Compounds for SHP2 protein degradation and their medical uses

Abstract

The present invention provides compounds of a specific chemical structure that exhibit excellent activity in degrading SHP2 protein, as well as their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts. The present invention also provides compositions containing such compounds, their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts. The present invention also provides pharmaceutical uses of compounds according to the present invention, their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or salts thereof, and compositions containing them, for the treatment or prevention of SHP2-related diseases (e.g., cancer). The present invention also provides methods for treating or preventing SHP2-related diseases (e.g., cancer), comprising administering an effective amount of a compound according to the present invention, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or salts thereof, or compositions containing them, to an individual in need of such treatment.

Description

Detailed Description of the Invention

[0001] [Technical Field] This application claims priority based on Korean Patent Application No. 10-2022-0135265 filed on October 19, 2022, and Korean Patent Application No. 10-2023-0016449 filed on February 7, 2023, and the contents disclosed in the specifications and drawings of those applications are incorporated herein in their entirety.

[0002] The present invention relates to a group of compounds having SHP2 protein degradation activity. In particular, the present invention relates to a group of compounds having a specific structure and having the activity of degrading SHP2 protein. The present invention also relates to compositions and methods for treating SHP2 protein-associated diseases using such compounds. That is, the present invention relates to the pharmaceutical use of the compounds according to the present invention for treating or preventing SHP2 protein-associated diseases.

[0003] [Background technology] Src homology 2 domain-containing phosphatase (SHP2) is a protein tyrosine phosphatase. Mutations in SHP2 are widespread in Noonan syndrome and Leopard syndrome. Activating mutations in SHP2 have also been identified in juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia, and acute myeloid leukemia. Somatic activating mutations in SHP2 are associated with various types of solid tumors, including lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, prostate cancer, and breast cancer (Bentires-Alj et al., Cancer. Res. 2004, 64, 8816-8820).

[0004] SHP2 is known to be involved in diverse signaling processes in cancer cells, such as the RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB, and mTOR pathways. In the RAS-ERK pathway, SHP2 acts as an upstream positive regulator, promoting RAS-RAF-MEK-ERK kinase cascade signaling. Therefore, SHP2 suppression inhibits the oncogenic function of the RAS-RAF-MEK-ERK pathway, resulting in cell growth suppression and apoptosis in cancer cells. Furthermore, SHP2 contributes to immune evasion as a key protein in the PD-1 / PD-L1-mediated T cell activation inhibitory signaling pathway in immune cells. In summary, SHP2 is a highly attractive target for cancer therapy. For example, the SHP2 inhibitor SHP099 selectively blocks SHP2 phosphatase activity and is known to suppress cancer cell growth in vitro and tumor growth in xenograft mouse models (Chen et al., Nature 2016, 535, 148-152; Garcia Fortanet et al., J. Med. Chem. 2016, 59, 7773-7782).

[0005] Allosteric SHP2 inhibitors are known to be effective in preclinical models of Kirsten rat sarcoma (KRAS)-mutant human cancers, and CRISPR-Cas9-mediated SHP2 inactivation has been shown to induce senescence and suppress tumor growth in xenograft models of KRAS-mutant tumors.

[0006] Summary of the Invention [Problem to be solved by the invention] Deletion of the SHP2 protein may provide an alternative and more effective strategy for inhibiting SHP2 activity. Therefore, the present invention aims to provide compounds having Src homology 2 domain-containing phosphatase (SHP2) degradation activity, pharmaceutical compositions containing the same as active ingredients, and medicinal uses of these compounds for the treatment or prevention of SHP2-related diseases (e.g., cancer or tumors).

[0007] Another object of the present invention is to provide a method for treating or preventing an SHP2-related disease (preferably, cancer or tumor), which comprises administering to a patient in need of treatment, amelioration, or prevention of an SHP2-related disease a compound according to the present invention, which degrades SHP2 and consequently reduces the level of SHP2.

[0008] [Means for solving the problem] The present invention relates to SHP2 targeted protein degradation (TPD) compounds that can target and degrade SHP2 protein through ubiquitination by E3 ubiquitin ligase, pharmaceutical compositions containing the same as active ingredients, and methods for treating or preventing SHP2-related diseases using them.

[0009] Compounds of the Invention A compound according to one embodiment of the present invention is a "SHP2-binding ligand-linker(-WL-)-VHL ligand" target protein degradation compound. In one aspect, the present application relates to compounds with different modes of action that are useful for modulating protein activity by inducing target protein degradation. In one aspect, the compounds with different modes of action include a VHL ligand that is an E3 ubiquitin ligase binding moiety and, preferably, a target protein binding moiety linked by a linker moiety, as specifically described herein. E3 ubiquitin ligase refers to a group of proteins that transfer ubiquitin and target substrate proteins for degradation. VHL is an E3 ubiquitin ligase protein that, in combination with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to a lysine on a target protein, thereby inducing degradation by the proteasome. Thus, the differentially active compound simultaneously binds to VHL and the target protein, bringing the target protein into proximity with VHL, thereby inducing degradation via ubiquitination and thereby inhibiting / suppressing the activity of the target protein. In certain embodiments, the differentially active compound comprises, for example, a SHP2-binding ligand and a VHL ligand covalently linked, directly or indirectly, to a chemical linker group -WL-.

[0010] According to one aspect of the present invention, there is provided a compound of the following Chemical Formula 1, its optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof:

[0011] [ka]

[0012] In the above Chemical Formula 1, R1 is

[0013] [ka]

[0014] and R 11is H, C 1-6 Alkyl, hydroxy, halogen, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein aryl and heteroaryl are independently and optionally, one or more hydrogen atoms in the ring are replaced by C 1-6 Alkyl, hydroxy, halogen, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 alkoxy-substituted, R 12 is amino, C 1-6 Aminoalkyl or C 1-6 alkylamino, R 13a and R 13b are independently H, C 1-6 Alkyl (preferably methyl), hydroxy, halogen, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl or C 1-6 is an alkoxy, R 14 are independently H, C 1-6 alkyl, hydroxy, halogen or CN; Z's are each independently -O-, -S-, -NH- or -CH2-; Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine); n is an integer from 0 to 5, R2 is H, C 1-6 alkyl or -NH2, R3 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -C(O)R 9a , -C(O)OR 9a , -C(O)NR 9a R 9b or CN, R4 is H, C 1-6 Alkyl, halogen (preferably Cl), C1-6 Haloalkyl or C 1-6 Alkoxy or -N(R 9a )-W's R 9a and form a heterocycle (preferably pyrrolidine, morpholine) or a heteroaryl (preferably pyrrole), wherein the heterocycle and heteroaryl are independently and optionally, one or more hydrogen atoms in the ring are replaced by C 1-6 Alkyl, halogen or C 1-3 substituted with haloalkyl, R5 is H, C 1-6 Alkyl, C 2-6 Alkynyl (preferably acetylenyl), halogen, —CN, or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole, or triazole), wherein heteroaryl optionally has one or more hydrogens in the ring replaced by C 1-6 Alkyl (preferably methyl, ethyl), halogen or C 1-3 substituted with haloalkyl, R6 is -NHC(O)R7 or heteroaryl (preferably triazole, pyrazole, isoxazole), where the heteroaryl optionally has one or more hydrogen atoms in the ring replaced by C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or C 3-6 cycloalkyl, where R7 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-10 cycloalkyl or heterocycle, wherein the cycloalkyl and heterocycle are independently and optionally, one or more hydrogens in the ring are replaced by C 1-6 substituted with alkyl, halogen or -CN; R 8a is H, C 1-6 Alkyl or C 3-6 is cycloalkyl, R 8b and R 8c are independently H, C 1-6 Alkyl, C 1-6alkoxy or halogen; X is -S-, -O-, -N(R 9a )-, -CH2-, -CHCH-, -CC-, -CH2O- or -OCH2-, Y is CH or N; W is a direct bond, -O- or -N(R 9a )- and R 9a and R 9b are independently H, C 1-6 Alkyl or C 1-6 is haloalkyl, L is represented by the following chemical formula 2:

[0015] [ka]

[0016] In Chemical Formula 2, A1 and A2 each independently represent a direct bond; C 3-10 cycloalkyl (preferably cyclohexane, cyclobutane), heterocycle (preferably piperidine, piperazine, azetidine, 7-azaspiro[3.5]nonane), aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl optionally have one or more hydrogen atoms in the ring replaced by C 1-6 Alkyl, halogen, C 1-3 substituted with haloalkyl, —OH or ═O; B1 and B2 each independently represent a direct bond, —O—, —N(R 10 )-, -C(O)-, -C(O)N(R 10 )- or -N(R 10 )C(O)—, where R 10 are each independently H or C 1-6 is alkyl, q1, q2, q3, q4 and q5 are each independently an integer of 0 to 10.

[0017] According to a preferred embodiment of the present invention, in the above Chemical Formula 1, R1 is

[0018] [ka]

[0019] and R 11 is H, C 1-6 Alkyl, hydroxy, halogen, C 1-6 Hydroxyalkyl or C 1-6 is haloalkyl, R 12 is amino, C 1-6 Aminoalkyl or C 1-6 alkylamino, R 13a and R 13b are independently H, C 1-6 Alkyl (preferably methyl), hydroxy, halogen, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl or C 1-6 is an alkoxy; R 14 are independently H, C 1-6 alkyl, hydroxy, halogen or CN; Z's are each independently -O-, -S-, -NH- or -CH2-; Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine); n is an integer from 0 to 5, R2 is H, C 1-6 alkyl or -NH2, R3 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C(O)NR 9a R 9b or CN, R4 is H, C 1-6 Alkyl, halogen (preferably Cl), C 1-6 Haloalkyl or C 1-6 Alkoxy or -N(R 9a )-W's R 9aand form a heterocycle (preferably pyrrolidine, morpholine) or a heteroaryl (preferably pyrrole), wherein the heterocycle and heteroaryl are independently and optionally, one or more hydrogen atoms in the ring are replaced by C 1-6 Alkyl, halogen or C 1-3 substituted with haloalkyl, R5 is H, C 1-6 Alkyl, C 2-6 Alkynyl (preferably acetylenyl), halogen, —CN, or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole, or triazole), wherein heteroaryl optionally has one or more hydrogens in the ring replaced by C 1-6 Alkyl (preferably methyl, ethyl), halogen or C 1-3 substituted with haloalkyl, R6 is -NHC(O)R7 or heteroaryl (preferably triazole, pyrazole, isoxazole), where the heteroaryl optionally has one or more hydrogen atoms in the ring replaced by C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or C 3-6 cycloalkyl, where R7 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-10 cycloalkyl or heterocycle, wherein the cycloalkyl and heterocycle are independently and optionally, one or more hydrogens in the ring are replaced by C 1-6 substituted with alkyl, halogen or -CN; R 8a is H, C 1-6 Alkyl or C 3-6 is cycloalkyl, R 8b and R 8c are independently H, C 1-6 Alkyl, C 1-6 alkoxy or halogen; X is -S-, -O-, -N(R 9a )- or -CH2-, Y is CH or N; W is a direct bond, -O- or -N(R 9a )- and R 9a and R 9b are independently H, C 1-6 Alkyl or C 1-6 is haloalkyl, L is represented by the following chemical formula 2:

[0020] [ka]

[0021] In Chemical Formula 2, A1 and A2 each independently represent a direct bond; C 3-10 cycloalkyl (preferably cyclohexane, cyclobutane), heterocycle (preferably piperidine, piperazine, azetidine, 7-azaspiro[3.5]nonane), aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl optionally have one or more hydrogen atoms in the ring replaced by C 1-6 Alkyl, halogen, C 1-3 substituted with haloalkyl, —OH or ═O; B1 and B2 each independently represent a direct bond, —O—, —N(R 10 )-, -C(O)-, -C(O)N(R 10 )- or -N(R 10 )C(O)—, where R 10 are each independently H or C 1-6 is alkyl, q1, q2, q3, q4, and q5 are each independently an integer of 0 to 10. The present invention provides a compound, its optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0022] The compounds of the present invention have desirable properties in terms of SHP2 degradation activity, stability in plasma, metabolic stability in the body, stability during storage, pharmacological properties, and physicochemical aspects. In addition to the above-mentioned features of the compound of the present invention, the compound of the present invention also has advantageous properties in terms of cancer cell proliferation inhibitory activity, (water) solubility, cell permeability, required dosage (good activity, solubility, etc., and good effects are exhibited even at low dosages), bioavailability, distribution in the body, distribution in cancer tissues, pharmacokinetic properties, pharmacodynamic activity, duration of efficacy, drug interactions, etc.

