 - 3.52 (m, 2H), 3.17 - 3.13 (m, 2H), 2.28 (s, 3H), 2.00 - 1.95 (m, 2H), 1.57 - 1.50 (m, 2H). 102 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Example 25: Synthesis of Target 25

[0209] Synthesis and Characterization of Compound 25-1.To a solution of Compound 23-2 (1.00 g, 2.99 mmol, 1 equiv.), 2-isopropenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (Compound 23a, 1.51 g, 8.96 mmol, 3 equiv.) and K2CO3 (1.24 g, 8.96 mmol, 3 equiv.) in dioxane (10.0 mL) and H2O (1.00 mL) was added Pd(dppf)Cl2.CH2Cl2(243 mg, 298 μmol, 0.1 equiv.) under N2at 20 °C. The mixture was degassed and purged with N2 three times, then heated to 80 °C and stirred at 80 °C for 8 h under N2 atmosphere. LC-MS showed Compound 23-2 was consumed and the desired m / z (RT = 1.223 mins) was detected. The reaction mixture was allowed to cool and then was poured into H2O (100 mL) and extracted two times with 50.0 mL ethyl acetate. The organic layers were combined and washed two times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure 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 5 / 1, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.51) to give tert-butyl N-[(1S)-1-(3-fluoro-5- isopropenyl-phenyl)-2-hydroxyethyl]carbamate (Compound 25-1, 1.00 g, crude) as yellow oil. LC-MS: m / z = 196.2 (M+H-100)+.1H NMR: (400 MHz, CDCl3) δ 7.17 (s, 1H), 7.07 (td, J = 10.0, 2.0 Hz, 1H), 6.93 (td, J = 9.2, 1.6 Hz, 1H), 5.38 (s, 1H), 5.29 (br d, J = 5.6 Hz, 1H), 5.18 - 5.12 (m, 1H), 4.77 (br s, 1H), 3.91 - 3.82 (m, 2H), 2.13 (s, 3H), 1.93 (br s, 1H), 1.45 (br s, 9H).19F NMR: (400 MHz, CDCl3) δ -113.061.

[0210] Synthesis and Characterization of Compound 25-2. 103 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 25-1 (1.00 g, 3.02 mmol, 1 equiv.) in MeOH (20.0 mL) was added palladium on carbon (Pd / C, 446 mg, 419 μmol, 10% purity, 0.139 equiv.) under N2 at 25 °C. The mixture was degassed and purged with H2three times, then stirred at 25 °C for 3 h under H2(50 psi) atmosphere. LC-MS showed Compound 25-1 was consumed and the desired m / z (RT = 1.258 mins) was detected. The reaction mixture was filtered, and the filter liquor was concentrated under reduced pressure 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 3 / 1, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.36) to give tert-butyl N- [(1S)-1-(3-fluoro-5-isopropylphenyl)-2-hydroxyethyl]carbamate (Compound 25-2, 700 mg, 2.10 mmol, yield over two steps: 70.0%, 89.1% purity) as colorless oil. LC-MS: m / z = 242.2 (M+H-56)+.1H NMR: (400 MHz, DMSO-d6) δ 7.00 (s, 1H), 6.95 - 6.88 (m, 2H), 4.81 (br s, 1H), 4.58 - 4.42 (m, 1H), 3.93 (s, 2H), 3.47 (br s, 1H), 2.93-2.82 (m, 1H), 1.37 (s, 9H), 1.18 (d, J = 7.2 Hz, 6H).19F NMR: (400 MHz, DMSO-d6) δ -114.283.

[0211] Synthesis and Characterization of Compound 25-3.To a solution of Compound 25-2 (350 mg, 1.05 mmol, 1 equiv.) in CH2Cl2 (3.50 mL) was added TEA (159 mg, 1.57 mmol, 218 μL, 1.5 equiv.) and MsCl (140 mg, 1.22 mmol, 94.5 μL, 1.17 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1.5 h. LC-MS showed Compound 25-2 was consumed and the desired m / z (RT = 0.561 min) was detected. The mixture was poured into iced NH4Cl (50.0 mL), then the aqueous phase was extracted two times with 30.0 mL CH2Cl2. The organic layers were combined and washed two times with 104 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give [(2S)-2-(tert-butoxycarbonylamino)-2-(3-fluoro-5- isopropylphenyl)ethyl]methanesulfonate (Compound 25-3, 393 mg, 1.05 mmol, 100% yield) as light yellow oil. LC-MS: m / z = 276.1 (M+H-100)+.

[0212] Synthesis and Characterization of Compound 25-4.To a solution of Compound 25-3 (393 mg, 1.05 mmol, 1 equiv.) in DMF (4.00 mL) was added NaN3 (120 mg, 1.85 mmol, 1.76 equiv.) at 20 °C. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. LC-MS showed Compound 25-3 was consumed and the desired m / z (RT = 1.524 mins) was detected. The mixture was cooled to 25 °C and poured into iced NaHCO3(80.0 mL), then the aqueous phase was extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed four times with 80.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 30 / 1, petroleum ether / ethyl acetate = 6 / 1 Rf = 0.57), then the fraction was concentrated to give tert-butyl N-[(1S)-2-azido-1-(3-fluoro-5- isopropylphenyl)ethyl]carbamate (Compound 25-4, 230 mg, 658 μmol, 62.7% yield, 92.3% purity) as colorless oil. LC-MS: m / z = 223.2 (M+H-100)+.1H NMR: (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.88 (td, J = 10.0, 2.0 Hz, 1H), 6.83 (dd, J = 9.2, 1.6 Hz, 1H), 5.06 (br d, J = 2.8 Hz, 1H), 4.85 (br d, J = 3.2 Hz, 1H), 3.67 - 3.58 (m, 2H), 2.97-2.85 (m, 1H), 1.45 (br s, 9H), 1.25 (s, 3H), 1.24 (s, 3H).19F NMR: (400 MHz, CDCl3) δ -112.859.

[0213] Synthesis and Characterization of Compound 25-5. 105 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 25-4 (230 mg, 658 μmol, 1 equiv.) in dioxane (3.00 mL) was added HCl / dioxane (4 M, 3.00 mL, 18.2 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 25-4 was consumed and the desired m / z (RT = 0.805 mins) was detected. The mixture was concentrated under reduced pressure at 35 °C to give (1S)-2-azido-1-(3-fluoro-5-isopropylphenyl)ethanamine (Compound 25-5, 130 mg, 502 μmol, 76.30% yield, HCl) as off-white solid. LC-MS: m / z = 223.3 [M+H]+.

[0214] Synthesis and Characterization of Compound 25-6.To a mixture of Compound 2-3 (100 mg, 331 μmol, 1 equiv.) and Compound 25-5 (103 mg, 398 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added HOBt (53.8 mg, 398 μmol, 1.2 equiv.) and EDCI (127 mg, 663 μmol, 123 μL, 2 equiv.). Next, DIEA (171 mg, 1.33 mmol, 231 μL, 4 equiv.) was added at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 8 h. LC-MS showed Compound 22-4 was consumed and the desired m / z (RT = 1.167 mins) was detected. The mixture was poured into H2O (50.0 mL), then the aqueous phase was extracted three times with 30.0 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give N-[(1S)-2-azido-1-(3-fluoro-5- isopropylphenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2- carboxamide (Compound 25-6, 200 mg, crude) as brown oil. LC-MS: m / z = 506.4 [M+H]+. 106 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0215] Synthesis and Characterization of Target 25.To a mixture of Compound 25-6 (200 mg, 395 μmol, 1 equiv.) in THF (3.60 mL) and H2O (0.400 mL) was added PPh3(155 mg, 593 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 25-6 was consumed and the desired m / z (RT = 0.888 min) was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250 mm × 50 mm, 10 µm; mobile phase: [Hexane-EtOH (0.1% NH3•H2O)]; gradient: 15%-55% EtOH over 15 min). The eluent was concentrated under reduced pressure and then dissolved in acetonitrile / H2O = 1 / 10 (22.0 mL). The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4- ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 25, 30.6 mg, 62.8 μmol, yield over two steps: 16.7%, 98.3% purity, 100% enantiomerically enriched) as light yellow solid. LC- MS: m / z = 480.4 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.74 (br s, 1H), 8.35 (br d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 7.03 - 6.92 (m, 2H), 6.51 (s, 1H), 6.10 (d, J = 8.0 Hz, 1H), 5.03 - 4.90 (m, 1H), 3.93 - 3.81 (m, 3H), 3.44 - 3.38 (m, 2H), 2.95 - 2.84 (m, 3H), 2.21 (s, 3H), 1.86 (br dd, J = 12.4, 1.6 Hz, 2H), 1.45 - 1.35 (m, 2H), 1.19 (dd, J = 6.8, 0.8 Hz, 6H).19F NMR: (400 MHz, DMSO-d6) δ -113.907. Example 26: Synthesis of Target 26

[0216] Synthesis and Characterization of Compound 26-2. 107 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of 2,4-dibromo-5-methyl-pyrimidine (Compound 26-1, 2.00 g, 7.94 mmol, 1 equiv.), Compound b (3.22 g, 7.94 mmol, 1 equiv.), K3PO4 (3.37 g, 15.9 mmol, 2 equiv.), and Pd(dppf)Cl2(581 mg, 794 μmol, 0.1 equiv.) in dioxane (20.0 mL) and H2O (4.00 mL) was degassed and purged with N2three times at 25 °C. The mixture was heated to 90 °C and stirred at 90 °C for 4 h under N2 atmosphere. LC-MS showed Compound 26-1 was consumed completely and the desired m / z (RT = 1.582 mins) was detected. The mixture was cooled to 25 °C and poured into water (20.0 mL) at 25 °C then extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, petroleum ether / ethyl acetate = 3 / 1, Rf= 0.30) and the fraction was concentrated to give methyl 4-(2-bromo-5-methyl-pyrimidin-4-yl)-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 26-2, 1.00 g, 2.22 mmol, 28.0 % yield) as a white solid. LC-MS: m / z = 451.9 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.50 (br d, J = 8.0 Hz, 2H), 3.73 (s, 3H), 2.49 (br s, 3H), 2.42 (s, 3H).

[0217] Synthesis and Characterization of Compound 26-3.A mixture of Compound 26-2 (1.00 g, 2.22 mmol, 1 equiv.), Compound 2 (337 mg, 3.33 mmol, 1.5 equiv.), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 277 mg, 444 μmol, 108 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 0.2 equiv.), Pd2(dba)3 (203 mg, 222 μmol, 0.1 equiv.) and Cs2CO3 (1.45 g, 4.44 mmol, 2 equiv.) in dioxane (10.0 mL) was degassed and purged with N2 three times at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 h under N2atmosphere. LC-MS showed Compound 26-2 was consumed and the desired m / z (RT = 0.500 min) was detected. The mixture was cooled to 25 °C and filtered, and the filtrate was concentrated to give the residue. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 42%-72% acetonitrile over 15 min) and the eluent was concentrated under 45 °C and lyophilized. The product methyl 4-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-tosyl-1H- pyrrole-2-carboxylate (Compound 26-3, (300 mg, crude) was obtained as a yellow solid. LC-MS: m / z = 471.1 [M+H]+.

[0218] Synthesis and Characterization of Compound 26-4.To a solution of Compound 26-3 (300 mg, 948 μmol, 1 equiv.) in THF (3.00 mL) and H2O (3.00 mL) was added LiOH•H2O (199 mg, 4.74 mmol, 5 equiv.) at 25 °C. The mixture was heated to 50 °C stirred at 50 °C for 12 h. LC-MS showed Compound 26-3 was consumed completely and the desired m / z (RT = 0.342 min) was detected. The reaction mixture was cooled to 25 °C and concentrated to give a residue. The residue was adjusted to pH 5 using 1 M HCl and the solid precipitated out. The suspension was filtered, and the filter cake was washed three times with 2.00 mL H2O and dried to give 4-[5-methyl-2-(tetrahydropyran-4- ylamino)pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid (Compound 26-4, 230 mg, crude) as a yellow solid. LC-MS: m / z = 303.2 [M+H]+.

[0219] Synthesis and Characterization of Compound 26-5. 109 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 26-4 (200 mg, 463 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 1-5 (130 mg, 556 μmol, 1.2 equiv., HCl), HOBt (75.1 mg, 556 μmol, 1.2 equiv.), EDCI (178 mg, 926 μmol, 2 equiv.), and DIEA (180 mg, 1.39 mmol, 242 μL, 3 equiv.) at 0 °C. The mixture was stirred at 25 °C for 4 h. LC-MS showed Compound 26-4 was consumed completely and the desired m / z (RT = 0.457 min) was detected. The mixture was poured into water (20.0 mL) at 20 °C and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2-azido-1-(3- chlorophenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]-1H-pyrrole- 2-carboxamide (Compound 26-5, 300 mg, crude) as a yellow solid and used in the next step without further purification. LC-MS: m / z = 481.2 [M+H]+.