[0023] According to a more preferred embodiment of the present invention, in Chemical Formula 1, R1 is

[0024] [ka]

[0025] and R 11 is H, C 1-6 Alkyl, hydroxy, halogen, C 1-3 Hydroxyalkyl or C 1-3 is haloalkyl, R 12 is amino, C 1-3 Aminoalkyl or C 1-3 alkylamino, R 13a and R 13b are independently H, C 1-6 Alkyl (preferably methyl), hydroxy, halogen, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 is an alkoxy, R 14 are independently H, C 1-3 alkyl, hydroxy, halogen or CN; Z's are each independently -O-, -NH- or -CH2-; Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine); n is an integer from 0 to 3, R2 is H, C 1-6 alkyl or -NH2, R3 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -C(O)NR 9a R 9b or CN, R4 is H, C 1-6 Alkyl, halogen (preferably Cl), C 1-6 Haloalkyl or C 1-6 Alkoxy or -N(R 9a )-W's R 9a and form a heterocycle (preferably pyrrolidine, morpholine) or a heteroaryl (preferably pyrrole), wherein the heterocycle and heteroaryl are independently and optionally, one or more hydrogen atoms in the ring are replaced by C 1-3 Alkyl, halogen or C 1-3 substituted with haloalkyl, R5 is H, C 1-6 alkyl, acetylenyl, halogen, —CN, or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole, or triazole), where heteroaryl optionally has one or more hydrogens in the ring replaced by C 1-6 Alkyl (preferably methyl, ethyl), halogen or C 1-3 substituted with haloalkyl, R6 is -NHC(O)R7 or heteroaryl (preferably triazole, pyrazole, isoxazole), where the heteroaryl optionally has one or more hydrogen atoms in the ring replaced by C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or C 3-6 cycloalkyl, where R7 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl or C 3-10 cycloalkyl, where the cycloalkyl optionally has one or more hydrogen atoms in the ring replaced by a C 1-3 substituted with alkyl, halogen or -CN; R 8a is H, C 1-6 Alkyl or C3-6 is cycloalkyl, R 8b and R 8c are independently H, C 1-6 alkyl or halogen; X is -S-, -O-, -N(R 9a )- or -CH2-, Y is CH or N; W is a direct bond, -O- or -N(R 9a )- and R 9a and R 9b are independently H, C 1-6 Alkyl or C 1-6 is haloalkyl, L is represented by the following chemical formula 2:

[0026] [ka]

[0027] In Chemical Formula 2, A1 and A2 each independently represent a direct bond; C 3-10 cycloalkyl (preferably cyclohexane, cyclobutane) or heterocycle (preferably piperidine, piperazine, azetidine, 7-azaspiro[3.5]nonane), wherein the cycloalkyl and heterocycle optionally have one or more hydrogen atoms in the ring replaced by C 1-6 Alkyl, halogen, C 1-3 substituted with haloalkyl, —OH or ═O; B1 and B2 each independently represent a direct bond, —O—, —N(R 10 )- or -C(O)-, where R 10 are each independently H or C 1-6 is alkyl, q1, q2, q3, q4, and q5 are each independently an integer of 0 to 5. The present invention provides a compound, its optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0028] According to a more preferred embodiment of the present invention, in Chemical Formula 1, R1 is

[0029] [ka]

[0030] and R 11 is H, C 1-6 Alkyl, hydroxy or C 1-3 is a hydroxyalkyl, R 12 is amino or C 1-3 is an aminoalkyl, R 13a and R 13b are independently H, C 1-6 Alkyl (preferably methyl), hydroxy, C 1-3 Hydroxyalkyl or C 1-3 is an alkoxy, R 14 are independently H, C 1-3 alkyl, hydroxy, halogen or CN; Z's are each independently -O-, -NH- or -CH2-; Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine); n is an integer from 0 to 3, R2 is H, C 1-6 alkyl or -NH2, R3 is H, C 1-6 Alkyl or C 1-6 is a hydroxyalkyl, R4 is H, C 1-6 Alkyl, halogen (preferably Cl), C 1-6 Haloalkyl or C 1-6 Alkoxy or -N(R 9a )-W's R 9aand form a heterocycle (preferably pyrrolidine, morpholine) or a heteroaryl (preferably pyrrole), wherein the heterocycle and heteroaryl are independently and optionally, one or more hydrogen atoms in the ring are replaced by C 1-3 Alkyl, halogen or C 1-3 substituted with haloalkyl, R5 is H, C 1-6 alkyl, acetylenyl, halogen, -CN, thiazole, pyrazole, pyrrole, oxazole or triazole, wherein the thiazole, pyrazole, pyrrole, oxazole or triazole optionally has one or more hydrogen atoms in the ring replaced by a C 1-6 Alkyl (preferably methyl, ethyl), halogen or C 1-3 substituted with haloalkyl, R6 is -NHC(O)R7, triazole, pyrazole or isoxazole, wherein the triazole, pyrazole or isoxazole optionally has one or more hydrogen atoms in the ring replaced by a C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or C 3-6 cycloalkyl, where R7 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Cyanoalkyl or C 3-6 cycloalkyl, where the cycloalkyl optionally has one or more hydrogen atoms in the ring replaced by a C 1-3 substituted with alkyl, halogen or -CN; R 8a is H, C 1-6 Alkyl or C 3-6 is cycloalkyl, R 8b and R 8c are independently H, C 1-3 alkyl or halogen; X is -S- or -O-; Y is CH or N; W is a direct bond, -O- or -N(R 9a )- and R 9a and R9b are independently H, C 1-3 Alkyl or C 1-3 is haloalkyl, L is represented by the following chemical formula 2:

[0031] [ka]

[0032] In Chemical Formula 2, A1 and A2 are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane optionally has one or more hydrogen atoms in the ring replaced with C 1-6 Alkyl, halogen, C 1-3 substituted with haloalkyl, —OH or ═O; B1 and B2 are each independently a direct bond, —O—, or —C(O)—; q1, q2, q3, q4, and q5 are each independently an integer of 0 to 5. The present invention provides a compound, its optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0033] According to a more preferable embodiment of the present invention, in the above Chemical Formula 1, R1 is

[0034] [ka]

[0035] and R 11 is H, C 1-6 alkyl or hydroxy; R 12 is amino or C 1-3 is an aminoalkyl, R 13a and R 13bare independently H, C 1-6 Alkyl, hydroxy or C 1-3 is a hydroxyalkyl, R 14 are independently H, C 1-3 alkyl or halogen; Z's are each independently -O- or -CH2-; Ring C is aryl or heteroaryl; n is an integer from 0 to 3, R2 is H, C 1-6 alkyl or -NH2, R3 is H, C 1-6 Alkyl or C 1-6 is a hydroxyalkyl, R4 is H, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl or C 1-6 Alkoxy or -N(R 9a )-W's R 9a and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring is replaced by a C 1-3 substituted with alkyl or halogen; R5 is H, C 1-6 alkyl, acetylenyl, halogen, -CN, thiazole, pyrazole or pyrrole, wherein the thiazole, pyrazole or pyrrole optionally has one or more hydrogen atoms in the ring replaced by a C 1-6 Alkyl, halogen or C 1-3 substituted with haloalkyl, R6 is -NHC(O)R7, triazole, pyrazole or isoxazole, wherein the triazole, pyrazole or isoxazole optionally has one or more hydrogen atoms in the ring replaced by a C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or C 3-6 cycloalkyl, where R7 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3Cyanoalkyl or C 3-6 cycloalkyl, where the cycloalkyl optionally has one or more hydrogen atoms in the ring replaced by a C 1-3 substituted with alkyl, halogen or -CN; R 8a is H, C 1-6 Alkyl or C 3-6 is cycloalkyl, R 8b and R 8c are independently H, C 1-3 alkyl or halogen; X is -S- or -O-; Y is CH or N; W is a direct bond, -O- or -N(R 9a )- and R 9a and R 9b are independently H, C 1-3 Alkyl or C 1-3 is haloalkyl, L is represented by the following chemical formula 2:

[0036] [ka]

[0037] In Chemical Formula 2, A1 and A2 are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane optionally has one or more hydrogen atoms in the ring replaced with C 1-6 substituted with alkyl, halogen, -OH or =O; B1 and B2 are each independently a direct bond or —C(O)—; q1, q2, q3, q4, and q5 are each independently an integer of 0 to 3. Provided is a compound of Formula 1, its optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0038] According to a more preferable embodiment of the present invention, in the above Chemical Formula 1, R1 is

[0039] [ka]

[0040] and R 11 is H or C 1-6 is alkyl, R 12 is amino or C 1-3 is an aminoalkyl, R 13a and R 13b are each independently H or C 1-6 is alkyl, R 14 are each independently H or C 1-3 is alkyl, Z's are each independently -O- or -CH2-; Ring C is aryl or heteroaryl; n is an integer from 0 to 3, R2 is H, C 1-6 alkyl or -NH2, R3 is H, C 1-6 Alkyl or C 1-6 is hydroxyalkyl, R4 is H, C 1-6 Alkyl, halogen or C 1-6 haloalkyl or -N(R 9a )-W's R 9a and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C 1-3 substituted with alkyl or halogen; R5 is H, C 1-6 alkyl, halogen, -CN, thiazole or pyrazole, wherein the thiazole or pyrazole optionally has one or more hydrogen atoms in the ring replaced by a C 1-6Alkyl, halogen or C 1-3 substituted with haloalkyl, R6 is -NHC(O)R7, triazole, pyrazole or isoxazole, wherein the triazole, pyrazole or isoxazole optionally has one or more hydrogen atoms in the ring replaced by a C 1-6 Alkyl, halogen, C 1-3 Haloalkyl or C 3-6 cycloalkyl, where R7 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Cyanoalkyl or C 3-6 cycloalkyl, wherein one or more hydrogen atoms in the ring are optionally replaced by halogen or —CN; R 8a is H, C 1-6 Alkyl or C 3-6 is cycloalkyl, R 8b and R 8c are independently H, C 1-3 alkyl or halogen; X is -S- or -O-; Y is CH or N; W is a direct bond or -N(R 9a )- and R 9a and R 9b are independently H, C 1-3 Alkyl or C 1-3 is haloalkyl, L is represented by the following chemical formula 2:

[0041] [ka]

[0042] In Chemical Formula 2, A1 and A2 are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane optionally has one or more hydrogen atoms in the ring replaced with C 1-6 substituted with alkyl, halogen, -OH or =O; B1 and B2 are each independently a direct bond or —C(O)—; q1, q2, q3, q4, and q5 are each independently an integer of 0 to 3. Provided is a compound of Formula 1, its optical isomers, stereoisomers, isotopic variations, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0043] Preferably, in the SHP2 target protein degradation compound according to the present invention, the moiety (SHP2 ligand) on the left side of the linker (-WL-) has one of the following structures. When it has the following structure, it not only has excellent SHP2 degradation activity but also meets the various objectives of the present invention described above.

[0044] [ka] JPEG2025536298000015.jpg83169

[0045] Preferably, in the SHP2-targeted protein degradation compound according to the present invention, the linker (-WL-) is any one of the following linkers: When such a linker is present, not only is SHP2 degradation activity excellent, but it is also desirable in terms of the various objectives of the present invention described above, particularly metabolic stability and stability during storage.

[0046] [ka] JPEG2025536298000017.jpg78169

[0047] Preferably, in the SHP2-targeted protein degradation compound according to the present invention, the moiety (VHL ligand) on the right side of the linker (-WL-) has one of the following structures: When the compound has the following structure, it has excellent SHP2 degradation activity and further meets the various objectives of the present invention described above.

[0048] [ka] JPEG2025536298000019.jpg180169 JPEG2025536298000020.jpg193169

[0049] One aspect of the present invention provides various forms of SHP2 target protein degradation compounds, their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts thereof, which are combinations of the above-mentioned (i) any one of the SHP2 ligand moieties, (ii) any one of the linker (-WL-) moieties, and (iii) any one of the VHL ligand moieties. Non-limiting examples of the compound of Formula 1 according to the present invention are the compounds prepared in Examples 1 to 124 described below. The number of each Example corresponds to the number of the compound. For example, the final compound prepared in Example 101 is numbered Compound 101.

[0050] One aspect of the present invention provides the compounds shown in the table below, their optical isomers, stereoisomers, isotopic variations, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0051] [Table 1] TIFF2025536298000022.tif220169TIFF2025536298000023.tif228169TIFF20255362980 00024.tif232169TIFF2025536298000025.tif229169TIFF2025536298000026.tif230169 TIFF2025536298000027.tif224169TIFF2025536298000028.tif220169TIFF20255362980 00029.tif233169TIFF2025536298000030.tif225169TIFF2025536298000031.tif214169 TIFF2025536298000032.tif228169TIFF2025536298000033.tif95169

[0052] As used herein, the terms "substituent," "radical," "group," "moiety," and "fragment" are used interchangeably. If a substituent is described as "optionally substituted" or "optionally substituted," it means that the substituent is unsubstituted or substituted with one or more of the defined substituents. If a substitutable position is unsubstituted, the default substituent is hydrogen.

[0053] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched, non-cyclic hydrocarbon having 1 to 10 or 1 to 6 carbon atoms (unless the number of carbon atoms is otherwise limited). "Lower alkyl" refers to a straight-chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethyl In one preferred embodiment of the present invention, alkyl is methyl, ethyl, or n-propyl.

[0054] The term "alkynyl" as used herein means a straight-chain or branched acyclic hydrocarbon having 2 to 10 or 2 to 6 carbon atoms (unless the number of carbon atoms is specifically limited) and containing at least one carbon-carbon triple bond. Representative straight-chain or branched (C2-C 10Alkynyl includes acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, and 9-decynyl. Such alkynyl groups may be optionally substituted.

[0055] The term "alkoxy" as used herein means -O-(alkyl), including -OCH, -OCHCH, -O(CH)CH, -OC(CH)H, -OC(CH) and the like, where alkyl is defined above. As used herein, "C 1-6 When written as "C1-6" or "C1-C6", this means that the number of carbon atoms is 1 to 6. For example, C 1-6 Alkyl means alkyl having 1 to 6 carbon atoms. As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine, or iodine. In a preferred embodiment of the present invention, the halogen is fluorine or chlorine.

[0056] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with a halogen atom. For example, haloalkyl includes -CF, -CHF, -CHF, -CBr, -CHBr, -CHBr, -CCl, -CHCl, -CHCI, -CI, -CHI, -CHI, -CHI, -CH-CF, -CH-CHF, -CH-CHF, -CH-CBr, -CH-CHBr, -CH-CHBr, -CH-CCl, -CH-CHCl, -CH-CHCI, -CH-CI, -CH-CHI, -CH-CHI, and the like. In a preferred embodiment of the present invention, haloalkyl is CF, where alkyl and halogen are as defined above.

[0057] As used herein, the term "hydroxyalkyl" refers to a linear or branched C alkyl group substituted with one or more hydroxy groups. 1-10 Alkyl or C 1-6 represents alkyl; examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0058] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated ring containing carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Examples of polycyclic rings include, but are not limited to, fused bicyclic rings such as octahydropentalene and decahydronaphthalene; spirocyclic rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, and spiro[5.5]undecane; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and bicyclo[2.2.2]octane. The cycloalkyl group may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic ring. In one preferred embodiment of the invention, the cycloalkyl group is cyclopropyl.

[0059] As used herein, "heterocycle" or "heterocycloalkyl" means a saturated 5- to 7-membered monocyclic or 7- to 12-membered bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Representative heterocycles include oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidinone, hydantoin, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, morpholine, tetrahydropyridine, tetrahydropyrimidine, and the like. Heterocycles include bicyclic rings in which a portion of the heterocycle is fused to a benzene or cyclopenta-1,3-diene ring. Heterocycles can be attached by heteroatoms or carbon atoms. Heterocycles also include fused bicyclic rings, spirocyclic rings, and bridged bicyclic rings in which one or more carbon atoms of the aforementioned polycyclic ring are replaced by nitrogen, oxygen, or sulfur atoms.Examples of such heterocyclic rings include, for example, when the heteroatom is nitrogen, fused heterobicyclic rings such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, and the like; 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, and the like. spiro rings such as nan, 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, and the like; and bridged heterobicyclic rings such as 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane, and the like. In a preferred embodiment of the present invention, the heterocycle is any one selected from azetidine, diazetidine, piperidine, piperazine, azaspiro[3.5]nonane, diazabicyclo[3.2.1]octane, and the like.

[0060] As used herein, the term "aryl" refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Carbocyclic aromatic groups can be optionally substituted.

[0061] As used herein, "heteroaryl" refers to a 5-10 member aromatic heterocycle containing at least one carbon atom and at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, including mono- and bicyclic ring systems. Representative heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, and the like. In a preferred embodiment of the present invention, the heteroaryl is thiazole, pyridine, or pyrazine.

[0062] In this specification, "*" or

[0063] [ka]

[0064] means that it is connected to other moieties.

[0065] In the present invention, "pharmaceutically acceptable salts" include salts of active compounds prepared from relatively non-toxic acids and bases, depending on the specific substituents found in the compounds referred to herein. When a compound of the present invention contains a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids, including acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, as well as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydrogen iodide, or phosphorous acids and the like. Also included are salts of amino acids such as arginate and its analogs, and organic acid analogs such as glucuronic acid or galacturonic acid and its analogs. Some specific compounds of the present invention have both basic and acidic functionalities that allow the compounds to be converted into basic or acid addition salts. Other examples of salts are disclosed in the literature known in the art.

[0066] As used herein, the term "compounds of the present invention" includes not only each compound of Formula 1 but also their optical isomers, stereoisomers, isotopic variations, hydrates, or solvates. Furthermore, unless a pharmaceutically acceptable salt is specifically mentioned, the term "compounds of the present invention" also includes pharmaceutically acceptable salts of the compounds of the present invention. In one embodiment, the compounds of the present invention may exist as stereoisomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee or more)). That is, when the compounds of Formula 1 according to the present invention or salts thereof are tautomers and / or stereoisomers (e.g., geometric isomers and conformational isomers), the separated isomers and mixtures thereof are also included within the scope of the compounds of the present invention. When the compounds of the present invention or salts thereof have asymmetric carbon atoms in their structure, optically active compounds and racemic mixtures thereof are also included within the scope of the compounds of the present invention.

[0067] As used herein, the term "isomer" means compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space.

[0068] As used herein, the term "stereoisomer" means an isomer that differs in the arrangement of the atoms in space.

[0069] Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images are termed "enantiomers." For example, if a compound has an asymmetric center, it may be bonded to four different groups to form a pair of enantiomers. Enantiomers are characterized by the absolute arrangement of the asymmetric center and are described by R and S sequencing rules, or by the way the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures of these. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0070] As used herein, a pure enantiomer of a compound is one that is substantially free of other enantiomers or stereoisomers of the compound. This state is referred to as enantiomeric excess. In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, 99%, 99.2%, or greater than 99.5%, 99.6%, or greater than 99.7%, 99.8%, or greater than 99.9% by weight. In certain embodiments, weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0071] As used herein, unless otherwise specified, the term "enantiomerically pure (R)-compound" means greater than or equal to about 95% by weight of (R)-compound and less than or equal to about 5% by weight of (S), at least about 99% by weight of (R)-compound and up to about 1% by weight of (S)-compound, or at least about 99.9% by weight of (R)-compound and up to about 0.1% by weight of (S)-compound. In certain embodiments, weights are based on the total weight of the compound.

[0072] As used herein, and unless otherwise specified, the term "enantiomerically pure (S)-compound" means greater than about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and up to about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and up to about 0.1% by weight of the (R)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0073] In the compositions provided herein, the enantiomerically pure compound or its pharmaceutically acceptable salt, solvate, hydrate, or precursor drug may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure (R)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition may contain, for example, about 95% or more (R)-compound by total weight and up to about 5% (S)-compound by weight. For example, a pharmaceutical composition containing an enantiomerically pure (S)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions may contain, for example, about 95% or more by weight of the (S)-compound and up to about 5% by weight of the (R)-compound. In certain embodiments, the active ingredient may be formulated with few or no excipients or carriers.

[0074] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all individual enantiomers and mixtures thereof, racemic or otherwise.

[0075] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and within the scope of the present invention.

[0076] In certain embodiments, the compounds disclosed herein contain one or more chiral centers, and each center may be in the R or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present invention.

[0077] In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced from a single preparation step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optical resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are desirable. In certain embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by exploiting these differences. In certain embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In certain embodiments, the optically pure enantiomers are recovered along with the resolving agent.

[0078] In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all tautomers possible within the chemical formulas described herein.

[0079] Tautomers are compounds that are interconvertible by the migration of a hydrogen atom accompanied by the conversion of a single bond and an adjacent double bond. A chemical equilibrium of tautomers exists among the possible bond arrangements of tautomers. Tautomeric forms may be involved in achieving optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the present invention. The exact proportion of tautomers will vary depending on various factors, including temperature, solvent, and pH.

[0080] As used herein, the term "isotopic variant" refers to a compound that contains an unusual proportion of an isotope at one or more of the atoms that constitute the compound. For example, an isotopic variant of a compound is radiolabeled, e.g., the hydrogen atoms may be selected from hydrogen, deuterium, and tritium, and carbon-13 ( 13 C), nitrogen-15( 15 N) and so on.

[0081] As used herein, the term "solvate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered to humans in minimal amounts.

[0082] As used herein, the term "hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0083] As used herein, the term "purified" means that when isolated, the isolate is greater than 90% pure, in one embodiment greater than 95% pure, in another embodiment greater than 99% pure, and in another embodiment greater than 99.9% pure.

[0084] Pharmaceutical Uses and Methods of Treatment of the Compounds of the Invention According to one aspect of the present invention, there is further provided a method of treating the following diseases or conditions in an individual suffering from or susceptible to such a disease or condition by administering to the individual a therapeutically effective amount of one or more of the compounds as described above. In one embodiment, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In yet another embodiment, the treatment is a restorative treatment.

[0085] 1. Disease or condition As used herein, the terms "prevention" or "preventing" means to bar the onset of symptoms or complications of a disease, condition or disorder. The compounds of the present invention are useful for a variety of therapeutic or prophylactic applications (e.g., cancer). Such compounds can be used to degrade SHP2 and reduce SHP2 activity, and can be used to treat SHP2-related diseases or prevent the progression of such diseases. Thus, according to one aspect of the present invention, there is provided a method for degrading intracellular SHP2. In such a method, the cell can be contacted with an effective amount of a compound of the present invention. In one embodiment, the cell is present in an individual. The method of the present invention comprises administering to an individual in need of treatment or prevention a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of the present invention.

[0086] In one embodiment, according to an aspect of the present invention, a method for degrading SHP2 in cells of an individual with an SHP2-related disease is provided. For example, as a specific example of the present invention, a method for degrading SHP2 in cells of an individual with an SHP2-related disease described below, thereby reducing SHP2 activity, can be provided. In another embodiment of the present invention, the compounds of the present invention can be used to degrade SHP2 in cancer cells, particularly leukemia, lymphoma, lung cancer, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, melanoma, neuroblastoma, glioma, sarcoma, and the like.

[0087] In another aspect, there is provided a method for treating an SHP2-related disorder, comprising administering to an individual a therapeutically effective amount of a compound of the present invention, or an optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof. Such a method comprises administering to an individual in need of treatment an amount of a compound of the present invention sufficient to degrade SHP2, i.e., a therapeutically effective amount. In such a method, the compound of the present invention may be administered to the individual in the form of a pharmaceutical composition described herein.

[0088] In a specific example of the present invention, the SHP2-associated disease may be cancer, metastasis, cardiovascular disease, immune disorder, or ocular disorder.

[0089] In a specific embodiment of the present invention, the SHP2-related disease is cancer. For example, the disease may be any one of the cancers listed in Table 2 of International Patent Application Publication WO2021 / 236775, but is not limited thereto. Specific examples include hematological cancer, acute lymphocytic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, lymphoma, cervical cancer, head and neck cancer, cranial cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, melanoma, colorectal cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma or sarcoma, papillary thyroid cancer, and combinations thereof. The descriptions in Table 2 of WO2021 / 236775 are incorporated herein by reference in their entirety. In another embodiment, the cancer is a solid tumor. In yet another embodiment, the cancer is a blood cancer. Examples of blood cancer include, but are not limited to, the cancers set forth in Table 3 of WO2021 / 236775. The disclosure of Table 3 of WO2021 / 236775 is incorporated herein by reference in its entirety. In yet another embodiment, the blood cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. In yet another embodiment, the cancer is a leukemia, for example, a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In yet another embodiment, the cancer is NUT midline carcinoma. In yet another embodiment, the cancer is multiple myeloma. In still other embodiments, the cancer is lung cancer, such as small cell lung cancer (SCLC). In still other embodiments, the cancer is neuroblastoma. In still other embodiments, the cancer is Burkitt's lymphoma. In still other embodiments, the cancer is cervical cancer. In still other embodiments, the cancer is head and neck cancer. In still other embodiments, the cancer is esophageal cancer. In still other embodiments, the cancer is gastric cancer. In still other embodiments, the cancer is pancreatic cancer. In still other embodiments, the cancer is liver cancer. In still other embodiments, the cancer is melanoma. In still other embodiments, the cancer is ovarian cancer.In yet another embodiment, the cancer is colon cancer, in yet another embodiment, the cancer is prostate cancer, in yet another embodiment, the cancer is breast cancer.

[0090] In yet another embodiment, the cancer according to the present invention is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, lymphoma, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, head and neck cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, melanoma, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid cancer.

[0091] That is, according to one aspect of the present invention, there is provided a pharmaceutical use of a compound of Chemical Formula 1, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or a pharmaceutically acceptable salt thereof for treating or preventing the above-mentioned diseases.