[0220] Synthesis and Characterization of Target 26.To a solution of Compound 26-5 (300 mg, 624 μmol, 1 equiv.) in THF (2.70 mL) and H2O (0.30 mL) was added PPh3 (245 mg, 936 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 6 h. LC-MS showed Compound 26-5 was consumed completely and the desired m / z (RT = 0.398 min) was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters XBridge® Prep OBD C18150 mm × 40 mm, 10 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 18%-48% acetonitrile over 20 min) and the eluent was concentrated under 30 °C 110 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) and lyophilized. The product N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]-4-[5-methyl-2- (tetrahydropyran-4-ylamino)pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 26, 70.04 mg, 149 μmol, 19.4% yield, 97.1% purity) was obtained as a white solid. LC-MS: m / z = 455.1 [M+H]+.1H NMR: (400 MHz, MeOD-d4) δ 8.03 (s, 1H), 7.64 - 7.55 (m, 2H), 7.43 (s, 1H), 7.38 - 7.24 (m, 3H), 5.12 - 5.08 (m, 1H), 4.12 - 4.02 (m, 1H), 4.02 - 3.92 (m, 2H), 3.58 (dt, J = 1.6, 11.6 Hz, 2H), 3.03 (d, J = 7.2 Hz, 2H), 2.35 (s, 3H), 2.06 - 1.96 (m, 2H), 1.67 - 1.52 (m, 2H). Example 27: Synthesis of Target 27

[0221] Synthesis and Characterization of Compound 27-2.To a solution of Compound a (3.00 g, 15.8 mmol, 1 equiv.) and benzofuran-5-amine (Compound d, 2.10 g, 15.8 mmol, 1 equiv.) in THF (30.0 mL) was dropwise added lithium bis(trimethylsilyl)amide (LiHMDS, 1 M, 39.5 mL, 2.5 equiv.) at 0 °C under N2 atmosphere. The mixture was stirred at 25 °C for 2 h under N2atmosphere. LC-MS showed Compound a was consumed and the desired m / z (RT = 0.446 min) was detected. The reaction mixture was poured into NH4Cl (100 mL), and the aqueous phase was extracted two times with 100 mL ethyl acetate. The organic layers were combined and washed two times with 100 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (diameter: 100- 200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, petroleum ether / ethyl acetate = 5 / 1, Rf= 0.50). The fraction was concentrated under reduced pressure to give N- (benzofuran-5-yl)-4-bromo-5-methyl-pyridin-2-amine (Compound 27-2, 4.20 g, 13.8 mmol, 87.4% yield, 99.7% purity) as a yellow solid. LC-MS: m / z = 305.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.08 - 7.99 (m, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.8, 2.0 Hz, 1H), 7.05 (s, 1H), 6.96 - 6.85 (m, 1H), 2.20 (s, 3H).

[0222] Synthesis and Characterization of Compound 27-3. 111 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound 27-2 (800 mg, 2.64 mmol, 1 equiv.), Compound c (861 mg, 3.43 mmol, 1.3 equiv.) , K3PO4 (1.68 g, 7.92 mmol, 3 equiv.) and Pd(dppf)Cl2 (193 mg, 264 μmol, 0.1 equiv.) in dioxane (8.00 mL) and H2O (1.60 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90°C for 6 h under N2atmosphere. LC-MS showed Compound 27-2 was consumed and the desired m / z (RT = 0.437 min) was detected. The mixture was cooled down to 25 °C, then poured into H2O (50.0 mL), then extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed two times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated to give the product. The crude product was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, petroleum ether / ethyl acetate =100 / 1 to 1 / 1, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.60). The fraction was concentrated under reduced pressure to give methyl 4-[2-(benzofuran-5- ylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxylate (Compound 27-3, 880 mg, 2.53 mmol, 96.0% yield, 100% purity) as a yellow solid. LC-MS: m / z = 348.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.75 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.42 - 7.49 (m, 1H), 7.40 - 7.31 (m, 2H), 7.05 (t, J = 2.0 Hz, 1H), 6.90 (dd, J = 2.0, 0.8 Hz, 1H), 6.86 (s, 1H), 3.80 (s, 3H), 2.27 (s, 3H).

[0223] Synthesis and Characterization of Compound 27-4.To a solution of Compound 27-3 (800 mg, 2.30 mmol, 1 equiv.) in THF (7.00 mL) and H2O (7.00 mL) was added LiOH•H2O (483 mg, 11.5 mmol, 5 equiv.) at 25 °C. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. LC-MS showed Compound 27-3 was 112 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) consumed and the desired m / z (RT = 0.402 min) was detected. The mixture was cooled to 25 °C. The mixture was concentrated to remove most of THF, then adjusted pH to 1 with 1 M HCl, filtered, and the filter cake was concentrated to get crude product. The crude product was used in the next step without further purification. The product 4-[2-(benzofuran-5- ylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 27-4, 700 mg, 2.10 mmol, 91.1% yield, 100% purity) was obtained as a yellow solid. LC-MS: m / z = 334.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.7 - 12.4 (m, 1H), 12.4 - 12.2 (m, 1H), 9.74 - 9.34 (m, 1H), 8.00 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.66 - 7.54 (m, 1H), 7.43 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 10.4 Hz, 2H), 6.97 (s, 1H), 2.31 (s, 3H).

[0224] Synthesis and Characterization of Compound 27-5.A mixture of Compound 27-4 (100 mg, 300 μmol, 1 equiv.) and Compound 22A (90.4 mg, 360 μmol, 1.2 equiv., HCl) in NMP (1.00 mL) was added HOBt (48.6 mg, 360 μmol, 1.2 equiv.), EDCI (115 mg, 560 μmol, 2 equiv.) and DIEA (77.5 mg, 560 μmol, 105 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 27-4 was consumed and the desired m / z (RT = 0.507 min) was detected. The reaction mixture was poured into H2O (20.0 mL), and the aqueous phase was extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed two times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was used to the next step. The product N-[(1S)-2- azido-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2-(benzofuran-5-ylamino)-5-methyl-4-pyridyl]- 1H-pyrrole-2-carboxamide (Compound 27-5, 300 mg, crude) was obtained as yellow oil. LC-MS: m / z = 530.2 [M+H]+.

[0225] Synthesis and Characterization of Target 27. 113 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound 27-5 (300 mg, 524 μmol, 1 equiv.), PPh3 (206 mg, 785 μmol, 1.5 equiv.) in THF (2.70 mL) and H2O (0.30 mL) at 25 °C, then the mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 27-5 was consumed and the desired m / z (RT = 0.641 min) was detected. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 40%-70% acetonitrile over 9 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3- chloro-5-fluorophenyl)ethyl]-4-[2-(benzofuran-5-ylamino)-5-methyl-4-pyridyl]-1H-pyrrole- 2-carboxamide (Target 27, 84.07 mg, 162.32 μmol, 31.00% yield, 97.3% purity) as an off- white solid. LC-MS: m / z = 504.2 [M+H]+.1H NMR: (400 MHz, MeOD) δ 7.89 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.21 (dd, J = 8.4, 1.6 Hz, 2H), 7.10 (dd, J = 8.8, 1.6 Hz, 2H), 6.87 (s, 1H), 6.78 (d, J = 1.6 Hz, 1H), 5.05 (t, J = 7.2 Hz, 1H), 2.99 (d, J = 6.8 Hz, 2H), 2.35 (s, 3H).19F NMR: (400 MHz, MeOD) δ -112.549. Example 28: Synthesis of Target 31

[0226] Synthesis and Characterization of Compound 31-1.114 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 27-4 (120 mg, 360 μmol, 1 equiv.) in NMP (1.20 mL) was added Compound 1-5 (101 mg, 432 μmol, 1.2 equiv., HCl), HOBt (58.4 mg, 432 μmol, 1.2 equiv.), EDCI (138 mg, 720 μmol, 2 equiv.), and DIEA (93.1 mg, 718 μmol, 125 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 27-4 was consumed and the desired m / z (RT = 0.498 min) was detected. The mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2- (benzofuran-5-ylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 31-1, 200 mg, 349 μmol, 96.9% yield, 89.3% purity) was obtained as brown oil. LC-MS: m / z = 512.2 [M+H]+.

[0227] Synthesis and Characterization of Target 31.To a solution of Compound 31-1 (200 mg, 349 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (137 mg, 523 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 31-1 was consumed and the desired m / z (RT = 0.649 min) was detected. The mixture was concentrated. The crude product was purified by prep- HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 30%-60% acetonitrile over 10 min), then it was lyophilized. The product N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]-4-[2-(benzofuran-5- ylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 31, 60.2 mg, 122 μmol, 35.1% yield, 98.8% purity) was obtained as a white solid. LC-MS: m / z = 486.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.80 (s, 1H), 8.42 (br d, J = 8.4 Hz, 1H), 8.10 115 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.50 - 7.26 (m, 9H), 7.21 (s, 1H), 6.93 - 6.87 (m, 2H), 4.97 - 4.88 (m, 1H), 2.86 (br d, J = 7.2 Hz, 2H), 2.31 (s, 3H). Example 29: Synthesis of Target 32

[0228] Synthesis and Characterization of Compound 32-1.To a solution of Compound a (2.00 g, 10.5 mmol, 1 equiv.) and 1,3-benzodioxol-5-amine (Compound j, 1.44 g, 10.5 mmol, 1 equiv.) in THF (20.0 mL) was dropwise added LiHMDS (1 M, 26.3 mL, 2.5 equiv.) at 0 °C under N2atmosphere. The mixture was stirred at 25 °C for 2 h under N2 atmosphere. LC-MS showed Compound 32-1 was consumed and the desired m / z (RT = 0.429 min) was detected. The reaction mixture was poured into NH4Cl (50.0 mL), and the aqueous phase was extracted two times with 50.0 mL ethyl acetate. The organic layers were combined and washed two times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, petroleum ether / ethyl acetate =100 / 1 to 5 / 1, petroleum ether / ethyl acetate = 5 / 1, Rf = 0.50). The fraction was concentrated under reduced pressure to give N-(1,3-benzodioxol-5- yl)-4-bromo-5-methyl-pyridin-2-amine (Compound 32-1, 2.60 g, 8.47 mmol, 80.4% yield, 100% purity) as a yellow solid. LC-MS: m / z = 308.9 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.01 (s, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.98 (s, 1H), 6.93 - 6.86 (m, 1H), 6.85 - 6.78 (m, 1H), 5.95 (s, 2H), 2.19 (s, 3H).

[0229] Synthesis and Characterization of Compound 32-2. 116 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound 32-1 (300 mg, 977 μmol, 1 equiv.), Compound c (319 mg, 1.27 mmol, 1.3 equiv.), K3PO4(622 mg, 2.93 mmol, 3 equiv.) and Pd(dppf)Cl2(71.5 mg, 97.7 μmol, 0.1 equiv.) in dioxane (3.00 mL) and H2O (0.60 mL) was degassed and purged with N2three times. The mixture was stirred at 90°C for 6 h under N2 atmosphere. LC-MS showed Compound 32-1 was consumed and the desired m / z (RT = 0.419 min) was detected. The mixture was cooled down to 25 °C, then poured into H2O (50.0 mL), then extracted three times with 50.0 mL ethyl acetate. The organic layers were combined and washed two times with 50.0 mL brine, dried over Na2SO4, filtered, and concentrated to give the product. The crude product was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, petroleum ether / ethyl acetate =100 / 1 to 1 / 1, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.60). The fraction was concentrated under reduced pressure to give methyl 4-[2-(1,3-benzodioxol- 5-ylamino)-5-methyl-4-pyridyl]-1H-pyrrole-2-carboxylate (Compound 32-2, 330 mg, 939 μmol, 96.1% yield, 100% purity) as a white solid. LC-MS: m / z = 352.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.2 (s, 1H), 8.64 (s, 1H), 7.94 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 2.8, 1.6 Hz, 1H), 7.03 (t, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 - 6.76 (m, 2H), 5.93 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H).

[0230] Synthesis and Characterization of Compound 32-3.To a solution of Compound 32-2 (330 mg, 939 μmol, 1 equiv.) in THF (3.00 mL) and H2O (3.00 mL) was added LiOH•H2O (197 mg, 4.70 mmol, 5 equiv.) at 25 °C. The mixture was 117 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) heated to 50 °C and stirred at 50 °C for 12 h. LC-MS showed Compound 32-2 was consumed and the desired m / z (RT = 0.385 min) was detected. The mixture was cooled to 25 °C. The mixture was concentrated to remove most of THF, then adjusted pH to 1 with 1 M HCl, filtered, and the filter cake was concentrated to get crude product. The crude product was used to the next step. The product 4-[2-(1,3-benzodioxol-5-ylamino)-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxylic acid (Compound 32-3, 300 mg, 856 μmol, 91.1% yield, 96.3% purity) was obtained as a red solid. LC-MS: m / z = 338.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.77 - 12.47 (m, 1H), 12.35 - 12.17 (m, 1H), 9.43 - 9.05 (m, 1H), 7.87 (s, 1H), 7.44 - 7.35 (m, 1H), 7.27 (s, 1H), 7.02 (s, 1H), 6.95 - 6.88 (m, 3H), 6.00 (s, 2H), 2.29 (s, 3H).