[0092] 2. Subjects Desirable individuals for treatment according to the present invention include mammalian individuals, including, but not limited to, humans, canines, felines, bovines, caprines, horses, ovines, porcines, rodents, lagomorphs, primates, and the like, including in utero mammals. In one embodiment, the individual desired for treatment according to the present invention is a human.

[0093] 3. Administration and Dosing The compounds of the invention are typically administered in a therapeutically effective amount.

[0094] As used herein, an "effective amount" refers to an amount of a compound of the invention sufficient to prevent, slow or minimize the progression of, or provide a therapeutic benefit in the treatment or management of an SHP2-related disorder. An "effective amount" also refers to an amount sufficient to inhibit or reduce SHP2 activity either in vitro or in vivo.

[0095] The compounds of the present invention can be administered by any desired route in the form of a pharmaceutical composition appropriate for such route and in an effective dose for the intended treatment. An effective dose is typically about 0.001 to 100 mg / kg body weight / day, preferably about 0.01 to 50 mg / kg body weight / day, in a single dose or in divided doses. Depending on the age, species, and disease or condition being treated, a dosage level below the lower limit of the above range may be desirable. In other cases, higher doses may still be used without adverse side effects. A larger dose can be divided into several smaller doses for daily administration.

[0096] 4. Other embodiments related to pharmaceutical uses Based on the foregoing, one aspect of the present invention provides a method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), comprising the step of administering to an individual in need thereof a therapeutically effective amount of a compound according to the present invention, or an optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0097] Based on the foregoing, one aspect of the present invention provides a method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample, comprising the step of contacting the patient or biological sample with a compound according to the present invention, or an optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0098] Based on the foregoing, one aspect of the present invention provides the use of a compound according to the present invention, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or a pharmaceutically acceptable salt thereof, for the production of a medicament for the degradation of Src homology 2 domain-containing phosphatase (SHP2) in a patient or biological sample.

[0099] Based on the above explanation, one aspect of the present invention provides use of a compound according to the present invention, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or a pharmaceutically acceptable salt thereof for producing a medicament for the treatment of a Src homology 2 domain-containing phosphatase (SHP2)-associated disease.

[0100] Pharmaceutical Compositions of the Compounds of the Invention In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Chemical Formula 1, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect of the present invention, the pharmaceutical composition is used for the treatment or prevention of SHP2-related diseases, particularly cancer, as described below. The term "pharmaceutically acceptable" means suitable for use as a pharmaceutical formulation, generally recognized as safe for such use, officially approved by a national regulatory agency for such use, or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0101] Pharmaceutical compositions, dosage forms and routes of administration For the treatment of the diseases or conditions described above, the compounds described herein can be administered as follows:

[0102] 1. Oral administration The compounds of the present invention can be administered orally, which includes swallowing. By oral administration, the compounds of the present invention can enter the gastrointestinal tract or can be absorbed directly into the bloodstream from the mouth, e.g., by buccal or sublingual administration.

[0103] Compositions suitable for oral administration may be solid, liquid, gel, or powder and may have the form of tablets, lozenges, capsules, granules, powders, and the like.

[0104] Compositions for oral administration may optionally be enteric coated and may exhibit delayed or sustained release due to the enteric coating, i.e., compositions for oral administration according to the present invention may be in a dosage form with an immediate or modified release pattern. Liquid dosage forms may include solutions, syrups, and suspensions, and such liquid compositions may be contained in soft or hard capsules. Such dosage forms may contain a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose, or oil. The dosage forms may also contain one or more emulsifying agents and / or suspending agents.

[0105] In tablet dosage forms, the active ingredient may be present in an amount of about 0.05 to 95% by weight, more typically about 2 to 50% by weight, based on the total weight of the tablet. Tablets may also contain a disintegrant, which may comprise about 0.5 to 35% by weight, more typically about 2 to 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0106] Lubricants included for tableting may desirably be present in an amount of about 0.1 to 5% by weight and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

[0107] Binders for tablet manufacture include gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc., and desirable diluents for tablet manufacture include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc.

[0108] The solubilizer that may be optionally contained in the tablet may be used in an amount of about 0.1 to 3% by weight based on the total weight of the tablet, and examples thereof include polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR, etc. TM (Nikkol), Oleyl Esters, Gelucire TM ), Caprylic / Caprylic Acid Mono / Diglyceride, Sorbitan Fatty Acid Ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but are not limited to these.

[0109] 2. Parenteral Administration The compounds of the present invention may be administered directly into the blood stream, muscle, or an internal organ. Preferred methods for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, intracranial injection, etc. Preferred devices for parenteral administration include injectors (including needle and needle-free injectors) and infusion methods.

[0110] Many parenteral dosage forms are liquid compositions, and such liquid compositions are aqueous solutions containing the active ingredient according to the present invention, salts, buffers, tonicity agents, and the like. Parenteral dosage forms can be prepared in a dried form (e.g., lyophilized) or as a sterile non-aqueous solution, which can be used in combination with a suitable vehicle, such as sterile water.

[0111] 3. Topical Administration The compounds of the present invention can be administered topically via the skin or transdermally. Dosage forms for such topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration dosage forms can include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical administration can also be achieved by electroporation, iontophoresis, phonophoresis, etc.

[0112] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and spaced-apart administration (administration of one or more therapeutic agents at a time that is different from the administration of additional therapeutic agents or formulations), so long as the therapeutic agents are present in the patient's body at some level, preferably in effective amounts, at the same time. In certain desirable embodiments, one or more compounds of the invention described herein are further combined and co-administered with at least one bioactive agent, including, in particular, an anti-cancer agent. In certain desirable embodiments, the co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer therapy.

[0113] [Effects of the invention] The present invention provides compounds that exhibit excellent SHP2 degradation activity and diverse pharmacological activities, pharmaceutical compositions containing the same as active ingredients, their medical uses (particularly for cancer or tumors), and therapeutic methods comprising administering them to individuals in need of treatment or prevention. The compounds of the present invention can be provided with excellent SHP2 degradation activity by introducing an SHP2-binding ligand into a VHL ligand via a linker of the present invention, thereby providing an effective treatment option for tumor cells, particularly cancers with KRAS mutations. Furthermore, the compounds of the present invention are excellent in various aspects, such as SHP2 degradation activity, plasma stability, metabolic stability, stability during storage, pharmacological properties, and physicochemical properties.

[0114] [Mode for Carrying Out the Invention] The present invention will be described below with reference to specific examples. However, the examples according to the present invention can be modified into many other forms, and the scope of the present invention should not be construed as being limited to the examples described below. The examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

[0115] Preparation of the Compounds of the Invention The synthesis processes of some compounds of the present invention are described below, and compounds not mentioned below can be prepared by similar methods by replacing the starting materials, intermediates and / or reactants.

[0116] Intermediate 1. Tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0117] [ka]

[0118] Step 1: Synthesis of 3-(tert-butylthio)-2-chloroaniline 2-Chloro-3-fluoroaniline (5 g, 34.34 mmol), 2-methylpropane-2-thiol (11.6 mL, 103.02 mmol), and CsCO (22 g, 68.68 mmol) were suspended in DMF (60 mL) and stirred at 120 °C for 16 hours. The reaction mixture was diluted with EtOAc (400 mL) and washed with distilled water (150 mL x 3) and brine (150 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7.8 g (quant.) of a brown oil.

[0119] Step 2: Synthesis of 3-amino-2-chlorobenzenethiol 3-(tert-Butylthio)-2-chloroaniline (7.8 g, 34.34 mmol) was suspended in concentrated HCl (126 ml) and stirred at 90° C. for 6 hours. After cooling the reaction mixture, the resulting solid was filtered and dried to yield 5.3 g (97%) of an ivory solid.

[0120] Step 3: Synthesis of 2-chloro-3-((5-chloropyrazin-2-yl)thio)aniline 3-Amino-2-chlorobenzenethiol (5.3 g, 33.20 mmol), 2-bromo-5-chloropyrazine (6.4 g, 33.20 mmol), Pd2(dba)3 (304 mg, 0.33 mmol), Xantphos (384 mg, 0.66 mmol), and DIPEA (11.6 mL, 66.40 mmol) were suspended in 1,4-dioxane (60 mL) and stirred at 95 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (3-15% EtOAc / hexane) to give 5.93 g (66%) of an ivory solid.

[0121] Step 4: Synthesis of tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-Chloro-3-((5-chloropyrazin-2-yl)thio)aniline (2.5 g, 9.19 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (2.3 g, 10.11 mmol), and DIPEA (7.2 mL, 41.34 mmol) were suspended in NMP (9 mL) and stirred at 130 °C for 16 h. Distilled water (150 mL) was added to the reaction mixture, followed by extraction with EtOAc (150 mL). The organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (3-30% EtOAc / hexane) to give 3.84 g (90%) of an ivory solid. The following intermediates 2 to 5 were synthesized in the same manner as in the synthesis of intermediate 1.

[0122] [Table 2]

[0123] Intermediate 6. Tert-butyl ((1-(5-(3-amino-2-chlorophenoxy)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0124] [ka]

[0125] Step 1: Synthesis of 2-chloro-5-(2-chloro-3-nitrophenoxy)pyrazine 2,5-Dichloropyrazine (1.72 g, 11.50 mmol), 2-chloro-3-nitrophenol (2.00 g, 11.50 mmol), and K2CO3 (3.19 g, 23.00 mmol) were suspended in DMF (20 mL) and stirred at 100 °C for 4 h. The reaction was quenched by the addition of saturated NH4Cl (aq.) and diluted with brine (200 mL). After dilution with EtOAc (400 mL), the organic layer was extracted, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% EtOAc / hexane) to give 1.91 g (58%) of a white solid.

[0126] Step 2: Synthesis of 2-chloro-3-((5-chloropyrazin-2-yl)oxy)aniline 2-Chloro-5-(2-chloro-3-nitrophenoxy)pyrazine (1.91 g, 6.68 mmol) was suspended in THF (100 mL), followed by the addition of saturated NH4Cl (aq.) and stirring at 60 °C for 48 h. After cooling to room temperature, the resulting dark suspension was filtered, and the filtrate was diluted with EtOAc (100 mL). The organic layer was extracted, washed with brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to yield 1.28 g (75%) of an off-white solid.

[0127] Step 3: Synthesis of tert-butyl ((1-(5-(3-amino-2-chlorophenoxy)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-Chloro-3-((5-chloropyrazin-2-yl)oxy)aniline (500 mg, 1.95 mmol) was suspended in NMP (2.5 mL), and then tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (535 mg, 2.34 mmol) and DIPEA (3.40 mL, 19.50 mmol) were added. The mixture was stirred at 130 °C for 1 day. The reaction mixture was cooled to room temperature and diluted with distilled water (50 mL) and EtOAc (80 mL). The organic layer was extracted, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to give 316 mg (36%) of a white solid.

[0128] Intermediate 7. (R)-N-((3S,4S)-8-(5-(indolin-4-ylthio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide

[0129] [ka]

[0130] Step 1: Synthesis of 4-bromoindoline 4-Bromo-1H-indole (1.28 ml, 10.20 mmol) was suspended in TFA (20 ml), triethylsilane (4.89 ml, 30.61 mmol) was added at 0°C, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The pH was adjusted to 10 with 2 M NaOH (aq.), and then distilled water (50 ml) was added and extracted with EtOAc (50 ml x 3). The organic layer was washed with brine (50 ml x 2) and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to obtain 1.90 g (crude) of a yellow oil.

[0131] Step 2: Synthesis of tert-butyl 4-bromoindoline-1-carboxylate 4-Bromoindoline (1.90 g, 9.59 mmol) was suspended in DCM (30 mL), followed by the addition of di-tert-butyl dicarbonate (3.14 g, 14.39 mmol) and TEA (4.01 mL, 28.78 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (30 mL) and brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-6% EtOAc / petroleum ether) to give 2.80 g (91%) of a yellow oil.

[0132] Step 3: Synthesis of tert-butyl 4-((3-methoxy-3-oxopropyl)thio)indoline-1-carboxylate Tert-butyl 4-bromoindoline-1-carboxylate (2.80 g, 9.39 mmol), methyl 3-mercaptopropanoate (3.05 mL, 28.17 mmol), TEA (3.92 mL, 28.17 mmol), Xantphos (1.09 g, 1.88 mmol), and Pd2(dba)3 (0.86 g, 0.94 mmol) were suspended in toluene (56 mL). The suspension was degassed and purged with N2 three times and then stirred at 100 °C for 16 h. Distilled water (100 mL) was added to the reaction mixture, followed by extraction with EtOAc (80 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / petroleum ether) to give 1.46 g (46%) of a yellow solid.

[0133] Step 4: Synthesis of potassium 1-(tert-butoxycarbonyl)indoline-4-thiolate Tert-butyl 4-((3-methoxy-3-oxopropyl)thio)indoline-1-carboxylate (1.45 g, 4.30 mmol) was suspended in THF (29 ml), and then t-BuOK (1 M, 8.59 ml) was added at -65°C and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1.20 g (crude) of a yellow liquid.