[0231] Synthesis and Characterization of Compound 32-4.A mixture of Compound 32-3 (100 mg, 285 μmol, 1 equiv.) and Compound 22A (86.0 mg, 343 μmol, 1.2 equiv., HCl) in NMP (1.00 mL) was added HOBt (46.3 mg, 343 μmol, 1.2 equiv.), EDCI (109 mg, 571 μmol, 2 equiv.) and DIEA (73.8 mg, 571 μmol, 99.4 μL, 2 equiv.) at 0 °C, then the mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 32-3 was consumed and the desired m / z (RT = 0.487 min) was detected. The reaction mixture was poured into H2O (20.0 mL), and the aqueous phase was extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed two times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was used to the next step. The product N-[(1S)-2- azido-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2-(1,3-benzodioxol-5-ylamino)-5-methyl-4- pyridyl]-1H-pyrrole-2-carboxamide (Compound 32-4, 300 mg, crude) was obtained as a yellow oil. LC-MS: m / z = 534.2 [M+H]+.

[0232] Synthesis and Characterization of Target 32. 118 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)A mixture of Compound 32-4 (300 mg, 508 μmol, 1 equiv.) and PPh3 (200 mg, 763 μmol, 1.5 equiv.) in THF (2.70 mL) and H2O (0.30 mL) was stirred at 25 °C for 12 h. LC-MS showed Compound 32-4 was consumed and the desired m / z (RT = 0.625 min) was detected. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 36%-66% acetonitrile over 9 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give a product. The crude product was purified by prep- HPLC (column: YMC-Actus Triart C18150 mm × 30 mm, 7 µm; mobile phase: [water (FA)- acetonitrile]; gradient: 5%-35% acetonitrile over 15 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2-(1,3-benzodioxol-5-ylamino)- 5-methyl-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 32, 64.88 mg, 115.0 μmol, 22.6% yield, 98.5% purity, FA) as a yellow solid. LC-MS: m / z = 508.2 [M+H]+.1H NMR: (400 MHz, MeOD) δ 8.45 (s, 1H), 7.85 (s, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 7.24 - 7.15 (m, 3H), 6.98 (s, 1H), 6.84 (s, 1H), 6.77 (s, 2H), 5.92 (s, 2H), 5.38 (t, J = 6.8 Hz, 1H), 3.39 (d, J = 7.2Hz, 2H), 2.33 (s, 3H).19F NMR: (400 MHz, MeOD) δ -111.565. Example 30: Synthesis of Target 34

[0233] Synthesis and Characterization of Compound 34-2. 119 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a mixture of (2S)-2-(tert-butoxycarbonylamino)-2-(3-chlorophenyl)acetic acid (Compound 34-1, 800 mg, 2.80 mmol, 1 equiv.) in DMF (8.00 mL) was added methylammonium chloride (283 mg, 4.20 mmol, 1.5 equiv.), N-methylimidazole (NMI, 1.15 g, 14.0 mmol, 1.12 mL, 5 equiv.), and N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH, 1.57 g, 5.60 mmol, 2 equiv.), the mixture was stirred at 20 °C for 1 h. LC-MS showed Compound 34-1 was consumed and one peak (RT = 0.512 min) with the desired m / z was detected. The mixture was poured into H2O (50.0 mL) and extracted two times with 50.0 mL ethyl acetate. The organic layers were combined and washed three times with 50.0 mL brine and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1, petroleum ether : ethyl acetate = 1 / 1, Rf= 0.50) and the fraction was concentrated to give tert-butyl N-[(1S)-1-(3-chlorophenyl)-2-(methylamino)-2-oxo- ethyl]carbamate (Compound 34-2, 800 mg, 2.68 mmol, 95.6% yield) as a white solid. LC- MS: m / z = 321.0 (M+H+Na)+.1H NMR: (400 MHz, DMSO-d6) δ 8.15 - 8.14 (m, 1H), 7.46 (m, 1H), 7.35 (m, 3H), 5.13 (d, J = 8.4 Hz, 1H), 2.57 (d, J = 3.2 Hz, 1H), 1.37 (s, 9H).

[0234] Synthesis and Characterization of Compound 34-3. ClTo a mixture of Compound 34-2 (1.00 g, 3.35 mmol, 1 equiv.) in THF (15.0 mL) was added BH3-THF (1.00 M, 10.0 mL, 3 equiv.) at 0 °C, then the mixture was stirred at 20 °C for 12 h. LC-MS showed Compound 34-2 (RT = 0.473 min) remained and one peak (RT = 0.423 min) with the desired m / z was detected. To the mixture was dropwise added MeOH (10.0 mL) and 120 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) stirred at 20 °C for 0.25 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250 mm × 70 mm, 10 µm; mobile phase: [Hexane-EtOH]; gradient: 1%-35% EtOH over 14 min) and the eluent was concentrated to give tert-butyl N-[(1S)-1-(3-chlorophenyl)-2-(methylamino)ethyl]carbamate (Compound 34-3, 200 mg, 702 μmol, 20.9% yield) as colorless oil. LC-MS: m / z = 285.0 [M+H]+.

[0235] Synthesis and Characterization of Compound 34-4.To a mixture of Compound 34-3 (200 mg, 702 μmol, 1 equiv.) in dioxane (2.00 mL) was added HCl / dioxane (2.00 M, 2.00 mL, 5.7 equiv.), the mixture was stirred at 20 °C for 2 h. LC-MS showed Compound 34-3 was consumed. The mixture was concentrated to give (1S)-1-(3-chlorophenyl)-N'-methyl-ethane-1,2-diamine (Compound 34-4, 120 mg, 542 μmol, 77.2% yield, HCl) as a white solid. LC-MS: m / z = 402.1 [M+H]+.

[0236] Synthesis and Characterization of Target 34.To a mixture of Compound 34-4 (120 mg, 542 μmol, 1.0 equiv., HCl) in NMP (3.00 mL) was added Compound 2-3 (163 mg, 542 μmol, 1 equiv.), DIEA (280 mg, 2.17 mmol, 378 μL, 4 equiv.), HOBt (87.9 mg, 651 μmol, 1.2 equiv.), and EDCI (208 mg, 1.09 mmol, 2 equiv.). The mixture was stirred at 20 °C for 12 h. LC-MS showed Compound 22-4 was 121 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) consumed and one peak (RT= 0.737 min) with the desired m / z was detected. The mixture was poured into H2O (20 mL) and extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH3•H2O)-acetonitrile]; gradient: 20%-50% acetonitrile over 12 min) and the eluent was concentrated to get a residue. The residue was purified by prep-HPLC (column: DAICEL CHIRALPAK IC 250 mm × 30 mm, 10 µm; mobile phase: [CO2-acetonitrile / i-PrOH(0.1% NH3•H2O)]; B%:45%, isocratic elution mode) and the eluent was concentrated and lyophilized to give N-[(1S)-1-(3- chlorophenyl)-2-(methylamino)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]- 1H-pyrrole-2-carboxamide (Target 34, 55.3 mg, 116 μmol, 21.4% yield, 98.3% purity) as an off-white solid. LC-MS: m / z = 468.3 [M+H]+.1H NMR: (400 MHz, MeOD) δ 7.74 (s, 1H), 7.46 (s, 1H), 7.33 -7.27 (m, 3H), 7.20 (s, 1H), 6.81 (s, 1H), 6.58 (s, 1H), 4.32 (t, J = 6.8 Hz 1H), 3.98 - 3.95 (m, 2H), 3.89 - 3.83 (m, 2H), 3.57 - 3.52 (m, 2H), 3.35 - 3.34 (m, 1H), 3.17 - 3.16 (m, 3H), 2.25 (s, 3H), 1.99 - 1.96 (m, 2H), 1.55 - 1.47 (m, 2H). Example 31: Synthesis of Target 36

[0237] Synthesis and Characterization of Compound 36-2.To a solution of 4-bromo-5-chloro-2-fluoro-pyridine(Compound 36-1, 900 mg, 4.28 mmol, 1 equiv.) and Compound 2 (519 mg, 5.13 mmol, 1.2 equiv.) in DMSO (9.00 mL) was added DIEA (1.66 g, 12.8 mmol, 2.23 mL, 3 equiv.) at 25 °C. The mixture was heated to 135 °C and stirred at 135 °C for 12 h. LC-MS showed Compound 36-1 was consumed and the desired m / z (RT = 0.508 min) was detected. The mixture was cooled to 25 °C and poured into H2O (30.0 mL), then the aqueous phase was extracted three times with 30.0 mL ethyl acetate. The organic layers were combined and washed three times with 30.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep- HPLC (column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water 122 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (FA)-acetonitrile]; gradient: 38%-68% acetonitrile over 15 min), then it was lyophilized. The product 4-bromo-5-chloro-N-tetrahydropyran-4-yl-pyridin-2-amine (Compound 36-2, 790 mg, 2.71 mmol, 63.4% yield, 100% purity) was obtained as a yellow solid. LC-MS: m / z = 292.9 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 6.94 (br d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 3.89 - 3.79 (m, 3H), 3.41 - 3.33 (m, 2H), 1.83 (br dd, J = 12.8, 2.0 Hz, 2H), 1.45 - 1.33 (m, 2H).

[0238] Synthesis and Characterization of Compound 36-3.A mixture of Compound 36-2 (500 mg, 1.71 mmol, 1 equiv.), Compound b (848 mg, 2.06 mmol, 1.2 equiv.), K3PO4(1.09 g, 5.14 mmol, 3 equiv.), Pd(dppf)Cl2(125 mg, 171 μmol, 0.1 equiv.) in dioxane (5.00 mL) and H2O (1.00 mL) was degassed and purged with N2 three times at 25 °C, and then the mixture was heated to 90 °C and stirred at 90 °C for 6 h under N2 atmosphere. LC-MS showed Compound 36-2 was consumed and the desired m / z (RT = 0.544 min) was detected. The mixture was cooled to 25 °C and poured into H2O (20.0 mL), then the aqueous phase was extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed one time with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1, petroleum ether / ethyl acetate = 1 / 1, Rf = 0.45), then the fraction was concentrated. The product methyl 4-[5-chloro-2- (tetrahydropyran-4-ylamino)-4-pyridyl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 36-3, 800 mg, 1.63 mmol, 95.2% yield, 100% purity) was obtained as yellow oil. LC-MS: m / z = 490.1 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.39 - 7.34 (m, 3H), 6.44 (s, 1H), 4.49 (br d, J = 6.8 Hz, 1H), 4.04 - 3.96 (m, 2H), 3.92 - 3.85 (m, 1H), 3.78 (s, 3H), 3.61 - 3.52 (m, 2H), 2.45 (s, 3H), 2.09 - 2.06 (m, 1H), 2.04 (br d, J = 1.6 Hz, 1H), 1.56 - 1.51 (m, 2H).

[0239] Synthesis and Characterization of Compound 36-4. 123 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 36-3 (700 mg, 1.43 mmol, 1 equiv.) in THF (7.00 mL) and H2O (7.00 mL) was added NaOH (286 mg, 7.14 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C stirred at 80 °C for 12 h. LC-MS showed Compound 36-3 was consumed and the desired m / z (RT = 0.355 min) was detected. The mixture was concentrated to remove most of THF, then adjusted pH to 2 - 3 with 1 M HCl, filtered, and the filter cake was concentrated to get crude product. The crude product was used in the next step without further purification. The product 4-[5-chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H- pyrrole-2-carboxylic acid (Compound 36-4, 415 mg, 1.29 mmol, 90.3% yield, 100% purity) was obtained as a gray solid. LC-MS: m / z = 322.1 [M+H]+.1H NMR: (400 MHz, DMSO- d6) δ 12.5 (br s, 1H), 12.2 (br s, 1H), 7.97 (s, 1H), 7.44 (br s, 1H), 7.09 (br s, 1H), 6.65 (s, 1H), 6.55 (br d, J = 7.6 Hz, 1H), 3.85 (br d, J = 11.6 Hz, 3H), 3.45 - 3.37 (m, 2H), 1.86 (br d, J = 12.0 Hz, 2H), 1.50 - 1.31 (m, 2H).

[0240] Synthesis and Characterization of Compound 36-5.To a solution of Compound 36-4 (120 mg, 373 μmol, 1 equiv.) in NMP (1.20 mL) was added Compound 1-5 (104 mg, 448 μmol, 1.2 equiv., HCl), HOBt (60.5 mg, 448 μmol, 1.2 equiv.), EDCI (143 mg, 746 μmol, 2 equiv.), and DIEA (96.4 mg, 746 μmol, 130 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 36-4 was consumed and the desired m / z (RT = 0.478 min) was detected. The mixture was poured into H2O (20.0 mL), then the aqueous phase was extracted three times with 20.0 mL ethyl 124 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[5- chloro-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Compound 36-5, 200 mg, 354 μmol, 95.0% yield, 88.6% purity) was obtained as brown oil. LC-MS: m / z = 500.2 [M+H]+.

[0241] Synthesis and Characterization of Target 36.To a solution of Compound 36-5 (200 mg, 354 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3(139 mg, 531 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 36-5 was consumed and the desired m / z (RT = 0.390 min) was detected. The mixture was concentrated. The filtrate was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 5 µm; mobile phase: [water (NH4HCO3)- acetonitrile]; gradient: 23%-53% acetonitrile over 10 min), then it was lyophilized. The product N-[(1S)-2-amino-1-(3-chlorophenyl)ethyl]-4-[5-chloro-2-(tetrahydropyran-4- ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 36, 50.5 mg, 107 μmol, 30.1% yield, 100% purity) was obtained as a white solid. LC-MS: m / z = 474.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.9 - 11.8 (m, 1H), 8.44 (br d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.41 - 7.28 (m, 7H), 6.66 - 6.64 (m, 1H), 6.60 (br d, J = 7.6 Hz, 1H), 4.92 (q, J = 7.2 Hz, 1H), 3.90 - 3.84 (m, 3H), 3.43 - 3.37 (m, 2H), 2.85 (br d, J = 6.8 Hz, 2H), 1.88 - 1.85 (m, 3H), 1.46 - 1.36 (m, 2H). Example 32: Synthesis of Target 37

[0242] Synthesis and Characterization of Compound 37-2. 125 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound a (9.20 g, 48.4 mmol, 1 equiv.) in DMSO (92.0 mL) was added Compound 2 (6.37 g, 62.9 mmol, 1.3 equiv.) and DIEA (18.7 g, 145 mmol, 25.3 mL, 3 equiv.) at 25 °C. The mixture was heated to 140 °C and stirred at 140 °C for 12 h. LC-MS showed that Compound a was consumed, and the desired m / z was detected. The mixture was cooled to 25 °C and poured into water (500 mL) at 20 °C and extracted three times with 200 mL ethyl acetate. The organic layers were combined and washed three times with 200 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, petroleum ether / ethyl acetate = 3 / 1, Rf = 0.30) and the fraction was concentrated to give 4-bromo-5-methyl-N-tetrahydropyran-4-yl-pyridin-2-amine (Compound 37-2, 4.90 g, 18.1 mmol, 37.3% yield) as a yellow solid. LC-MS: m / z = 271.2 [M+H]+.

[0243] Synthesis and Characterization of Compound 37-3.To a solution of Compound 37-2 (3.90 g, 14.4 mmol, 1 equiv.) and bis(pinacolato)diboron (B2(pin)2, 7.30 g, 28.8 mmol, 2 equiv.) in DMF (39.0 mL) was added potassium acetate (AcOK, 2.82 g, 28.8 mmol, 2 equiv.), XPhos (1.37 g, 2.88 mmol, 0.2 equiv.), Pd2(dba)3 (1.32 g, 1.44 mmol, 0.1 equiv.) at 25 °C. The mixture was heated to 95 °C and stirred at 95 °C for 16 h. LC-MS showed that Compound 37-2 was consumed completely, and the desired m / z was detected. The mixture was cooled to 25 °C and poured into water (200 mL) at 20 °C and extracted three times with 200 mL ethyl acetate. The combined organic layers were washed three times with 200 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18250 126 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) mm × 70 mm, 10 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 1%-20% acetonitrile over 10 min) and the eluent was concentrated under 30 °C and lyophilized to give [5-methyl- 2-(tetrahydropyran-4-ylamino)-4-pyridyl]boronic acid (Compound 37-3, 1.10 g, 4.66 mmol, 27.5% yield) as a white solid. LC-MS: m / z = 237.3 [M+H]+.1H NMR: (400 MHz, DMSO- d6) δ 8.14 (s, 2H), 7.68 (s, 1H), 6.49 (s, 1H), 6.10 (br d, J = 7.6 Hz, 1H), 3.87 - 3.82 (m, 3H), 3.38 (br d, J = 2.0 Hz, 2H), 2.11 (s, 3H), 1.83 (br d, J = 12.4 Hz, 2H), 1.46 - 1.31 (m, 2H).

[0244] Synthesis and Characterization of Compound 37-4.A mixture of Compound 37-3 (570 mg, 2.41 mmol, 1 equiv.), methyl 5-bromo-2- tetrahydropyran-2-yl-1,2,4-triazole-3-carboxylate (Compound h, 700 mg, 2.41 mmol, 1 equiv.), K3PO4(1.02 g, 4.83 mmol, 2 equiv.), and Xphos Pd G4 (208 mg, 241 μmol, 0.1 equiv.) in H2O (2.80 mL) and THF (14.0 mL) was degassed and purged with N23 times at 25 °C, and then the mixture was stirred at 70 °C for 2 h under N2 atmosphere. LC-MS showed that Compound 37-3 was consumed completely, and the desired m / z was detected. The reaction mixture was cooled to 25 °C and used in the next step directly. The product methyl 5-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-2-tetrahydropyran-2-yl-1,2,4-triazole- 3-carboxylate (Compound 37-4, 760 mg, 1.89 mmol, 78.5% yield) as brown oil. LC-MS: m / z = 402.1 [M+H]+.

[0245] Synthesis and Characterization of Compound 37-5.To a solution of Compound 37-4 (760 mg, 1.89 mmol, 1 equiv.) in THF (15.2 mL) was added HCl (1.00 M, 15.2 mL, 8.03 equiv.) at 25 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed that Compound 37-4 was consumed completely, and the desired m / z was 127 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) detected. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC(column: Phenomenex Luna™ C18150 mm × 40 mm, 15 µm; mobile phase: [water (FA)-acetonitrile]; gradient: 0%-30% acetonitrile over 15 min) and the eluent was concentrated under reduced pressure at 45 °C and lyophilized to give methyl 3-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-1,2,4-triazole-5-carboxylate (Compound 37-5, 170 mg, 536 μmol, 28.3% yield, 100% purity) was obtained as a white solid. LC-MS: m / z = 318.3 [M+H]+.

[0246] Synthesis and Characterization of Compound 37-6.To a solution of Compound 37-5 (150 mg, 473 μmol, 1 equiv.) in THF (4.00 mL) and H2O (4.00 mL) was added LiOH•H2O (99.2 mg, 2.36 mmol, 5 equiv.) at 25 °C. The mixture was heated to 50 °C stirred at 50 °C for 6 h. LC-MS showed that Compound 37-5 was consumed completely, and the desired m / z was detected. The reaction mixture was concentrated and adjusted to pH 3 and solids precipitated out. The suspension was filtered, and the filter cake was dried to give 3-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-1,2,4-triazole-5- carboxylic acid (Compound 37-6, 150 mg, crude) as a white solid. LC-MS: m / z = 304.2 [M+H]+.

[0247] Synthesis and Characterization of Compound 37-7.128 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 37-6 (150 mg, 494 μmol, 1 equiv.) in NMP (1.50 mL) was added Compound 1-5 (138 mg, 593 μmol, 1.2 equiv., HCl), HOBt (80.2 mg, 593 μmol, 1.2 equiv.), EDCI (190 mg, 989 μmol, 2 equiv.), and DIEA (192 mg, 1.48 mmol, 258 μL, 3 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed that Compound 37-6 was consumed completely, and the desired m / z was detected. The reaction mixture was filtered, and the filtrate was used for purification. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [water (FA)- acetonitrile]; gradient: 12%-42% acetonitrile over 15 min) and the eluent was concentrated under reduced pressure at 40 °C and lyophilized to give N-[(1S)-2-azido-1-(3- chlorophenyl)ethyl]-3-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-1,2,4- triazole-5-carboxamide (Compound 37-7, 80.0 mg, 166 μmol, 33.6% yield, 100% purity) as a white solid. LC-MS: m / z = 482.1 [M+H]+.1H NMR: (400 MHz, MeOD-d4) δ 8.15 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 7.46 - 7.31 (m, 3H), 7.06 (br s, 1H), 5.34 (br dd, J = 6.0, 7.6 Hz, 1H), 3.99 (br d, J = 11.2 Hz, 2H), 3.94 - 3.85 (m, 1H), 3.84 - 3.73 (m, 2H), 3.56 (br t, J = 11.4 Hz, 2H), 2.40 (s, 3H), 2.10 - 1.94 (m, 2H), 1.66 - 1.47 (m, 2H).

[0248] Synthesis and Characterization of Compound 37-8.To a solution of Compound 37-7 (70.0 mg, 145 μmol, 1 equiv.) in THF (1.26 mL) and H2O (0.14 mL) was added PPh3 (57.1 mg, 218 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 6 h. LC-MS showed that Compound 37-7 was consumed completely, and the desired m / z was detected. The reaction mixture was used for next step directly. The product N-[(1S)- 1-(3-chlorophenyl)-2-[(triphenylphosphanylidene)amino]ethyl]-3-[5-methyl-2- (tetrahydropyran-4-ylamino)-4-pyridyl]-1H-1,2,4-triazole-5-carboxamide (Compound 37-8, 104 mg, crude) was diluted in solvents as yellow oil. LC-MS: m / z = 716.2 [M+H]+.

[0249] Synthesis and Characterization of Target 37. 129 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 37-8 (104 mg, 145 μmol, 1 equiv.) in THF (2.00 mL) was added NaOH (2.0 M, 200 μL, 2.75 equiv.). The mixture was stirred at 25 °C for 8 h. LC-MS showed the compound 37-8 was consumed completely and the desired m / z was detected. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 10 µm; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 18%-38% B over 8 min) and the eluent was concentrated under 40 °C and lyophilized to give N-[(1S)-2-amino-1-(3- chlorophenyl)ethyl]-3-[5-methyl-2-(tetrahydropyran-4-ylamino)-4-pyridyl]-1H-1,2,4- triazole-5-carboxamide (Target 37, 36.57 mg, 77.2 μmol, 53.1% yield, 96.2% purity) as a white solid. LC-MS: m / z = 456.1 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.38 - 8.14 (m, 1H), 8.02 (s, 1H), 7.38 - 7.32 (m, 1H), 7.31-7.28 (m, 1H), 7.25 - 7.21 (m, 1H), 6.92 (s, 1H), 5.20 (br d, J = 3.2 Hz, 1H), 4.82 - 4.54 (m, 1H), 3.97 (br d, J = 11.6 Hz, 2H), 3.93 - 3.81 (m, 1H), 3.52 (br t, J = 11.6 Hz, 2H), 3.35 - 3.16 (m, 2H), 2.40 (s, 3H), 2.05-1.95 (m, 2H), 1.56 - 1.44 (m, 2H).

[0250] Synthesis and Characterization of Compound h.To a solution of methyl 3-bromo-1H-1,2,4-triazole-5-carboxylate (Compound h-1, 3.00 g, 14.5 mmol, 1 equiv.) in THF (60.0 mL) was added DHP (3.68 g, 43.7 mmol, 3.99 mL, 3 equiv.) and TsOH•H2O (277 mg, 1.46 mmol, 0.1 equiv.) at 25 °C. The mixture was heated to 70 °C and stirred at 70 °C for 6 h. TLC (petroleum ether / ethyl acetate = 3 / 1, I2) showed that 130 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Compound h-1 (Rf = 0.10) was consumed completely, and a new spot (Rf = 0.40) was formed. The mixture was poured into water (20.0 mL) at 20 °C and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, petroleum ether / ethyl acetate = 3 / 1, Rf= 0.40) and the fraction was concentrated to give Compound h (1.40 g, 4.83 mmol, 33.1% yield) as a yellow solid.1H NMR: (400 MHz, MeOD-d4) δ 6.30 (dd, J = 2.8, 9.2 Hz, 1H), 4.77 (br s, 2H), 4.11 - 4.04 (m, 1H), 4.01 (s, 3H), 3.78 - 3.69 (m, 1H), 2.44 - 2.26 (m, 1H), 2.12 (br dd, J = 4.8, 8.8 Hz, 1H), 1.99 (br dd, J = 3.2, 13.2 Hz, 1H), 1.79 (br d, J = 4.4 Hz, 1H). Example 33: Synthesis of Target 41

[0251] Synthesis and Characterization of Compound 41-3.To a mixture of methyl 4-(2,5-dichloropyrimidin-4-yl)-1-(p-tolylsulfonyl)pyrrole-2- carboxylate (Compound 41-2, 1.00 g, 2.35 mmol, 1 equiv.) in dioxane (20.0 mL) was added Compound 7 (474 mg, 3.05 mmol, 1.3 equiv., HCl), BINAP (292 mg, 469 μmol, 0.2 equiv.), Pd2(dba)3 (214 mg, 234 μmol, 0.1 equiv.), and Cs2CO3 (1.53 g, 4.69 mmol, 2 equiv.) under N2. The mixtrue was stirred at 80 °C for 10 h. LC-MS showed that Compound 41-2 was consumed completely and the desired product (RT = 0.617 min) was detected. The mixture was poured into H2O (100 mL) and extracted two times with 100 mL ethyl acetate. The combined organic layers were washed two times with 100 mL brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1, product: petroleum ether / ethyl acetate = 3 / 1, Rf = 0.25 ) and the solvent was concentrated. The product methyl 4-[5-chloro-2-[[(3S,4S)-3- fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate) (Compound 41-3, 660 mg, 1.17 mmol, 49.7% yield, 90.0% purity) was obtained as the yellow solid. LC-MS: m / z = 509.2 [M+H]+.1H NMR: (400 MHz,CDCl3) δ 8.63 (d, J = 2.0 131 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) Hz, 1H), 8.28 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.80 - 7.72 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 5.45 (br d, J = 8.8 Hz, 1H), 4.85 - 4.66 (m, 1H), 4.38 - 4.00 (m, 3H), 3.79 (s, 3H), 3.74 - 3.51 (m, 2H), 2.45 (s, 3H), 2.08 - 1.85 (m, 2H).