[0134] Step 5: Synthesis of tert-butyl 4-((5-chloropyrazin-2-yl)thio)indoline-1-carboxylate 2,5-Dichloropyrazine (1.30 g, 8.73 mmol) was suspended in THF (12 mL), followed by the addition of potassium 1-(tert-butoxycarbonyl)indoline-4-thiolate (1.20 g, 4.15 mmol) and stirring at room temperature for 2 hours. After adding sat. NH4Cl (aq.) (30 mL), the reaction mixture was extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (0-15% EtOAc / petroleum ether) to yield 601 mg (40%) of a white solid.

[0135] Step 6: Synthesis of tert-butyl 4-((5-((3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)indoline-1-carboxylate (R)-2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (181 mg, 0.66 mmol) was suspended in NMP (2 mL) and DIPEA (0.23 mL, 1.32 mmol) was added, followed by tert-butyl 4-((5-chloropyrazin-2-yl)thio)indoline-1-carboxylate (120 mg, 0.33 mmol). The mixture was stirred at 130 °C for 5 h. After adding sat. NHCl (aq.), the reaction mixture was extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-100% EtOAc / hexane) to give 116 mg (58%) of a colorless oil.

[0136] Step 7: Synthesis of (R)-N-((3S,4S)-8-(5-(indolin-4-ylthio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide Tert-butyl 4-((5-((3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)indoline-1-carboxylate (116 mg, 0.19 mmol) was suspended in DCM (10 mL), followed by addition of TFA (2.5 mL) and stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then diluted with EtOAc (50 mL). The organic layer was basified with 1 M NaOH (aq.), washed with brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% MeOH / DCM + 0.1% NH4OH) to give 71 mg (73%) of a colorless oil.

[0137] Intermediate 8. Tert-butyl ((1-(5-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0138] [ka]

[0139] Step 1: Synthesis of tert-butyl 8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate 8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (3 g, 14.01 mmol) and di-tert-butyl dicarbonate (3.67 g, 16.82 mmol) were suspended in DCM (20 mL), followed by the addition of TEA (5.85 mL, 42.04 mmol) and DMAP (171 mg, 1.40 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with distilled water (30 mL) and brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% EtOAc / petroleum ether) to give 3.40 g (77%) of a yellow oil.

[0140] Step 2: Synthesis of tert-butyl 8-((3-methoxy-3-oxopropyl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate Tert-butyl 8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (3 g, 9.55 mmol), methyl 3-mercaptopropanoate (2.59 mL, 23.87 mmol), TEA (3.99 mL, 28.65 mmol), Xantphos (1.11 g, 1.91 mmol), and Pd2(dba)3 (0.87 g, 0.95 mmol) were suspended in toluene (30 mL). The suspension was degassed and purged with N2 three times and then stirred at 100 °C for 12 h. Distilled water (40 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-25% EtOAc / petroleum ether) to give 2.40 g (68%) of a yellow oil.

[0141] Step 3: Synthesis of potassium 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-thiolate tert-Butyl 8-((3-methoxy-3-oxopropyl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (1.45 g, 4.30 mmol) was suspended in THF (29 mL), and then t-BuOK (1 M, 8.59 mL) was added at -65°C and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1.20 g (crude) of a yellow liquid.

[0142] Step 4: Synthesis of tert-butyl 8-((5-chloropyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate 2,5-Dichloropyrazine (3.51 g, 23.57 mmol) was suspended in THF (20 mL), followed by the addition of potassium 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-thiolate (2.40 g, 7.86 mmol) and stirring at room temperature for 2 hours. Distilled water (20 mL) was added to the reaction mixture, followed by extraction with EtOAc (20 mL x 3). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-30% EtOAc / petroleum ether) to yield 1.70 g (56%) of a yellow solid.

[0143] Step 5: Synthesis of tert-butyl 8-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate tert-Butyl N-[(4-methyl-4-piperidyl)methyl]carbamate (1.12 g, 4.92 mmol), tert-butyl 8-((5-chloropyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (1.70 g, 4.48 mmol), and K2CO3 (1.86 g, 13.43 mmol) were suspended in DMSO (20 mL). The suspension was degassed and purged with N2 three times and then stirred at 80 °C for 3 h. Sat. NH4Cl (aq.) was added to the reaction mixture, which was then extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-30% EtOAc / hexanes) to give 2.00 g (80%) of a yellow solid.

[0144] Step 6: Synthesis of (1-(5-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methanamine tert-Butyl 8-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (2 g, 3.50 mmol) was suspended in MeOH (25 mL), and then 4 M HCl in MeOH (8.75 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (80 mL), and the organic layer was basified with 1 M NaOH (aq.), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (20-70% EtOAc / petroleum ether) to give 780 mg (60%) of a yellow solid.

[0145] Step 7: Synthesis of tert-butyl ((1-(5-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (1-(5-((3,4-Dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methanamine (700 mg, 1.88 mmol), di-tert-butyl dicarbonate (411 mg, 1.88 mmol), and TEA (0.52 mL, 3.77 mmol) were suspended in DCM (7 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of saturated NH4Cl (aq.) and extraction with EtOAc (10 mL × 2). The organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters x Bridge Prep OBD C18 150 mm x 40 mm x 10 μm; mobile phase: [H2O (0.1% NH4HCO3)-ACN]; B%: 40% to 70%, 15 min) to give 290 mg (32%) of a yellow solid.

[0146] Intermediate 9 was synthesized in the same manner as intermediate 8.

[0147] [Table 3]

[0148] Intermediate 10. tert-Butyl ((1-(5-((3-fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0149] [ka]

[0150] Step 1: Synthesis of ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate 2,5-Dichloropyrazine (500 mg, 3.36 mmol) and ethyl 3-mercaptopropanoate (455 mg, 3.39 mmol) were suspended in DMF (2.5 mL), followed by addition of K2CO3 (464 mg, 3.36 mmol) and stirring at room temperature for 16 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL x 5). The organic layer was washed with brine (5 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-25% EtOAc / petroleum ether) to yield 593 mg (68%) of a colorless oil.

[0151] Step 2: Synthesis of potassium 5-chloropyrazine-2-thiolate Ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate (1.60 g, 6.49 mmol) was suspended in THF (25 mL), and then t-BuOK (1.46 g, 12.97 mmol) was added at -30°C, followed by stirring at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 1.20 g (crude) of an orange solid.

[0152] Step 3: Synthesis of 3,3-difluoro-4-iodoindolin-2-one 4-Iodoindoline-2,3-dione (10 g, 36.63 mmol) was suspended in DCM (350 mL) and then DAST (17.71 g, 109.88 mmol) was added at 0°C. The mixture was stirred at room temperature for 24 hours. Distilled water (100 mL) was added to the reaction mixture, which was then extracted with DCM (50 mL x 3). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized in PE at room temperature for 30 minutes to yield 11.20 g (93%) of a brown solid.

[0153] Step 4: Synthesis of 3,3-difluoro-4-iodoindoline 3,3-Difluoro-4-iodoindolin-2-one (5 g, 16.95 mmol) was suspended in THF (30 mL) and then BH3-THF (1 M, 59.32 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. 10% citric acid (aq.) (100 mL) and distilled water (200 mL) were added to the reaction mixture at 0 °C, followed by extraction with EtOAc (150 mL × 3). The organic layer was washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 4.76 g (crude) of a yellow oil.

[0154] Step 5: Synthesis of 1-(3,3-difluoro-4-iodoindolin-1-yl)ethan-1-one 3,3-Difluoro-4-iodoindoline (4.76 g, 16.94 mmol) was suspended in EtOAc (60 mL) and then DIPEA (7.38 mL, 42.34 mmol) and AcCl (3.01 mL, 42.34 mmol) were added dropwise at 0 °C. The mixture was stirred at the same temperature for 2 h. Distilled water (150 mL) was added to the reaction mixture, followed by extraction with EtOAc (80 mL x 3). The organic layer was washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-25% EtOAc / petroleum ether) to give 2.87 g (51%) of a green solid.

[0155] Step 6: Synthesis of 1-(4-((5-chloropyrazin-2-yl)thio)-3,3-difluoroindolin-1-yl)ethan-1-one 1-(3,3-Difluoro-4-iodoindolin-1-yl)ethan-1-one (1.50 g, 4.64 mmol), potassium 5-chloropyrazine-2-thiolate (1.03 g, 5.57 mmol), DIPEA (1.62 mL, 9.29 mmol), Xantphos (269 mg, 0.46 mmol), and Pd(dba) (213 mg, 0.23 mmol) were suspended in 1,4-dioxane (25 mL). The suspension was degassed and purged with N three times and then stirred at 70 °C for 5 h. Distilled water (80 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-25% EtOAc / petroleum ether) to give 830 mg (42%) of a yellow solid.

[0156] Step 7: Synthesis of tert-butyl ((1-(5-((1-acetyl-3,3-difluoroindolin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 1-(4-((5-chloropyrazin-2-yl)thio)-3,3-difluoroindolin-1-yl)ethan-1-one (830 mg, 2.43 mmol) and tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (665 mg, 2.91 mmol) were suspended in DMSO (8 mL), followed by addition of K2CO3 (1.01 g, 7.29 mmol) and stirring at 80 °C for 12 h. Distilled water (20 mL) was added to the reaction mixture, followed by extraction with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / petroleum ether) to give 510 mg (39%) of a yellow solid.

[0157] Step 8: Synthesis of tert-butyl ((1-(5-((3-fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate tert-Butyl ((1-(5-((1-acetyl-3,3-difluoroindolin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (450 mg, 0.84 mmol) was suspended in MeOH (2.7 mL) and HO (2.7 mL), followed by addition of NaOH (134.91 mg, 3.37 mmol) and stirring at 50 °C for 4 h. The reaction mixture was concentrated under reduced pressure, followed by addition of saturated NH4Cl (aq.) (5 mL), followed by extraction with EtOAc (5 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-45% EtOAc / petroleum ether) to give 250 mg (62%) of a yellow solid.

[0158] Intermediate 11. tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0159] [ka]

[0160] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 3-hydroxyazetidine-1-carboxylate 3-Hydroxyazetidine hydrochloride (1 g, 9.13 mmol) and Na2CO3 (2.9 g, 27.38 mmol) were suspended in a 1:1 mixture of HO and 1,4-dioxane (80 mL) and stirred at 0 °C for 10 min. Fmoc-Cl (2.36 g, 9.13 mmol) was added and stirred at room temperature for 2 h. Distilled water (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-60% EtOAc / hexane) to give 2.52 g (93%) of a white solid.

[0161] Step 2: Synthesis of (9H-fluoren-9-yl)methyl 3-oxoazetidine-1-carboxylate (9H-Fluoren-9-yl)methyl 3-hydroxyazetidine-1-carboxylate (1.11 g, 3.76 mmol) and DMP (1.75 g, 4.13 mmol) were suspended in DCM (17 mL) and stirred at room temperature for 2 hours. Sat. NaSO (aq.) (40 mL) was added to the reaction mixture, followed by extraction with DCM (50 mL). The organic layer was washed with distilled water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-25% EtOAc / hexane) to yield 1.1 g (100%) of a white solid.

[0162] Step 3: Synthesis of (9H-fluoren-9-yl)methyl 3-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carboxylate tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1, 1.50 g, 3.23 mmol), (9H-fluoren-9-yl)methyl 3-oxoazetidine-1-carboxylate (2.37 g, 8.08 mmol), and Ti(Oi-Pr) (1.9 mL, 6.47 mmol) were suspended in THF (12 mL) and stirred at 70 °C for 16 hours. NaBH (306 mg, 8.08 mmol) and MeOH (4 mL) were added, and the mixture was stirred at room temperature for 1 hour. Distilled water (50 mL) was added to the reaction mixture, which was then extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-15% EtOAc / DCM) to give 1.62 g (68%) of an ivory solid.

[0163] Step 4: Synthesis of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (9H-Fluoren-9-yl)methyl 3-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carboxylate (900 mg, 1.21 mmol) and EtNH (6.3 ml, 60.70 mmol) were suspended in DCM (6.3 ml) and stirred at room temperature for 3 hours. Distilled water (20 ml) was added to the reaction mixture, which was then extracted with DCM (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 739 mg of a crude ivory solid.

[0164] Intermediates 12 to 16 were synthesized in the same manner as in the synthesis of Intermediate 11.

[0165] [Table 4]

[0166] Intermediate 17. tert-Butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0167] [ka]

[0168] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 4-hydroxypiperidine-1-carboxylate 4-Hydroxypiperidine (1 g, 9.89 mmol) and Na2CO3 (3.14 g, 29.66 mmol) were suspended in a 1:1 HO:1,4-dioxane mixture (82 mL) and stirred at 0 °C for 10 min. Fmoc-Cl (2.56 g, 9.89 mmol) was added and stirred at room temperature for 16 h. Distilled water (30 mL) was added to the reaction mixture, followed by extraction with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (20-70% EtOAc / hexane) to give 2.95 g (92%) of a white solid.

[0169] Step 2: Synthesis of (9H-fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate (9H-Fluoren-9-yl)methyl 4-hydroxypiperidine-1-carboxylate (2.71 g, 8.38 mmol) and DMP (3.90 g, 9.22 mmol) were suspended in DCM (38 mL) and stirred at room temperature for 3 hours. Sat. NaSO (aq.) (40 mL) was added to the reaction mixture, followed by extraction with DCM (50 mL). The organic layer was washed with distilled water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-35% EtOAc / hexane) to yield 2.76 g (quant.) of a white solid.

[0170] Step 3: Synthesis of (9H-fluoren-9-yl)methyl 4-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carboxylate tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (intermediate 1,150 mg, 0.32 mmol), (9H-fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate (260 mg, 0.81 mmol), NaBH(OAc) (206 mg, 0.97 mmol), and acetic acid (0.3 mL) were suspended in a 1:1 ACN:DCM mixture (2.1 mL) and stirred at room temperature for 4 hours. To the reaction mixture was added sat. NaHCO (aq.) (10 mL), followed by extraction with DCM (10 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (1-40% EtOAc / hexane) to give 334 mg (crude) of an ivory solid.

[0171] Step 4: Synthesis of tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (9H-Fluoren-9-yl)methyl 4-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carboxylate (334 mg, crude) and piperidine (0.64 mL, 6.47 mmol) were suspended in DCM (1.5 mL) and stirred at room temperature for 2 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to give 80.1 mg of an ivory solid (45%, 2 steps).

[0172] Intermediates 18 to 24 were synthesized in the same manner as in the synthesis of intermediate 17.

[0173] [Table 5] TIFF2025536298000046.tif150169

[0174] Intermediate 25. tert-Butyl ((4-methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)piperidin-4-yl)methyl)carbamate

[0175] [ka]

[0176] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 4-(8-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)piperidine-1-carboxylate tert-Butyl ((1-(5-((3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 8, 30 mg, 0.06 mmol), (9H-fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate (102 mg, 0.32 mmol), phenylsilane (34 mg, 0.32 mmol), and TFA (24 μL, 0.32 mmol) were suspended in ACN (2 mL) and stirred at room temperature for 3 hours. Sat. NaHCO3 (aq.) (5 mL) was added to the reaction mixture, which was then extracted with DCM (5 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-40% EtOAc / hexane) to give 37 mg (75%) of an ivory solid.

[0177] Step 2: Synthesis of tert-butyl ((4-methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)piperidin-4-yl)methyl)carbamate ((9H-Fluoren-9-yl)methyl 4-(8-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)piperidine-1-carboxylate (40 mg, 0.05 mmol) was suspended in DCM (0.8 mL), followed by addition of piperidine (0.1 mL, 1.03 mmol) and stirring at room temperature for 2 hours. Distilled water (10 mL) was added to the reaction mixture, followed by extraction with DCM (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (amine-silica, 0-3% MeOH / DCM) to yield 24 mg (84%) of a white solid. Intermediate 26 was synthesized in the same manner as intermediate 25.

[0178] [Table 6]

[0179] Intermediate 27. tert-Butyl ((1-(5-((3-fluoro-1-(piperidin-4-yl)-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0180] [ka]

[0181] Step 1: Synthesis of tert-butyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate tert-Butyl 4-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol), 2-nitrobenzenesulfonyl chloride (6.6 g, 29.81 mmol), TEA (6.9 mL, 49.68 mmol), and DMAP (303 mg, 2.48 mmol) were suspended in DCM (48 mL) and stirred at room temperature for 3 hours. Distilled water (50 mL) was added to the reaction mixture, followed by extraction with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-30% EtOAc / hexane) to give 5.89 g (61%) of a white solid.

[0182] Step 2: Synthesis of piperidin-4-yl 2-nitrobenzenesulfonate hydrochloride tert-Butyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate (300 mg, 0.78 mmol) was suspended in DCM (5.2 ml), and then 4 M HCl in dioxane (1.9 ml) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 243 mg (quantity) of a white solid.

[0183] Step 3: Synthesis of 2-(trimethylsilyl)ethyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate Piperidin-4-yl 2-nitrobenzenesulfonate hydrochloride (243 mg, 0.78 mmol) and TEA (0.43 mL, 3.11 mmol) were suspended in DCM (2.6 mL), followed by the addition of 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (221 mg, 0.85 mmol) and stirring at room temperature for 1 hour. Distilled water (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to give 327 mg (98%) of a white solid.

[0184] Step 4: Synthesis of 2-(trimethylsilyl)ethyl 4-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-fluoro-1H-indol-1-yl)piperidine-1-carboxylate tert-Butyl ((1-(5-((3-fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 10, 10 mg, 0.02 mmol), 2-(trimethylsilyl)ethyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate (27 mg, 0.06 mmol), and Cs2CO3 (14 mg, 0.04 mmol) were suspended in DMF (0.05 ml) and stirred at 70 °C for 16 hours. Distilled water (5 ml) was added to the reaction mixture, which was then extracted with EtOAc (5 ml). The organic layer was washed with brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-40% EtOAc / hexane) and (0-10% EtOAc / DCM) to give 10.6 mg (crude) of an ivory solid.

[0185] Step 5: Synthesis of tert-butyl ((1-(5-((3-fluoro-1-(piperidin-4-yl)-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-(Trimethylsilyl)ethyl 4-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-fluoro-1H-indol-1-yl)piperidine-1-carboxylate (10.6 mg, crude) was suspended in THF (0.05 mL), and TBAF (1.0 M in THF, 30 μL, 0.03 mmol) was added and stirred at 50 °C for 1 h. Distilled water (5 mL) was added to the reaction mixture, followed by extraction with EtOAc (5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-5% MeOH / DCM) to give 3.7 mg (25%, 2 steps) of an ivory solid.

[0186] Intermediate 28. tert-Butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0187] [ka]

[0188] Step 1: Synthesis of tert-butyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate 3-Chloro-2-fluoro-4-iodopyridine (500 mg, 1.94 mmol), 1-Boc-3-aminoazetidine (669 mg, 3.88 mmol), and DIPEA (0.68 mL, 3.88 mmol) were suspended in DMSO (7.5 mL) and stirred at 100°C for 2 hours. Distilled water (30 mL) was added to the reaction mixture, followed by extraction with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-15% EtOAc / hexane) to give 540 mg (68%) of a white solid.

[0189] Step 2: Synthesis of N-(azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine tert-Butyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate (440 mg, 1.07 mmol) was suspended in DCM (10.6 ml), and TFA (2.6 ml) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 800 mg (quantity) of a brown oil.

[0190] Step 3: Synthesis of 2-(trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate N-(azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine (800 mg, 1.07 mmol) and TEA (0.60 mL, 4.30 mmol) were suspended in DCM (3.8 mL). 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (279 mg, 1.07 mmol) was added at 0 °C and stirred at room temperature for 1 h. Distilled water (15 mL) was added to the reaction mixture, followed by extraction with DCM (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-15% EtOAc / hexane) to give 468 mg (96%) of a colorless oil.

[0191] Step 4: Synthesis of tert-butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (504 mg, 2.21 mmol), 2,5-dibromopyrazine (500 mg, 2.10 mmol), and DIPEA (1.1 mL, 6.31 mmol) were suspended in NMP (2 mL) and stirred at 130°C for 1 hour. Distilled water (20 mL) was added to the reaction mixture, followed by extraction with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-15% EtOAc / hexane) to give 705 mg (87%) of a yellow solid.

[0192] Step 5: Synthesis of methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanoate tert-Butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (705 mg, 1.83 mmol), methyl 3-mercaptopropionate (0.22 mL, 2.01 mmol), Pd2(dba)3 (84 mg, 0.09 mmol), Xantphos (106 mg, 0.18 mmol), and DIPEA (0.64 mL, 3.66 mmol) were suspended in 1,4-dioxane (3.6 mL) and stirred at 90 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (1-35% EtOAc / hexane) to give 680 mg (88%) of a yellow oil.

[0193] Step 6: Synthesis of sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanoate (243 mg, 0.57 mmol) was suspended in THF (1.28 ml), and NaOEt (ca. 20% in EtOH, 0.21 ml, 0.63 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 278 mg of a crude yellow solid.

[0194] Step 7: Synthesis of 2-(trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate 2-(Trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate (200 mg, 0.44 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (278 mg, crude, 0.57 mmol), Pd(dba) (20 mg, 0.02 mmol), Xantphos (25 mg, 0.04 mmol), and DIPEA (0.15 mL, 0.88 mmol) were suspended in 1,4-dioxane (1 mL) and stirred at 90°C for 16 hours. Distilled water (15 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL). The organic layer was washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (1-40% EtOAc / hexane) to give 278 mg (95%) of a yellow solid.

[0195] Step 8: Synthesis of tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-(Trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate (37.8 mg, 0.06 mmol) and TBAF (1.0 M in THF, 0.17 mL, 0.17 mmol) were suspended in THF (0.43 mL) and stirred at 50°C for 2 hours. Distilled water (5 mL) was added to the reaction mixture, followed by extraction with DCM (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 28.5 mg (96%) of an ivory solid.

[0196] Intermediates 29 to 34 were synthesized in the same manner as in the synthesis of intermediate 28.

[0197] [Table 7]

[0198] Intermediate 35. (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylic acid

[0199] [ka]

[0200] Step 1: Synthesis of (1S,3S)-methyl 3-((3-chloro-4-iodopyridin-2-yl)amino)cyclobutane-1-carboxylate 3-Chloro-2-fluoro-4-iodopyridine (1 g, 3.88 mmol), methyl (1S,3S)-3-aminocyclobutane-1-carboxylate hydrochloride (644 mg, 3.88 mmol), and DIPEA (2 mL, 11.65 mmol) were suspended in DMSO (12 mL) and stirred at 100 °C for 4 h. Distilled water (30 mL) was added to the reaction mixture, followed by extraction with EtOAc (30 mL x 2). The organic layer was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / Hex) to give 600 mg (42%) of a yellow solid.

[0201] Step 2: Synthesis of (1S,3S)-methyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylate Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (905 mg, 2.51 mmol), (1S,3S)-methyl 3-((3-chloro-4-iodopyridin-2-yl)amino)cyclobutane-1-carboxylate (460 mg, 1.25 mmol), Pd2(dba)3 (14 mg, 0.06 mmol), Xantphos (73 mg, 0.13 mmol), and DIPEA (0.43 mL, 2.51 mmol) were suspended in 1,4-dioxane (4 mL) and stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to give 680 mg (94%) of an ivory solid.

[0202] Step 3: Synthesis of (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylic acid (1S,3S)-Methyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylate (377 mg, 0.65 mmol) and LiOH (41 mg, 0.98 mmol) were suspended in a 4:1:1 (2 mL) mixture of THF:HO:MeOH and stirred at room temperature for 2 h. The reaction mixture was adjusted to pH 1-2 with 1 M HCl (aq.) and then extracted with EtOAc (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-66% EtOAc / hexane) to give 241 mg (66%) of an orange solid.

[0203] Intermediates 36 to 48 were synthesized in the same manner as in the synthesis of Intermediate 35.

[0204] [Table 8] TIFF2025536298000054.tif214169TIFF2025536298000055.tif41169

[0205] Intermediate 49. tert-Butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0206] [ka]

[0207] Step 1: Synthesis of methyl 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylate tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (4.63 g, 20.28 mmol), methyl 3,6-dibromopyrazine-2-carboxylate (5 g, 16.9 mmol), and TEA (4.7 mL, 33.8 mmol) were suspended in DMF (75 mL) and stirred at 80°C for 2 hours. Distilled water (50 mL) was added to the reaction mixture, followed by extraction with EtOAc (50 mL x 2). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-15% EtOAc / Hex) to give 7.18 g (96%) of a yellow solid.

[0208] Step 2: Synthesis of tert-butyl ((1-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate Methyl 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylate (3 g, 6.77 mmol) was suspended in EtOH (16 mL), and NaBH (640 mg, 16.92 mmol) and CaCl (1.5 mg, 13.53 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 16 h. To the reaction mixture was added sat. NH Cl (aq.) (40 mL), followed by extraction with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-20% EtOAc / hexane) to give 1.08 g (39%) of a yellow solid.

[0209] Step 3: Synthesis of methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propanoate tert-Butyl ((1-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (1.07 g, 2.58 mmol), methyl 3-mercaptopropionate (0.31 mL, 2.83 mmol), Pd2(dba)3 (118 mg, 0.13 mmol), Xantphos (149 mg, 0.26 mmol), and DIPEA (0.93 mL, 5.15 mmol) were suspended in 1,4-dioxane (10 mL) and stirred at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (1-40% EtOAc / hexane) to give 1.07 g (82%) of a yellow oil.