[0252] Synthesis and Characterization of Compound 41-4.To a mixture of Compound 41-3 (630 mg, 1.24 mmol, 1 equiv.) in THF (6.30 mL) and H2O (6.30 mL) was added NaOH (247 mg, 6.19 mmol, 5 equiv.) at 20 °C. The mixture was stirred at 50 °C for 10 h. LC-MS showed that Compound 41-3 was consumed completely and the desired product was detected. The mixture was cooled to 25 °C, then concentrated under reduced pressure to remove THF and adjusted to pH 3 using 1.00 M HCl. The mixture was then filtered and the filter cake was concentrated under reduced pressure to give a residue. The product 4-[5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin- 4-yl]-1H-pyrrole-2-carboxylic acid (Compound 41-4, 400 mg, crude) was obtained as a yellow solid. LC-MS: m / z = 341.1 [M+H]+.1H NMR: (400 MHz,DMSO-d6) δ 12.76 - 12.49 (m, 1H), 12.40 - 12.19 (m, 1H), 8.29 (s, 1H), 7.83 (br s, 1H), 7.49 (s, 1H), 7.24 (br d, J = 6.8 Hz, 1H), 4.91 - 4.65 (m, 1H), 4.23 - 4.07 (m, 1H), 4.03 - 3.88 (m, 2H), 3.66 - 3.47 (m, 2H), 2.07 (s, 4H), 1.88 - 1.99 (m, 1H), 1.71 - 1.62 (m, 1H).

[0253] Synthesis and Characterization of Compound 41-5.132 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a mixture of Compound 41-4 (100 mg, 293 μmol, 1 equiv.) and Compound 22A (88.4 mg, 352 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added EDCI (112 mg, 586 μmol, 2 equiv.), HOBt (47.5 mg, 352 μmol, 1.2 equiv.) and DIEA (151 mg, 1.17 mmol, 204 μL, 4 equiv.) at 0 °C. The mixture was stirred at 20 °C for 10 h. LC-MS showed that Compound 41-4 was consumed completely, and the desired product was detected. The mixture was poured into H2O (25.0 mL) and extracted two times with 30.0 mL ethyl acetate. The combined organic layers were washed five times with 30.0 mL brine, dried over Na2SO4, filtered, and concentrated. The product N-[(1S)-2-azido-1-(3-chloro-5-fluorophenyl)ethyl]-4- [5-chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2- carboxamide (Compound 41-5, 134 mg, crude) was obtained as a yellow oil. LC-MS: m / z = 537.1 [M+H]+.

[0254] Synthesis and Characterization of Target 41.To a mixture of Compound 41-5 (134 mg, 249 μmol, 1 equiv.) in THF (2.00 mL) and H2O (0.200 mL) was added PPh3 (98.1 mg, 374 μmol, 1.5 equiv.) at 20 °C for 10 h. LC-MS showed that Compound 41-5 was consumed completely and the desired product was detected. The mixture was concentrated. The residue was purified by prep-HPLC (column: Waters XBridge® C18150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)- acetonitrile]; gradient: 25%-55% acetonitrile over 12.0 min) and lyophilized. The mixture was purified by prep-HPLC (column: Boston Green ODS 150 mm × 30 mm, 5 µm; mobile phase: [H2O (0.225% FA)-acetonitrile]; gradient: 18%-48% acetonitrile over 11.0 min) and lyophilized. The product N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-chloro-2- [[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 41, 44.06 mg, 77.3 μmol, 31.0% yield, 97.8% purity, FA) was obtained as an off- white solid. LC-MS: m / z = 511.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 9.02 - 8.69 (m, 1H), 8.38 - 8.20 (m, 2H), 7.81 - 7.67 (m, 2H), 7.37 - 7.29 (m, 2H), 7.26 - 7.06 (m, 2H), 5.15 - 4.98 (m, 1H), 4.92 - 4.68 (m, 1H), 4.25 - 3.87 (m, 4H), 3.73 - 3.64 (m, 2H), 133 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 3.05 - 2.95 (m, 2H), 1.95 (dq, J = 12.4, 4.0Hz, 1H), 1.80 - 1.56 (m, 1H).19F NMR: (400 MHz, DMSO-d6) -110.790. Example 34: Synthesis of Target 42

[0255] Synthesis and Characterization of Compound 42-2.To a solution of 2,5-dichloropyrimidin-4-amine (Compound 42-1, 12.0 g, 73.2 mmol, 1 equiv.) in MeCN (250 mL) was added isopentyl nitrite (25.7 g, 219 mmol, 29.6 mL, 3 equiv.) and CuBr2 (32.7 g, 146 mmol, 6.85 mL, 2 equiv.) at 0 °C. The mixture was heated to 80 °C and stirred at 80 °C for 2 h. LC-MS showed that Compound 42-1 was consumed completely, and the desired m / z was detected. The reaction mixture was cooled to 25 °C and poured into water (20.0 mL) at 20 °C and extracted three times with 100 mL ethyl acetate. The organic layers were combined and washed three times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1, petroleum ether / ethyl acetate = 10 / 1, Rf = 0.80) and the fraction was concentrated to give 4- bromo-2, 5-dichloro-pyrimidine (Compound 42-2, 14.3 g, 62.7 mmol, 85.7% yield) as a white solid. LC-MS: m / z = 228.9 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.94 (s, 1H).

[0256] Synthesis and Characterization of Compound 42-3.42-2 42-3 To a mixture of Compound 42-2 (8.00 g, 35.1 mmol, 1 equiv.) and Compound b (14.2 g, 35.1 mmol, 1 equiv.) in dioxane (80.0 mL) and H2O (16.0 mL) was added K3PO4(22.4 g, 105 134 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) mmol, 3 equiv.) and Pd(dppf)Cl2 (2.57 g, 3.51 mmol, 0.1 equiv.) at 25 °C under N2. The mixture was degassed and purged with N23 times at 25 °C, and then the mixture was heated to 85 °C and stirred at 85 °C for 1 h. LC-MS showed that Compound 42-2 was consumed completely, and the desired m / z was detected. The reaction mixture was cooled to 25 °C, poured into water (100 mL), and extracted three times with 100 mL CH2Cl2. The organic layers were combined and washed three times with 100 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, 20% CH2Cl2 in petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, petroleum ether / ethyl acetate = 5 / 1, Rf= 0.50) and the fraction was concentrated to give methyl 4-(2,5-dichloropyrimidin-4-yl)-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 42-3, 8.50 g, 19.9 mmol, 56.8% yield) as a white solid. LC-MS: m / z = 426.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 3.73 (s, 3H), 2.42 (s, 3H).

[0257] Synthesis and Characterization of Compound 42-4.A mixture of Compound 42-3 (1.00 g, 2.35 mmol, 1 equiv.), Compound 8 (474 mg, 3.05 mmol, 1.3 equiv., HCl), BINAP (292 mg, 469 μmol, 0.2 equiv.), Pd2(dba)3 (215 mg, 234 μmol, 0.1 equiv.), and Cs2CO3 (1.53 g, 4.69 mmol, 2 equiv.) in dioxane (20.0 mL) was degassed and purged with N23 times at 25 °C, and then the mixture was heated to 80 °C and stirred at 80 °C for 16 h under N2. LC-MS showed that Compound 42-3 was consumed completely, and the desired m / z was detected. The mixture was cooled to 25 °C, poured into water (30.0 mL), and extracted three times with 30.0 mL ethyl acetate. The combined organic layers were washed three times with 30.0 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, 20% CH2Cl2in petroleum ether / ethyl acetate = 1 / 0 to 5 / 1, petroleum ether / ethyl acetate = 3 / 1, Rf= 0.30) and the fraction was concentrated to give methyl 4-[5- chloro-2-[[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1-(p- tolylsulfonyl)pyrrole-2-carboxylate (Compound 42-4, 695 mg, 1.37 mmol, 58.2% yield) as a 135 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) yellow solid. LC-MS: m / z = 509.0 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.63 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 5.44 (br d, J = 9.2 Hz, 1H), 4.91 - 4.63 (m, 1H), 4.38 - 4.14 (m, 2H), 4.08 (br dd, J = 4.0, 11.6 Hz, 1H), 3.79 (s, 3H), 3.73 - 3.52 (m, 2H), 2.45 (s, 3H), 2.01 (dq, J = 4.4, 12.3 Hz, 1H), 1.95 - 1.87 (m, 1H).

[0258] Synthesis and Characterization of Compound 42-5.To a solution of Compound 42-4 (650 mg, 1.28 mmol, 1 equiv.) in THF (13.0 mL) and H2O (13.0 mL) was added NaOH (255 mg, 6.39 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 h. LC-MS showed that Compound 42-4 was consumed completely, and the desired m / z was detected. The reaction mixture was cooled to 25 °C and the mixture was concentrated under reduced pressure to remove THF. The aqueous phase was adjusted pH 6 using 1N HCl then the solids precipitated out. The suspension was filtered and washed three times with 3.00 mL H2O. The filter cake was dried to give 4-[5-chloro-2-[[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H- pyrrole-2-carboxylic acid. (Compound 42-5, 430 mg, 1.26 mmol, 98.8% yield) as a yellow solid. LC-MS: m / z = 341.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 13.2 - 12.4 (m, 1H), 12.3 (br s, 1H), 8.29 (s, 1H), 7.83 (br s, 1H), 7.49 (s, 1H), 7.26 (br d, J = 6.8 Hz, 1H), 4.99 - 4.56 (m, 1H), 4.27 - 4.05 (m, 1H), 4.04 - 3.95 (m, 1H), 3.95 - 3.87 (m, 1H), 3.69 - 3.52 (m, 2H), 1.93 (dq, J = 4.8, 12.4 Hz, 1H), 1.74 - 1.61 (m, 1H).

[0259] Synthesis and Characterization of Compound 42-6. 136 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 42-5 (100 mg, 293 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 22A (81.1 mg, 323 μmol, 1.1 equiv., HCl), HOBt (47.6 mg, 352 μmol, 1.2 equiv.), EDCI (112 mg, 587 μmol, 2 equiv.), and DIEA (114 mg, 880 μmol, 153 μL, 3 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS (EW58668-11-P1A) showed that Compound 42-5 was consumed completely, and the desired m / z was detected. The reaction mixture was poured into iced water (10.0 mL) and the solid precipitated out. The suspension was filtered and washed two times with water 2.00 mL. The filter cake was dried to give N-[(1S)-2-azido-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-chloro-2-[[(3R,4R)-3- fluorotetrahydro-pyran -4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 42-6, 150 mg, crude) as a yellow solid. LC-MS: m / z = 537.3 [M+H]+.

[0260] Synthesis and Characterization of Target 42.To a solution of Compound 42-6 (150 mg, 279 μmol, 1 equiv.) in THF (3.00 mL) and H2O (0.30 mL) was added PPh3(146 mg, 558 μmol, 2 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 42-6 was consumed completely and the desired m / z (RT = 0.499 min) was detected. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [H2O (0.225% FA)-acetonitrile]; gradient: 10%-40% acetonitrile over 15.0 min) and the eluent was concentrated under reduced pressure at 45 °C and 137 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) lyophilized to give N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-chloro-2- [[(3R,4R)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 42, 81.19 mg, 142 μmol, 51.1% yield, 97.9% purity, FA) as an off-white solid. LC- MS: m / z = 511.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.1 (br s, 1H), 8.87 (br s, 1H), 8.39 - 8.21 (m, 2H), 7.83 - 7.69 (m, 2H), 7.42 - 7.30 (m, 2H), 7.28 - 7.00 (m, 2H), 5.17 - 5.02 (m, 1H), 4.91 - 4.69 (m, 1H), 4.24 - 4.12 (m, 1H), 4.11 - 3.95 (m, 2H), 3.94 - 3.81 (m, 2H), 3.02 (br d, J = 7.2 Hz, 2H), 2.02 - 1.89 (m, 1H), 1.67 (br dd, J = 3.6, 12.8 Hz, 1H).19F NMR: (400 MHz, DMSO-d6) -110.739. Example 35: Synthesis of Targets 43-P1 and 43-P2

[0261] Synthesis and Characterization of Compound 43-2.- To a solution of methyl 4-(2,5-dichloropyrimidin-4-yl)-1-(p-tolylsulfonyl)pyrrole-2- carboxylate (Compound 43-1, 1.70 g, 3.99 mmol, 1 equiv.) and Compound 18-1 (931 mg, 5.98 mmol, 1.5 equiv., HCl) in dioxane (17.0 mL) was added Cs2CO3 (2.60 g, 7.98 mmol, 2 equiv.), BINAP (497 mg, 798 μmol, 0.2 equiv.), and Pd2(dba)3(365 mg, 399 μmol, 0.1 equiv.) at 25 °C under N2. The mixture was degassed and purged with N23 times. Then the mixture was heated to 80 °C and stirred at 80 °C for 12 h under N2. LC-MS showed Compound 43-1 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 two times with 20.0 mL ethyl acetate. The combined organic phase was washed two times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (diameter: 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, petroleum ether / ethyl acetate = 3 / 1, Rf = 0.20). The fraction was filtered and concentrated under reduced pressure to give methyl 4-[5-chloro- 2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]-1-(p-tolylsulfonyl)pyrrole-2- carboxylate (Compound 43-2, 710 mg, 933 μmol, 23.4% yield, 66.9% purity) as a yellow solid. LC-MS: m / z = 509.0 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.64 (d, J = 2.0 Hz, 138 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 1H), 8.29 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 5.21 (d, J = 7.6 Hz, 1H), 4.60 - 4.39 (m, 1H), 4.34 - 4.23 (m, 1H), 4.12 - 4.05 (m, 1H), 3.95 - 3.85 (m, 1H), 3.79 (s, 3H), 3.67 - 3.54 (m, 2H), 2.45 (s, 3H), 2.40 - 2.29 (m, 1H), 1.72 - 1.62 (m, 1H).

[0262] Synthesis and Characterization of Compound 43-3.To a solution of Compound 43-2 (660 mg, 868 μmol, 1 equiv.) in THF (6.00 mL) and H2O (6.00 mL) was added NaOH (174 mg, 4.34 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 h. LC-MS showed Compound 43-2 was consumed and the desired m / z was detected. The mixture was cooled to 25 °C and concentrated to remove most of THF. The pH was adjusted to 3-4 with 1 M HCl and filtered. The filter cake was concentrated to give 4-[5-chloro-2-[(3-fluorotetrahydropyran-4- yl)amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid (Compound 43-3, 430 mg, 810 μmol, 93.3% yield, 64.2% purity) as a yellow solid. LC-MS: m / z = 341.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.75 - 12.54 (m, 1H), 12.33 (s, 1H), 8.33 - 8.22 (m, 1H), 8.29 (s, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 4.68 - 4.42 (m, 1H), 4.29 - 4.11 (m, 1H), 4.07 - 3.92 (m, 1H), 3.86 - 3.75 (m, 1H), 3.55 - 3.37 (m, 2H), 2.06 - 1.95 (m, 1 H), 1.65 - 1.48 (m, 1 H).

[0263] Synthesis and Characterization of Compound 43-4.139 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 43-3 (400 mg, 754 μmol, 1 equiv.) in NMP (4.00 mL) was added Compound 22A (227 mg, 904 μmol, 1.2 equiv., HCl), HOBt (122 mg, 904 μmol, 1.2 equiv.), EDCI (289 mg, 1.51 mmol, 2 equiv.), and DIEA (195 mg, 1.51 mmol, 263 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 43-3 was consumed and the desired m / z was detected. The reaction mixture was poured into H2O (50.0 mL), and the aqueous phase was extracted two times with 50.0 mL ethyl acetate. The combined organic phase was washed two times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2-azido-1-(3- chloro-5-fluorophenyl)ethyl]-4-[5-chloro-2-[(3-fluorotetrahydropyran-4-yl)amino]pyrimidin- 4-yl]-1H-pyrrole-2-carboxamide (Compound 43-4, 670 mg, crude) was obtained as yellow oil. LC-MS: m / z = 537.3 [M+H]+.

[0264] Synthesis and Characterization of Compound 43-5.To a solution of Compound 43-4 (620 mg, 711 μmol, 1 equiv.) in THF (5.40 mL) and H2O (0.60 mL) was added PPh3(280 mg, 1.07 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 43-4 was consumed and the desired m / z was detected. The mixture was concentrated. The crude product was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [H2O (0.225% FA)-acetonitrile]; gradient: 20%-40% acetonitrile over 10.0 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-chloro-2- [(3-fluorotetrahydropyran-4-yl)amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 43-5, 100 mg, 193 μmol, 23.8% yield, 98.9% purity) as a yellow solid. LC- MS: m / z = 511.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.88 - 8.74 (m, 1H), 8.32 - 8.22 (m, 2H), 7.79 - 7.67 (m, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.23 (d, J = 140 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 9.6 Hz, 1H), 5.14 - 4.99 (m, 1H), 4.66 - 4.44 (m, 1H), 4.30 - 4.15 (m, 1H), 4.05 - 3.96 (m, 1H), 3.88 - 3.76 (m, 2H), 2.99 (d, J = 7.2 Hz, 2H), 2.09 - 1.94 (m, 1H), 1.68 - 1.50 (m, 1H).

[0265] Synthesis and Characterization of Targets 43-P1 and 43-P2.Compound 43-5 was purified by prep-HPLC (column: DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 µm; mobile phase: [CO2-IPA:acetonitrile=4:1 (0.1% NH3•H2O)]; B%: 40%, isocratic elution mode) and concentrated to give N-[(1S)-2-amino-1-(3-chloro-5- fluorophenyl)ethyl]-4-[5-chloro-2-[[(3R,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin- 4-yl]-1H-pyrrole-2-carboxamide (Target 43-P1, 30.5 mg, 59.7 μmol, 30.8% yield, 100% purity) as a white solid and N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-chloro- 2-[[(3S,4R)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 43-P2, 36.48 mg, 70.84 μmol, 36.63% yield, 99.3% purity) as a white solid. LC- MS: P1, m / z = 511.2 [M+H]+. SFC: P1, RT = 1.909 mins, enantiomerically enriched to 100% under 220 nm.1H NMR: P1 (400 MHz, DMSO-d6) δ 8.73 - 8.60 (m, 1H), 8.29 (s, 1H), 7.80 - 7.67 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.22 (d, J = 9.6 Hz, 1H), 5.04 - 4.92 (m, 1H), 4.65 - 4.45 (m, 1H), 4.27 - 4.15 (m, 1H), 4.05 - 3.95 (m, 1H), 3.87 - 3.75 (m, 1H), 3.52 - 3.44 (m, 2H), 2.91 (d, J = 6.4 Hz, 2H), 2.09 - 1.97 (m, 1H), 1.66 - 1.50 (m, 1H), 1.23 (s, 1H).19F NMR: (400 MHz, DMSO-d6) δ -110.975. LC-MS: P2, m / z = 511.2 [M+H]+. SFC: P2, RT = 2.116 mins enantiomerically enriched to 97.1% under 220 nm.1H NMR: P2 (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H), 7.80 - 7.70 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.22 (d, J = 9.6 Hz, 1H), 5.02 - 4.91 (m, 1H), 4.67 - 4.42 (m, 1H), 4.23 (s, 1H), 4.07 - 3.93 (m, 1H), 3.88 - 3.77 (m, 1H), 3.54 - 141 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 3.42 (m, 2H), 2.95 - 2.83 (m, 2H), 2.09 - 1.94 (m, 1H), 1.67- 1.49 (m, 1H), 1.23 (s, 1H).19F NMR: (400 MHz, DMSO-d6) δ -110.993. Example 36: Synthesis of Target 44

[0266] Synthesis and Characterization of Compound 44-1.To a mixture of Compound 41-4 (100 mg, 293 μmol, 1 equiv.) and Compound 25-5 (91.1 mg, 352 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added EDCI (112 mg, 586 μmol, 2 equiv.), HOBt (47.5 mg, 352 μmol, 1.2 equiv.), and DIEA (151 mg, 1.17 mmol, 204 μL, 4 equiv.) at 0 °C. The mixture was stirred at 20 °C for 10 h. LC-MS showed Compound 41-4 was consumed completely and the desired product was detected. The mixture was poured into H2O (25.0 mL) and extracted two times with 30.0 mL ethyl acetate. The organic layers were combined and washed five times with 30.0 mL brine, dried over Na2SO4, filtered, and concentrated. The product N-[(1S)-2-azido-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[5- chloro-2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2- carboxamide (Compound 44-1, 180 mg, crude) was obtained as a gray oil. LC-MS: m / z = 545.2 [M+H]+.

[0267] Synthesis and Characterization of Target 44.To a mixture of Compound 44-1 (180 mg, 330 μmol, 1 equiv.) in THF (2.00 mL) and H2O (0.200 mL) was added PPh3 (129 mg, 495 μmol, 1.5 equiv.) at 20 °C and stirred for 10 h. 142 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) LC-MS showed Compound 44-1 was consumed completely and the desired product was detected. The mixture was concentrated. The residue was purified by prep-HPLC (column: Waters XBridge® C18150 mm × 25 mm, 5 µm; mobile phase: [H2O (10 mM NH4HCO3)- acetonitrile]; gradient: 23%-53% acetonitrile over 15.0 min) and lyophilized. The product N- [(1S)-2-amino-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[5-chloro-2-[[(3S,4S)-3- fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 44, 43.83 mg, 80.3 μmol, 24.3% yield, 95.1% purity) was obtained as an off-white solid. LC- MS: m / z = 519.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.63 - 8.44 (m, 1H), 8.30 (s, 1H), 7.75 (d, J = 16.8 Hz, 2H), 7.27 - 7.07 (m, 2H), 7.04 - 6.82 (m, 2H), 5.04 - 4.73 (m, 2H), 4.23 - 4.07 (m, 1H), 4.05 - 3.89 (m, 2H), 3.70 - 3.47 (m, 4H), 2.93 - 2.83 (m, 3H), 1.91 - 2.01 (m, 1H), 1.67 (br d, J = 10.4 Hz, 1H), 1.23 - 1.16 (m, 6H).19F NMR: EW58288-24-P1N1- FNMR, (400 MHz, DMSO-d6) -113.995. Example 37: Synthesis of Target 45

[0268] Synthesis and Characterization of Compound 45-1.To a solution of Compound 42-5 (100 mg, 293 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 25-5 (83.5 mg, 323 μmol, 1.1 equiv., HCl), HOBt (47.6 mg, 352 μmol, 1.2 equiv.), EDCI (112 mg, 587 μmol, 2 equiv.), and DIEA (114 mg, 880 μmol, 153 μL, 3 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 42-5 was consumed completely and the desired m / z was detected. The reaction mixture was poured into ice water (10.0 mL) and the solid precipitated out. The suspension was filtered and washed two times with 2.00 mL water. The filter cake was dried to give N-[(1S)-2-azido- 1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[5-chloro-2-[[(3R,4R)-3-fluorotetrahydropyran-4- yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 45-1, 150 mg, crude) as a yellow solid. LC-MS: m / z = 545.4 [M+H]+. 143 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)

[0269] Synthesis and Characterization of Target 45.To a solution of Compound 45-1 (150 mg, 275 μmol, 1 equiv.) in THF (3.00 mL) and H2O (0.30 mL) was added PPh3 (144 mg, 550 μmol, 2 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 45-1 was consumed completely and the desired m / z was detected. The reaction mixture was concentrated to give the residue. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [H2O (0.225% FA)-acetonitrile]; gradient: 10%-40% acetonitrile over 15.0 min) and the eluent was concentrated under reduced pressure at 45 °C and lyophilized to give N-[(1S)-2-amino-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[5-chloro-2-[[(3R,4R)-3- fluorotetrahydropyran-4-yl]amino]pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 45, 52.54 mg, 89.8 μmol, 32.6% yield, 96.6% purity, FA) as an off-white solid. LC-MS: m / z = 519.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 8.93 - 8.67 (m, 1H), 8.38 - 8.28 (m, 2H), 7.82 - 7.69 (m, 2H), 7.26 - 7.09 (m, 2H), 6.99 (br dd, J = 10.0, 17.2 Hz, 2H), 5.13 - 5.01 (m, 1H), 4.91 - 4.70 (m, 1H), 4.25 - 4.10 (m, 1H), 4.09 - 3.96 (m, 2H), 3.94 - 3.85 (m, 2H), 3.04 - 2.96 (m, 2H), 2.89 (td, J = 6.8, 14.0 Hz, 1H), 2.04 - 1.89 (m, 1H), 1.74 - 1.64 (m, 1H), 1.20 (d, J = 1.2 Hz, 3H), 1.18 (d, J = 1.2 Hz, 3H).19F NMR: (400 MHz, DMSO-d6) -113.710. Example 38: Synthesis of Target 46

[0270] Synthesis and Characterization of Compound 46-5.144 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a mixture of Compound 26-4 (100 mg, 330 μmol, 1 equiv.) and Compound 22A (99.6 mg, 396 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added HOBt (53.6 mg, 396 μmol, 1.2 equiv.) and EDCI (126 mg, 661 μmol, 2 equiv.). Then DIEA (171 mg, 1.32 mmol, 230 μL, 4 equiv.) was added at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 12 h. LC-MS showed Compound 26-4 was consumed and the desired m / z was formed. The mixture was poured into H2O (30.0 mL), then the aqueous phase was extracted two times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 40.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give N-[(1S)-2-azido-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-methyl-2- (tetrahydropyran-4-ylamino)pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 46-5, 200 mg, crude) as yellow oil. LC-MS: m / z = 499.2 [M+H]+.