[0210] Step 4: Synthesis of sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propanoate (167 mg, 0.37 mmol) was suspended in THF (1.2 ml), and NaOEt (ca. 20% in EtOH, 0.16 ml, 0.40 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 143 mg (crude) of a yellow solid.

[0211] Step 5: Synthesis of 2-(trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate 2-(Trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate (111 mg, 0.24 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate (143 mg, crude, 0.37 mmol), Pd(dba) (11 mg, 0.01 mmol), Xantphos (14 mg, 0.24 mmol), and DIPEA (0.13 mL, 0.73 mmol) were suspended in 1,4-dioxane (0.8 mL) and stirred at 90°C for 16 hours. Distilled water (15 mL) was added to the reaction mixture, which was then extracted with EtOAc (15 mL). The organic layer was washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (1-20% EtOAc / hexane) to give 71 mg (55%) of a yellow solid.

[0212] Step 6: tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-(Trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate (50 mg, 0.09 mmol) and TBAF (1.0 M in THF, 0.28 mL, 0.28 mmol) were suspended in THF (0.93 mL) and stirred at 50°C for 2 hours. Distilled water (5 mL) was added to the reaction mixture, which was then extracted with DCM (5 mL). The organic layer was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to give 51 mg of a crude ivory solid.

[0213] Intermediate 50 was synthesized in the same manner as intermediate 49.

[0214] [Table 9]

[0215] Intermediate 51. 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid

[0216] [ka]

[0217] Step 1: Synthesis of methyl 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate (132 mg, 0.34 mmol), methyl 1-(3-chloro-4-iodopyridin-2-yl)piperidine-4-carboxylate (86 mg, 0.23 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol), and DIPEA (0.11 mL, 0.68 mmol) were suspended in 1,4-dioxane (1.1 mL) and stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to give 104 mg (74%) of an ivory solid.

[0218] Step 2: Synthesis of 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid Methyl 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate (102 mg, 0.16 mmol) and LiOH (10 mg, 0.25 mmol) were suspended in a THF:HO mixture (3:1, 0.72 mL) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 1-2 with 1 M HCl (aq.) and then extracted with EtOAc (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 104 mg (99%) of an orange solid.

[0219] Intermediates 52 to 54 were synthesized in the same manner as in the synthesis of Intermediate 51.

[0220] [Table 10]

[0221] Intermediate 55. tert-Butyl ((1-(5-((2-chloro-3-(piperidin-4-yl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0222] [ka]

[0223] Step 1: Synthesis of tert-butyl 4-(3-amino-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate 3-Bromo-2-chloroaniline (200 mg, 0.97 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (329 mg, 1.07 mmol), Pd(dppf) (79 mg, 0.10 mmol), and CsCO (631 mg, 1.94 mmol) were suspended in a 4:1 mixture of 1,4-dioxane and HO (4 mL) and stirred at 90 °C for 2 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (1-10% EtOAc / hexanes) to give 270 mg (90%) of a yellow gum.

[0224] Step 2: Synthesis of tert-butyl 4-(3-amino-2-chlorophenyl)piperidine-1-carboxylate tert-Butyl 4-(3-amino-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (201 mg, 0.65 mmol) was suspended in MeOH (4.6 mL), followed by addition of Pd / C (23 mg, 10% purity) and stirring under a hydrogen atmosphere at room temperature for 3.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (1-10% EtOAc / hexane) to give 41.8 mg (21%) of a colorless oil.

[0225] Step 3: Synthesis of tert-butyl 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylate tert-Butyl 4-(3-amino-2-chlorophenyl)piperidine-1-carboxylate (41.8 mg, 0.13 mmol) was suspended in a 2 M HCl (aq.):dioxane mixture (2:1, 0.87 mL). Sodium nitrite (10 mg, 0.15 mmol) and HO (0.03 mL) were added at 0 °C and the mixture was stirred at 0 °C for 15 min. NaI (22 mg, 0.15 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 10 min. Distilled water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / hexane) to give 24.2 mg (43%) of a brown oil.

[0226] Step 4: Synthesis of 4-(2-chloro-3-iodophenyl)piperidine hydrochloride tert-Butyl 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylate (24.2 mg, 0.06 mmol) was suspended in DCM (0.57 ml), and then 4 M HCl in dioxane (0.14 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 19.8 mg (quantity) of a white solid.

[0227] Step 5: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylate 4-(2-Chloro-3-iodophenyl)piperidine hydrochloride (19.8 mg, 0.06 mmol) and TEA (32 μL, 0.23 mmol) were suspended in DCM (0.2 mL), followed by the addition of 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (14.9 mg, 0.06 mmol) and stirring at room temperature for 1 hour. Distilled water (5 mL) was added to the reaction mixture, which was then extracted with DCM (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / hexane) to give 22.6 mg (85%) of a brown oil.

[0228] Step 6: Synthesis of 2-(trimethylsilyl)ethyl 4-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-1-carboxylate 2-(Trimethylsilyl)ethyl 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylate (22.6 mg, 0.05 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (crude, 0.05 mmol), Pd2(dba)3 (2.2 mg, 0.002 mmol), Xantphos (2.8 mg, 0.04 mmol), and DIPEA (17 μL, 0.10 mmol) were suspended in 1,4-dioxane (0.11 mL) and stirred at 90°C for 1 hour. Distilled water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-30% EtOAc / hexane) to give 16.5 mg (50%) of an ivory solid.

[0229] Step 7: Synthesis of tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-yl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-(Trimethylsilyl)ethyl 4-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-1-carboxylate (16.5 mg, 0.02 mmol) was suspended in THF (0.05 ml), and then TBAF (1.0 M in THF, 30 μl, 0.03 mmol) was added and stirred at 50°C for 1 hour. Distilled water (5 ml) was added to the reaction solution, which was then extracted with DCM (5 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 16 mg (quantity) of an ivory solid.

[0230] Intermediate 56. tert-Butyl ((1-(5-((3-chloro-2-(piperidin-4-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0231] [ka]

[0232] Step 1: Synthesis of tert-butyl (2,3-dichloropyridin-4-yl)carbamate 2,3-Dichloro-4-iodopyridine (500 mg, 1.83 mmol), tert-butyl carbamate (257 mg, 2.19 mmol), Pd2(dba)3 (84 mg, 0.09 mmol), Xantphos (106 mg, 0.18 mmol), and Cs2CO3 (1.19 g, 3.65 mmol) were suspended in toluene (8 mL) and stirred at 90 °C for 16 h. Distilled water (30 mL) was added to the reaction mixture, followed by extraction with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-5% EtOAc / hexane) to give 380 mg (79%) of an ivory solid.

[0233] Step 2: Synthesis of tert-butyl 4-(3-amino-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-Butyl 4-((tert-butoxycarbonyl)amino)-3-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (356 mg, 1.35 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (920 mg, 2.98 mmol), Pd(dppf) (220 mg, 0.27 mmol), and CsCO (882 mg, 2.71 mmol) were suspended in a 1,4-dioxane:HO mixture (4:1, 5.6 mL) and reacted in a microwave reactor at 130 °C for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (0-30% EtOAc / hexanes) to give 369 mg (67%) of a brown gum.

[0234] Step 3: Synthesis of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)piperidine-1-carboxylate tert-Butyl 4-(3-amino-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (369 mg, 0.90 mmol) was suspended in MeOH (3.6 mL), followed by the addition of platinum(IV) oxide (21 mg) and stirring at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / hexane) to give 204 mg (55%) of a white solid.

[0235] Step 4: Synthesis of 4-(2-chloro-3-iodophenyl)piperidine trifluoroacetic acid tert-Butyl 4-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)piperidine-1-carboxylate (204 mg, 0.50 mmol) was suspended in DCM (4.34 ml), and then TFA (1.86 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give 415 mg (quantity) of a brown oil.

[0236] Step 5: Synthesis of tert-butyl 4-(4-amino-3-chloropyridin-2-yl)piperidine-1-carboxylate 4-(2-Chloro-3-iodophenyl)piperidinetrifluoroacetic acid (415 mg, 0.50 mmol) and triethanolamine (0.28 mL, 1.98 mmol) were suspended in DCM (1.8 mL), followed by the addition of di-tert-butyl dicarbonate (113 mg, 0.52 mmol) and stirring at room temperature for 1 hour. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to yield 147 mg (95%) of a white solid.

[0237] Step 6: Synthesis of 3-chloro-4-iodo-2-(piperidin-4-yl)pyridine tert-Butyl 4-(4-amino-3-chloropyridin-2-yl)piperidine-1-carboxylate (60 mg, 0.19 mmol) was suspended in 50% sulfuric acid (aq.) (0.96 mL), and then sodium nitrite (14.6 mg, 0.21 mmol) and HO (0.1 mL) were added at 0°C. The mixture was stirred at 0°C for 30 minutes. KI (160 mg, 0.96 mmol) was added to the reaction mixture and stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 8 with saturated NaHCO3 (aq.) and then extracted with DCM (10 × 2 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to give 29.8 mg (48%) of an ivory solid.

[0238] Step 7: Synthesis of 2-(trimethylsilyl)ethyl 4-(3-chloro-4-iodopyridin-2-yl)piperidine-1-carboxylate 3-Chloro-4-iodo-2-(piperidin-4-yl)pyridine (33.5 mg, 0.10 mmol) and TEA (43 μL, 0.31 mmol) were suspended in DCM (0.35 mL), followed by addition of 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (28.3 mg, 0.11 mmol) and stirring at room temperature for 1 hour. Distilled water (5 mL) was added to the reaction mixture, followed by extraction with DCM (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-15% EtOAc / hexane) to give 34.9 mg (72%) of a white solid.

[0239] Step 8: Synthesis of 2-(trimethylsilyl)ethyl 4-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-1-carboxylate 2-(Trimethylsilyl)ethyl 4-(3-chloro-4-iodopyridin-2-yl)piperidine-1-carboxylate (34.9 mg, 0.07 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (crude, 0.09 mmol), Pd2(dba)3 (3.4 mg, 0.004 mmol), Xantphos (4.3 mg, 0.07 mmol), and DIPEA (26 μL, 0.15 mmol) were suspended in 1,4-dioxane (0.25 mL) and stirred at 90°C for 1 hour. Distilled water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-40% EtOAc / hexane) to give 43 mg (83%) of an ivory solid.

[0240] Step 9: Synthesis of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 2-(Trimethylsilyl)ethyl 4-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-1-carboxylate (42 mg, 0.06 mmol) was suspended in THF (0.41 mL), and then TBAF (1.0 M in THF, 0.19 mL, 0.19 mmol) was added and the mixture was stirred at 50 °C for 2 hours. Distilled water (5 mL) was added to the reaction mixture, and the mixture was extracted with DCM (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to give 32 mg (97%) of an ivory solid.

[0241] Intermediate 57. 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid

[0242] [ka]

[0243] Step 1: Synthesis of tert-butyl (3-bromo-2-chlorophenyl) (tert-butoxycarbonyl)carbamate 3-Bromo-2-chloroaniline (300 mg, 1.45 mmol) and DMAP (18 mg, 0.14 mmol) were suspended in THF (2.6 mL), followed by the addition of di-tert-butyl dicarbonate (951 mg, 4.36 mmol) and heating to reflux for 1 hour. Distilled water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-15% EtOAc / hexane) to give 582 mg (98%) of a white solid.

[0244] Step 2: Synthesis of tert-butyl (3-bromo-2-chlorophenyl)carbamate tert-Butyl (3-bromo-2-chlorophenyl) (tert-butoxycarbonyl)carbamate (550 mg, 1.35 mmol) and K2CO3 (561 mg, 4.06 mmol) were suspended in MeOH (2.4 mL) and then heated to reflux for 2 hours. Distilled water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-5% EtOAc / hexane) to give 582 mg (75%) of an ivory solid.

[0245] Step 3: Synthesis of ethyl 1-(3-((tert-butoxycarbonyl)amino)-2-chlorophenyl)piperidine-4-carboxylate tert-Butyl (3-bromo-2-chlorophenyl)carbamate (243 mg, 0.79 mmol), ethyl piperidine-4-carboxylate (249 mg, 1.59 mmol), Pd(OAc)2 (8.9 mg, 0.04 mmol), BINAP (49 mg, 0.08 mmol), and Cs2CO3 (516 mg, 1.59 mmol) were suspended in 1,4-dioxane (2.6 mL) and stirred at 90 °C for 16 h. Distilled water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / hexane) to give 254 mg (84%) of an ivory solid.