[0271] Synthesis and Characterization of Target 46.To a mixture of Compound 46-5 (200 mg, 400 μmol, 1 equiv.) in THF (3.60 mL) and H2O (0.40 mL) was added PPh3 (157 mg, 601 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 46-5 was consumed and the desired m / z was formed. The mixture was concentrated under reduced pressure at 35 °C to give a residue. The crude product was purified by prep-HPLC (column: Waters XBridge® C18150 mm × 25 mm, 5 µm; mobile phase: [H2O (0.05% NH3•H2O)-acetonitrile]; gradient: 20%-50% acetonitrile over 12.0 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3- chloro-5-fluorophenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]-1H- pyrrole-2-carboxamide (Target 46, 58.82 mg, 123 μmol, yield over two steps: 37.3%, 99.4% purity, 100% enantiomerically enriched) as an off-white solid. LC-MS: m / z = 473.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.02 - 11.75 (m, 1H), 8.49 (br d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.32 - 7.27 (m, 2H), 7.24 - 7.18 (m, 1H), 6.58 (br d, J = 8.0 Hz, 1H), 5.03 - 4.89 (m, 1H), 4.03 - 3.82 (m, 3H), 3.45 - 3.38 (m, 4H), 2.88 (br d, J = 6.8 Hz, 145 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 2H), 2.27 (s, 3H), 1.85 (br d, J = 10.4 Hz, 2H), 1.56 - 1.46 (m, 2H).19F NMR: EW58290- 24-P1A1 (400 MHz, DMSO-d6) δ -111.076. Example 39: Synthesis of Target 47

[0272] Synthesis and Characterization of Compound 47-2.To a mixture of Compound 26-4 (100 mg, 330 μmol, 1 equiv.) and Compound 25-5 (102 mg, 396 μmol, 1.2 equiv., HCl) in NMP (2.00 mL) was added HOBt (53.6 mg, 396 μmol, 1.2 equiv.) and EDCI (126 mg, 661 μmol, 2 equiv.). Then DIEA (171 mg, 1.32 mmol, 230 μL, 4 equiv.) was added at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 12 h. LC-MS showed Compound 26-4 was consumed and the desired m / z was formed. The mixture was poured into H2O (30.0 mL), then the aqueous phase was extracted two times with 20.0 mL ethyl acetate. The combined organic phase was washed three times with 40.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to give N-[(1S)-2-azido-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[5-methyl-2- (tetrahydropyran-4-ylamino)pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 47-2, 200 mg, crude) as yellow oil. LC-MS: m / z = 507.3 [M+H]+.

[0273] Synthesis and Characterization of Target 47.146 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a mixture of Compound 47-2 (200 mg, 394 μmol, 1 equiv.) in THF (3.60 mL) and H2O (0.40 mL) was added PPh3 (155 mg, 592 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 47-2 was consumed and the desired m / z was formed. The mixture was concentrated under reduced pressure at 35 °C to give a residue. The crude product was purified by prep-HPLC (column: Waters XBridge® C18150 mm × 50 mm, 10 µm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 22%-52% acetonitrile over 14.0 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3- fluoro-5-isopropylphenyl)ethyl]-4-[5-methyl-2-(tetrahydropyran-4-ylamino)pyrimidin-4-yl]- 1H-pyrrole-2-carboxamide (Target 47, 58.76 mg, 120 μmol, yield over two steps: 36.5%, 98.8% purity, 100% enantiomerically enriched) as an off-white solid. LC-MS: m / z = 481.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.21 - 11.64 (m, 1H), 8.45 (br d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 7.08 (s, 1H), 6.98 (br d, J = 10.0 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.57 (br d, J = 8.0 Hz, 1H), 5.01 - 4.89 (m, 1H), 3.99 - 3.93 (m, 1H), 3.87 (br d, J = 10.8 Hz, 2H), 3.44 - 3.37 (m, 4H), 2.93 - 2.89 (m, 1H), 2.88 - 2.83 (m, 2H), 2.27 (s, 3H), 1.85 (br d, J = 10.8 Hz, 2H), 1.55 - 1.46 (m, 2H), 1.19 (dd, J = 6.8, 1.2 Hz, 6H).19F NMR: (400 MHz, DMSO-d6) δ -114.018. Example 40: Synthesis of Target 48

[0274] Synthesis and Characterization of Compound 48-1.A mixture of Compound 43-1 (2.00 g, 4.69 mmol, 1 equiv.), Compound d (937 mg, 7.04 mmol, 1.5 equiv.), K2CO3 (1.30 g, 9.38 mmol, 2 equiv.), BINAP (584 mg, 938 μmol, 0.2 equiv.), and Pd2(dba)3(430 mg, 469 μmol, 0.1 equiv.) in dioxane (20.0 mL) was degassed and purged with N23 times at 25 °C, and then the mixture was heated to 80 °C and stirred at 80 °C for 16 h under N2 atmosphere. LC-MS showed Compound 43-1 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 three times with 30.0 mL CH2Cl2. The organic 147 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) layers were combined and washed one time with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to ethyl acetate / CH2Cl2= 1 / 1, petroleum ether / ethyl acetate = 3 / 1, Rf = 0.40), then the fraction was concentrated. The product methyl 4-[2-(benzofuran-5-ylamino)-5-chloro-pyrimidin-4-yl]-1-(p-tolylsulfonyl)pyrrole-2- carboxylate (Compound 48-1, 750 mg, 1.43 mmol, 30.6% yield) was obtained as a gray solid. LC-MS: m / z = 523.0 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.71 (d, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.39 - 7.34 (m, 3H), 7.18 (s, 1H), 6.79 (d, J = 1.6 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H).

[0275] Synthesis and Characterization of Compound 48-2.To a solution of Compound 48-1 (700 mg, 1.34 mmol, 1 equiv.) in THF (7.00 mL) and H2O (7.00 mL) was added NaOH (268 mg, 6.69 mmol, 5 equiv.) at 25 °C. The mixture was heated to 80 °C stirred at 80 °C for 12 h. LC-MS showed Compound 48-1 was consumed and the desired m / z was detected. The mixture was cooled to 25 °C and concentrated to remove most of THF, adjusted to pH 5 using 1 M HCl, and filtered. The filter cake was concentrated to get crude product. The crude product was used in the next step without purification. The product 4-[2-(benzofuran-5-ylamino)-5-chloro-pyrimidin-4-yl]-1H-pyrrole- 2-carboxylic acid (Compound 48-2, 500 mg, 1.10 mmol, 82.1% yield, 78.0% purity) was obtained as a gray solid. LC-MS: m / z = 355.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.59 (br dd, J = 2.0, 8.8 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.24 (s, 1H), 6.91 (s, 1H).

[0276] Synthesis and Characterization of Compound 48-3. 148 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 48-2 (100 mg, 220 μmol, 1 equiv.) in NMP (1.00 mL) was added Compound 22A (66.3 mg, 264 μmol, 1.2 equiv., HCl), HOBt (35.7 mg, 264 μmol, 1.2 equiv.), and EDCI (84.3 mg, 440 μmol, 2 equiv.) and DIEA (56.8 mg, 440 μmol, 76.6 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 48-2 was consumed and the desired m / z was detected. The mixture was poured into H2O (10.0 mL), then the aqueous phase was extracted three times with 5.00 mL ethyl acetate. The combined organic phase was washed four times with 10.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used in the next step without purification. The product N-[(1S)-2-azido-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2- (benzofuran-5-ylamino)-5-chloro-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 48-3, 210 mg, crude) was obtained as a gray solid. LC-MS: m / z = 551.1 [M+H]+.

[0277] Synthesis and Characterization of Compound Target 48.To a solution of Compound 48-3 (190 mg, 267 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3(105 mg, 400 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 48-3 was consumed and the desired m / z was detected. The mixture was concentrated. The filtrate was purified by prep-HPLC (column: Waters XBridge® BEH C18100 mm × 25 mm, 10 µm; mobile phase: [H2O (10 mM NH4HCO3)- acetonitrile]; gradient: 52%-72% acetonitrile over 8.0 min), then it was lyophilized. The 149 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) product N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2-(benzofuran-5-ylamino)-5- chloro-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 48, 52.8 mg, 100 μmol, 37.7% yield, 100% purity) was obtained as an off-white solid. LC-MS: m / z = 525.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.65 (br d, J = 8.4 Hz, 1H), 8.45 (d, J = 1.2 Hz, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.62 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.33 - 7.27 (m, 2H), 7.23 (br d, J = 9.6 Hz, 1H), 6.94 (s, 1H), 4.96 (q, J = 7.2 Hz, 1H), 2.88 (br d, J = 6.4 Hz, 2H).19F NMR: (400 MHz, DMSO-d6) δ = -111.031 ppm. Example 41: Synthesis of Target 49

[0278] Synthesis and Characterization of Compound 49-1.To a solution of Compound 48-2 (100 mg, 220 μmol, 1 equiv.) in NMP (1.00 mL) was added Compound 1-5 (61.5 mg, 264 μmol, 1.2 equiv., HCl), HOBt (35.7 mg, 264 μmol, 1.2 equiv.), EDCI (84.3 mg, 440 μmol, 2 equiv.), and DIEA (56.8 mg, 440 μmol, 76.6 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 48-2 was consumed and the desired m / z was detected. The mixture was poured into H2O (10.0 mL), then the aqueous phase was extracted three times with 5.00 mL ethyl acetate. The combined organic phase was washed four times with 10.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used in the next step without purification. The product N-[(1S)-2-azido-1-(3-chlorophenyl)ethyl]-4-[2-(benzofuran-5- ylamino)-5-chloro-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 49-1, 180 mg, crude) was obtained as a gray solid. LC-MS: m / z = 533.1 [M+H]+.

[0279] Synthesis and Characterization of Compound Target 49. 150 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 49-1 (160 mg, 255 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (100 mg, 382 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 49-1 was consumed and the desired m / z was detected. The mixture was concentrated. The filtrate was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 10 µm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 52%-72% acetonitrile over 8.0 min), then it was lyophilized. The product N-[(1S)- 2-amino-1-(3-chlorophenyl)ethyl]-4-[2-(benzofuran-5-ylamino)-5-chloro-pyrimidin-4-yl]- 1H-pyrrole-2-carboxamide (Target 49, 47.4 mg, 91.6 μmol, 42.0% yield, 98.2% purity) was obtained as an off-white solid. LC-MS: m / z = 507.1 [M+H]+.1H NMR: (400 MHz, DMSO- d6) δ 9.64 (s, 1H), 8.65 (br d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 1.6, 10.4 Hz, 2H), 7.61 - 7.56 (m, 1H), 7.54 - 7.50 (m, 1H), 7.44 (s, 1H), 7.39 - 7.33 (m, 2H), 7.32 - 7.28 (m, 1H), 6.96 - 6.92 (m, 1H), 5.00 - 4.89 (m, 1H), 2.88 (br d, J = 4.0 Hz, 2H). Example 42: Synthesis of Target 50

[0280] Synthesis and Characterization of Compound 50-1.To a solution of Compound 26-2 (900 mg, 2.00 mmol, 1 equiv.) and Compound 7 (466 mg, 3.00 mmol, 1.5 equiv., HCl) in dioxane (18.0 mL) was added Cs2CO3 (1.30 g, 4.00 mmol, 2 equiv.), BINAP (249 mg, 400 μmol, 0.2 equiv.), and Pd2(dba)3(183 mg, 200 μmol, 0.1 equiv.) at 25 °C under N2. The mixture was degassed and purged with N2three times. Then 151 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) the mixture was heated to 80 °C and stirred at 80 °C for 16 h under N2. LC-MS showed Compound 26-2 was consumed and the desired m / z (RT = 0.575 min) was detected. The residue was poured into H2O (60.0 mL) and extracted two times with 60.0 mL ethyl acetate. The combined organic phase was washed one time with 80.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate / = 100 / 2 to 100 / 10, petroleum ether / ethyl acetate = 1 / 1, Rf= 0.25). The fraction was concentrated under reduced pressure to give methyl 4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5- methyl-pyrimidin-4-yl]-1-(p-tolylsulfonyl)pyrrole-2-carboxylate (Compound 50-1, 570 mg, 1.12 mmol, 55.8% yield, 95.6% purity) as a yellow solid. LC-MS: m / z = 489.1 [M+H]+.1H NMR: (400 MHz, CDCl3) δ 8.23 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 5.31 (t, J = 4.2 Hz, 1H), 4.82 - 4.70 (m, 1H), 4.32 - 4.19 (m, 2H), 4.07 (dd, J = 11.6, 4.0 Hz, 1H), 3.78 (s, 3H) 3.70 - 3.61 (m, 1H), 3.60 - 3.55 (m, 1H), 2.45 (s, 3H), 2.36 (s, 3H), 1.98 (td, J = 12.0, 4.4 Hz, 1H), 1.92 - 1.87 (m, 1H).

[0281] Synthesis and Characterization of Compound 50-2.To a solution of Compound 50-1 (550 mg, 1.08 mmol, 1 equiv.) in THF (21.0 mL) and H2O (11.0 mL) was added NaOH (215 mg, 5.38 mmol, 5 equiv.) at 25 °C. The mixture was heated to 50 °C and stirred at 50 °C for 36 h. LC-MS showed Compound 50-1 was consumed completely and an intermediate state was detected. The mixture was heated to 80 °C and stirred at 80 °C for 3 h. LC-MS showed the intermediate state remained and the desired m / z (RT = 0.367 min) was detected. The mixture was cooled to 25 °C and concentrated to remove most of THF, then adjusted to pH 5-6 with 1 M HCl and filtered. The filter cake was concentrated to get crude product. The product 4-[2-[[(3S,4S)-3- fluorotetrahydropyran-4-yl]amino]-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid (Compound 50-2, 330 mg, 961 μmol, 89.4% yield, 93.3% purity) was obtained as a yellow 152 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) solid. The crude product was used in the next step. LC-MS: m / z = 321.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 4.84 - 4.72 (m, 1H), 4.21 - 4.08 (m, 1H), 4.02 - 3.96 (m, 1H), 3.91 - 3.88 (m, 1 H), 3.64 - 3.50 (m, 2H), 2.25 (s, 3H), 1.96 - 1.85 (m, 1H), 1.69 - 1.63 (m, 1H).

[0282] Synthesis and Characterization of Compound 50-3.To a solution of Compound 50-2 (80.0 mg, 233 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 22A (70.2 mg, 280 μmol, 1.2 equiv., HCl), HOBt (37.8 mg, 280 μmol, 1.2 equiv.), EDCI (89.3 mg, 466 μmol, 2 equiv.) and DIEA (60.2 mg, 466 μmol, 81.2 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 50-2 was consumed completely and the desired m / z was detected. The reaction mixture was poured into water (30.0 mL) and extracted three times with 20.0 mL ethyl acetate. The organic layers were combined and washed three times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2- azido-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]- 5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide as (Compound 50-3, 120 mg, crude) as yellow oil. The crude product was used into the next step. LC-MS: m / z = 517.1 [M+H]+.

[0283] Synthesis and Characterization of Target 50.To a solution of Compound 50-3 (120 mg, 232 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (91.3 mg, 348 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred 153 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) at 25 °C for 12 h. LC-MS showed Compound 50-3 was consumed completely and the desired m / z was detected. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (neutral condition: column: Waters XBridge® C18150 mm × 25 mm, 5 µm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 28%- 58% acetonitrile over 9.0 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, and the residual aqueous was lyophilized to give N-[(1S)-2- amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4- yl]amino]-5-methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 50, 61.56 mg, 123 μmol, 53.2% yield over two steps, 98.4% purity) as an off-white solid. LC-MS: m / z = 491.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.30 - 7.27 (m, 2H) 7.22 - 7.20 (m, 1H), 6.58 - 6.50 (m, 1H), 4.94 (q, J = 6.8 Hz, 1H), 4.87 - 4.74 (m, 1H), 4.21 - 4.10 (m, 1H), 4.00 (t, J = 12.8 Hz, 1H), 3.90 (dd, J = 10.8, 4.0 Hz, 1H), 3.65 - 3.47 (m, 2H), 2.87 (d, J = 6.8 Hz, 2H), 2.29 (s, 3H), 1.95 - 1.89 (m, 1H), 1.69 - 1.64 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ -204.4, -111.1. Example 43: Synthesis of Target 51To a solution of Compound 48-2 (100 mg, 220 μmol, 1 equiv.) in NMP (1.00 mL) was added Compound 25-5 (68.3 mg, 264 μmol, 1.2 equiv., HCl), HOBt (35.7 mg, 264 μmol, 1.2 equiv.), EDCI (84.3 mg, 440 μmol, 2 equiv.), and DIEA (56.8 mg, 440 μmol, 76.6 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 48-2 was consumed and the desired m / z was detected. The mixture was poured into H2O (10.0 mL), then the aqueous phase was extracted three times with 5.00 mL ethyl acetate. The organic layers were combined and washed four times with 10 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was used in the next step without purification. The product N-[(1S)-2-azido-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[2- 154 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) (benzofuran-5-ylamino)-5-chloro-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 51-1, 210 mg, crude) was obtained as a gray solid. LC-MS: m / z = 559.2 [M+H]+.

[0285] Synthesis and Characterization of Target 51.To a solution of Compound 51-1 (190 mg, 282 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3 (111 mg, 423 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 51-1 was consumed and the desired m / z was detected. The mixture was concentrated. The filtrate was purified by prep-HPLC (column: Waters XBridge® 150 mm × 25 mm, 10 µm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 58%-78% acetonitrile over 8.0 min), then it was lyophilized. The product N-[(1S)- 2-amino-1-(3-fluoro-5-isopropylphenyl)ethyl]-4-[2-(benzofuran-5-ylamino)-5-chloro- pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 51, 50.4 mg, 90.1 μmol, 41.0% yield, 95.3% purity) was obtained as an off-white solid. LC-MS: m / z = 533.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.61 (br d, J = 8.4 Hz, 1H), 8.45 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 1.6, 12.4 Hz, 2H), 7.61 - 7.57 (m, 1H), 7.55 - 7.50 (m, 1H), 7.09 (s, 1H), 7.01 (br d, J = 9.6 Hz, 1H), 6.98 - 6.92 (m, 2H), 4.95 (q, J = 6.8 Hz, 1H), 2.93 - 2.85 (m, 3H), 1.19 (d, J = 6.8 Hz, 6H).19F NMR: (400 MHz, DMSO-d6) δ = -113.943 ppm. Example 44: Synthesis of Target 52

[0286] Synthesis and Characterization of Compound 52-1. 155 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 50-2 (80.0 mg, 233 μmol, 1 equiv.) in NMP (2.00 mL) was added Compound 1-5 (65.8 mg, 280 μmol, 1.2 equiv., HCl), HOBt (37.8 mg, 280 μmol, 1.2 equiv.), EDCI (89.3 mg, 466 μmol, 2 equiv.), and DIEA (60.2 mg, 466 μmol, 81.2 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 50-2 was consumed completely and the desired m / z was detected. The reaction mixture was poured into water (30.0 mL) and extracted three times with 20.0 mL ethyl acetate. The combined organic phase was washed three times with 20.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product N-[(1S)-2-azido-1- (3-chlorophenyl)ethyl]-4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5-methyl- pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Compound 52-1, 116 mg, crude) was obtained as yellow oil. The crude product was used in the next step without further purification. LC- MS: m / z = 499.1 [M+H]+.To a solution of Compound 52-1 (116 mg, 232 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3(91.5 mg, 349 μmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 52-1 was consumed completely and the desired m / z was detected. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (neutral condition: column: Waters XBridge® C18150 mm × 25 mm, 5 µm; mobile phase: [H2O (10 mM NH4HCO3)-acetonitrile]; gradient: 25%- 156 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 55% acetonitrile over 9.0 mins). The eluent was concentrated under reduced pressure to remove acetonitrile and H2O, and the residual aqueous was lyophilized to give N-[(1S)-2- amino-1-(3-chlorophenyl)ethyl]-4-[2-[[(3S,4S)-3-fluorotetrahydropyran-4-yl]amino]-5- methyl-pyrimidin-4-yl]-1H-pyrrole-2-carboxamide (Target 52, 62.27 mg, 128 μmol, 54.9% yield over two steps, 97.0% purity) as an off-white solid. LC-MS: m / z = 473.1 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 7.38 - 7.28 (m, 3H), 6.54 - 6.52 (m, 1H), 4.93 (q, J = 7.2 Hz, 1H), 4.86 - 4.74 (m, 1H), 4.21 - 4.12 (m, 1H), 4.03 - 3.96 (m, 1H), 3.90 (dd, J = 11.2, 2.8 Hz, 1H), 3.65 - 3.47 (m, 2H), 2.88 - 2.85 (m, 2H), 2.29 (s, 3H), 1.94 - 1.89 (m, 1H), 1.68 - 1.64 (m, 1H).19F NMR: (400 MHz, DMSO-d6) δ -204.4. Example 45: Synthesis of Target 53

[0288] Synthesis and Characterization of Compound 53-5.To a solution of Compound 36-4 (100 mg, 311 μmol, 1 equiv.) in NMP (1.00 mL) was added Compound 22A (93.6 mg, 373 μmol, 1.2 equiv., HCl), HOBt (50.4 mg, 373 μmol, 1.2 equiv.) and EDCI (119 mg, 622 μmol, 2 equiv.) and DIEA (80.3 mg, 622 μmol, 108 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 36-4 was consumed and the desired m / z (RT = 0.552 min) was detected. The reaction mixture was poured into H2O (50.0 mL), and the aqueous phase was extracted two times with 50.0 mL ethyl acetate. The organic layers were combined and washed two times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give Compound 53-5 (200 mg, crude) as yellow oil. LC-MS: m / z = 518.3 [M+H]+.

[0289] Synthesis and Characterization of Target 53. 157 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)To a solution of Compound 53-5 (180 mg, 316 μmol, 1 equiv.) in THF (1.80 mL) and H2O (0.20 mL) was added PPh3(124 mg, 474 μmol, 1.5 equiv.). The mixture was stirred at 25 °C for 12 h. LC-MS showed Compound 53-5 was consumed and the desired m / z (RT = 0.495 min) was detected. The mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna™ C18150 mm × 25 mm, 10 µm; mobile phase: [H2O (0.225% FA)-acetonitrile]; gradient: 5%-35% acetonitrile over 10.0 min). The eluent was concentrated under reduced pressure to remove acetonitrile. The residual aqueous solution was lyophilized to give N-[(1S)-2-amino-1-(3-chloro-5-fluorophenyl)ethyl]-4-[5-chloro-2- (tetrahydropyran-4-ylamino)-4-pyridyl]-1H-pyrrole-2-carboxamide (Target 53, 60.3 mg, 119 μmol, 38.3% yield, 97.3% purity) as a white solid. LC-MS: m / z = 492.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ 12.20 - 11.86 (m, 1H), 9.00 (d, J = 4.0 Hz, 1H), 8.41 - 8.22 (m, 1H), 7.98 (s, 1H), 7.42 - 7.31 (m, 4H), 7.25 (d, J = 9.6 Hz, 1H), 6.74 - 6.50 (m, 2H), 5.22 - 5.12 (m, 1H), 3.98 - 3.80 (m, 4H), 3.47 - 3.34 (m, 2H), 3.10 (d, J = 6.8 Hz, 2H), 1.93 - 1.79 (m, 2H), 1.51 - 1.32 (m, 2H).19F NMR: (400 MHz, DMSO-d6) δ -110.559. Example 46: Synthesis of Targets 56-P1 and 56-P2

[0290] Synthesis and Characterization of Compound 56-1.158 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) To a solution of Compound 36-4 (240 mg, 746 μmol, 1 equiv.) in NMP (2.40 mL) was added 2-azido-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanamine (Compound f, 255 mg, 895 μmol, 1.2 equiv., HCl), HOBt (121 mg, 895 μmol, 1.2 equiv.), EDCI (286 mg, 1.49 mmol, 2 equiv.), and DIEA (193 mg, 1.49 mmol, 260 μL, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 h. LC-MS showed Compound 36-4 was consumed and the desired m / z was detected. The reaction mixture was poured into H2O (50.0 mL), and the aqueous phase was extracted two times with 50.0 mL ethyl acetate. The combined organic phase was washed two times with 50.0 mL brine, dried with anhydrous Na2SO4, filtered, and concentrated under re...

Claims

Atty. Dkt. No.: 115872-3155 (SK2024-037-03) CLAIMS 1. A compound or a pharmaceutically acceptable salt thereof according to Formula Iwherein R1is 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; and R6, R7, and R8are each independently alkyl, cycloalkyl, halo, amino, amide, hydroxy, or alkoxy.

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 IA220 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 3. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein R1is. 221 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 4. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein R2is methyl or Cl.

5. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein R3is methyl, ,.

6. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein R4is H or methyl.

7. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein Z1is CH or N. 222 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 8. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein Z2is CH or N.

9. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein Z3is CH or N.

10. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein the223 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)pharmacuetically acceptable salt of any one thereof.

11. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein the224 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)thereof. 225 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03) 12. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein the226 4934-3961-6791.3Atty. Dkt. No.: 115872-3155 (SK2024-037-03)pharmacuetically acceptable salt of any one thereof.

13. A composition comprising a compound of any one of Claims 1-12 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of Claims 1-12, wherein the compound is present in an amount effective to treat a cancer.

15. The pharmaceutical composition of Claim 14, wherein the cancer expresses a RAS pathway mutation, optionally wherein the RAS pathway mutation is KRAS-G13D.

16. 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 1-12.

17. The method of Claim 16, wherein the cancer expresses a RAS pathway mutation, optionally wherein the RAS pathway mutation is KRAS-G13D.

18. A medicament for treating a cancer in a subject, the medicament comprising a compound of any one of Claims 1-12.

19. The medicament of Claim 18, wherein the medicament further comprises a pharmaceutically acceptable carrier.

20. The medicament of Claim 18, wherein the medicament comprises an effective amount of the compound for treating the cancer. 227 4934-3961-6791.3

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