[0246] Step 4: Synthesis of ethyl 1-(3-amino-2-chlorophenyl)piperidine-4-carboxylate Ethyl 1-(3-((tert-butoxycarbonyl)amino)-2-chlorophenyl)piperidine-4-carboxylate (254 mg, 0.66 mmol) was suspended in DCM (6.6 mL), and then TFA (1.65 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 8 with saturated NaHCO3 (aq.) and then extracted with DCM (10 × 2 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 185 mg (99%) of an ivory solid.

[0247] Step 5: Synthesis of ethyl 1-(2-chloro-3-iodophenyl)piperidine-4-carboxylate Ethyl 1-(3-amino-2-chlorophenyl)piperidine-4-carboxylate (100 mg, 0.35 mmol) was suspended in a 2 M HCl (aq.):dioxane mixture (2:1, 2.29 mL). Sodium nitrite (26.8 mg, 0.39 mmol) and HO (0.08 mL) were added at 0 °C and stirred at 0 °C for 15 min. NaI (58 mg, 0.39 mmol) was added to the reaction mixture and stirred at room temperature for 30 min. Distilled water (5 mL) was added to the reaction mixture, followed by extraction with EtOAc (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% EtOAc / hexane) to give 86 mg (62%) of a brown oil.

[0248] Step 6: Synthesis of ethyl 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylate Ethyl 1-(2-chloro-3-iodophenyl)piperidine-4-carboxylate (86 mg, 0.22 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (crude, 0.22 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), Xantphos (12.6 mg, 0.02 mmol), and DIPEA (76 μL, 0.44 mmol) were suspended in 1,4-dioxane (0.5 mL) and stirred at 90°C for 1 h. Distilled water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-30% EtOAc / hexane) to give 88 mg (67%) of an ivory solid.

[0249] Step 7: Synthesis of 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid Ethyl 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylate (88 mg, 0.15 mmol) was suspended in a mixed solvent of THF:MeOH:HO (3:2:1, 1 mL), and LiOH·HO (12 mg, 0.29 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 2 with 1 M HCl (aq.) and then extracted with EA (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 84 mg (100%) of an ivory solid.

[0250] Intermediates 58 to 60 were synthesized in the same manner as in the synthesis of intermediate 57.

[0251] [Table 11]

[0252] Intermediate 61. (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0253] [ka]

[0254] Step 1: Synthesis of (2S,4R)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (2S,4R)-Methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (7.85 g, 43.23 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethyldimethylbutanoic acid (10 g, 43.23 mmol), EDCI (16.57 g, 86.46 mmol), HOBt (7 g, 86.46 mmol), and DIPEA (45 mL, 259.38 mmol) were suspended in DMF (216 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with saturated NH4Cl (aq.) (300 mL) and saturated NaHCO3 (aq.) (300 mL) and then extracted with EtOAc (150 mL × 2). The organic layer was washed with brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 11 g (71%) of an ivory solid.

[0255] Step 2: Synthesis of (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2S,4R)-Methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (781 mg, 2.18 mmol) and LiOH (366 mg, 8.72 mmol) were suspended in a 1:1 HO:THF mixture (10 mL) and stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH 1-2 with 1 M HCl (aq.) and then extracted with EtOAc (15 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 680 mg (91%) of a white solid.

[0256] Step 3: Synthesis of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile 4-Bromo-2-hydroxybenzonitrile (2 g, 10.15 mmol) and 4-methylthiazole (1.83 mL, 20.20 mmol) were suspended in DMAC (40 mL), followed by the addition of KOAc (1.98 g, 20.20 mmol) and Pd(OAc)2 (45 mg, 0.20 mmol). The mixture was heated to reflux for 16 hours. Distilled water (100 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to yield 980 mg (45%) of an ivory solid.

[0257] Step 4: Synthesis of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol 2-Hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (864 mg, 3.99 mmol) was suspended in THF (22 mL), and then LAH (2.0 M in THF, 8 mL, 15.98 mmol) was slowly added at 0°C. The mixture was heated to reflux for 3 hours. After the temperature of the reaction mixture was lowered to 0°C, distilled water (0.5 mL) was slowly added, and the mixture was neutralized with Rochelle salt solution (20 mL). The mixture was then filtered through a Celite filter. The filtrate was purified by MPLC (DCM:MeOH:NH4OH = 15:1:0.1) to give 416 mg (47%) of a yellow solid.

[0258] Step 5: Synthesis of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 2-(Aminomethyl)-5-(4-methylthiazol-5-yl)phenol (416 mg, 1.89 mmol), (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (650 mg, 1.89 mmol), HATU (789 mg, 2.08 mmol), and DIPEA (0.98 mL, 5.66 mmol) were suspended in DMF (6 mL) and stirred at room temperature for 16 h. Distilled water (25 mL) was added to the reaction mixture, which was then extracted with EtOAc (15 mL × 2). The organic layer was washed with brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% MeOH / DCM) to give 898 mg (87%) of a pale yellow solid.

[0259] Step 6: Synthesis of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide tert-Butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (885 mg, 1.62 mmol) was suspended in DCM (30 mL), followed by addition of 4 M HCl in dioxane (8 mL) and stirring at room temperature for 2 hours. The reaction mixture was neutralized with saturated NaHCO3 (aq.) (20 mL) and then extracted with DCM (10 mL x 2). The organic layer was washed with brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-10% MeOH / DCM) to give 522 mg (72%) of a yellow solid.

[0260] Step 7: Synthesis of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (399 mg, 0.89 mmol), 1-fluorocyclopropane-1-carboxylic acid (92.6 mg, 0.89 mmol), HATU (381 mg, 0.89 mmol), and DIPEA (0.8 mL, 4.47 mmol) were suspended in DMF (4 mL) and stirred at room temperature for 16 h. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (11 mL × 2). The organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% MeOH / DCM) to give 377 mg (79%) of a white solid.

[0261] Intermediates 62 to 64 were synthesized in the same manner as in the synthesis of Intermediate 61.

[0262] [Table 12]

[0263] Intermediate 65. (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid

[0264] [ka]

[0265] Step 1: Synthesis of (1S,4S)-methyl 4-(((2-nitrophenyl)sulfonyl)oxy)cyclohexane-1-carboxylate Methyl (1S,4S)-4-hydroxycyclohexane-1-carboxylate (4 g, 25.29 mmol), TEA (7 mL, 50.57 mmol), and DMAP (309 mg, 2.52 mmol) were suspended in DCM (120 mL). 2-Nitrobenzenesulfonyl chloride (22.4 g, 101.14 mmol) dissolved in DCM (25 mL) was added slowly at 0 °C and stirred at room temperature for 2 h. Distilled water (200 mL) was added to the reaction mixture, which was then extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% EtOAc / hexane) to give 7.14 g (82%) of a colorless oil.

[0266] Step 2: Synthesis of (1S,4R)-methyl 4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylate (1S,4S)-Methyl 4-(((2-nitrophenyl)sulfonyl)oxy)cyclohexane-1-carboxylate (3.9 g, 11.26 mmol), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate 61, 1.5 g, 2.82 mmol), and CsCO (1.8 g, 5.63 mmol) were suspended in DMF (60 mL) and stirred at 50 °C for 16 hours. Distilled water (100 mL) was added to the reaction mixture, which was then extracted with EtOAc (100 mL × 2). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (amine-silica, 0-5% MeOH / DCM) to give 1.3 g (70%) of an ivory solid.

[0267] Step 3: Synthesis of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (1S,4R)-Methyl 4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylate (1.8 g, 2.75 mmol) and LiOH (231 mg, 5.51 mmol) were suspended in a 4:1:1 mixture of THF:HO:MeOH (12 mL) and stirred at room temperature for 4 h. The reaction mixture was adjusted to pH 1-2 with 1 M HCl (aq.) and then extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% MeOH / DCM) to give 896 mg (49%) of an ivory solid.

[0268] Intermediates 66 and 67 were synthesized in the same manner as in the synthesis of Intermediate 65.

[0269] [Table 13]

[0270] Intermediate 68. (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0271] [ka]

[0272] (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate 61, 350 mg, 0.657 mmol) and 1-bromo-2-chloroethane (0.2 mL, 2.628 mmol) were suspended in DMF (2 mL), followed by addition of KCO (272 mg, 1.971 mmol) and KI (218 mg, 1.314 mmol) and stirring at 70 °C for 16 hours. Distilled water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 234 mg (60%) of an ivory solid.

[0273] Intermediate 69 was synthesized in the same manner as intermediate 68.

[0274] [Table 14]

[0275] Intermediate 70. 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid

[0276] [ka]

[0277] Step 1: Synthesis of ethyl 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylate (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 68, 100 mg, 0.15 mmol), ethyl piperidine-4-carboxylate (17.6 mg, 0.11 mmol), and K2CO3 (46 mg, 0.37 mmol) were suspended in DMF (0.15 mL) and stirred at 70 °C for 16 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 67 mg (84%) of an ivory solid.

[0278] Step 2: Synthesis of 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid Ethyl 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylate (67 mg, 0.09 mmol) and LiOH (7.9 mg, 0.19 mmol) were suspended in a THF:MeOH:HO mixture (3:2:1, 0.26 mL) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 2 with 1 M HCl (aq.) and then concentrated under reduced pressure to yield 87 mg of a crude ivory solid.

[0279] Intermediate 71. (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide

[0280] [ka]

[0281] Step 1: Synthesis of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate 1-(2-Hydroxyethyl)piperazine (2.8 ml, 23.04 mmol) was suspended in THF (23 ml), and then BocO (5.8 ml, 25.35 mmol) was added at 0°C and stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated NH4Cl (aq.) (50 ml) and extracted with DCM (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield 5.6 g (quant.) of a colorless oil.

[0282] Step 2: Synthesis of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.6 g, 24.66 mmol), TEA (6.8 mL, 49.33 mmol), and DMAP (120 mg, 0.99 mmol) were suspended in DCM (123 mL). 2-Nitrobenzenesulfonyl chloride (5.4 g, 24.66 mmol) dissolved in DCM (25 mL) was added slowly at 0 °C and stirred at room temperature for 2 h. Distilled water (200 mL) was added to the reaction mixture, which was then extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to give 2.9 g (49%) of a yellow solid.

[0283] Step 3: Synthesis of tert-butyl 4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazine-1-carboxylate tert-Butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.4 g, 5.91 mmol), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate 61, 1.1 g, 1.97 mmol), and CsCO (1.3 g, 3.94 mmol) were suspended in DMF (44 mL) and stirred at 50 °C for 16 hours. Distilled water (100 mL) was added to the reaction mixture, which was then extracted with EtOAc (100 mL × 2). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (amine-silica, 0-5% MeOH / DCM) to give 833 mg (57%) of an ivory solid.

[0284] Step 4: Synthesis of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide tert-Butyl 4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazine-1-carboxylate (819 mg, 1.10 mmol) was suspended in DCM (9 mL), followed by the addition of 4 M HCl in dioxane (2 mL) and stirring at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO3 (aq.) (30 mL) and then extracted with DCM (3 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-5% MeOH / DCM) to yield 739 mg (quant.) of an ivory solid. Intermediates 72 to 79 were synthesized in the same manner as intermediate 71. In the case of intermediates 72 to 79, O-nosylates were obtained as the result of step 2.

[0285] [Table 15] TIFF2025536298000073.tif217169

[0286] Intermediate 80. (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide

[0287] [ka]

[0288] Step 1: Synthesis of 2-(trimethylsilyl)ethyl carbamate 2-(Trimethylsilyl)ethanol (3 g, 25.4 mmol) was suspended in toluene (42 mL), followed by the addition of 1,1-carbonyldiimidazole (8.23 g, 30.48 mmol) and stirring at room temperature for 5 hours. Ammonium hydroxide (28% in HO, 8.3 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. Distilled water (50 mL) was added to the reaction mixture, followed by extraction with EtOAc (50 mL). The organic layer was washed with 1 M HCl (aq.) (30 mL) and saturated NH4Cl (aq.) (30 mL) and dried over anhydrous magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure to yield 4.17 g (100%) of a white solid.

[0289] Step 2: Synthesis of 2-(trimethylsilyl)ethyl 4-bromo-2-hydroxybenzylcarbamate 4-Bromohydroxybenzaldehyde (1.27 g, 6.35 mmol), 2-(trimethylsilyl)ethyl carbamate (4.17 g, 25.4 mmol), and triethylsilane (4.05 mL, 25.4 mmol) were suspended in ACN (30 mL). TFA (3.79 mL, 50.8 mmol) was added slowly and the mixture was stirred at room temperature for 16 hours. After adding saturated NaHCO3 (aq.) (50 mL), the reaction mixture was extracted with DCM (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-15% EtOAc / hexane) to give 1.79 g (83%) of a white solid.

[0290] Step 3: Synthesis of 2-(trimethylsilyl)ethyl 2-hydroxy-4-(4-methylthiazol-5-yl)benzylcarbamate 2-(Trimethylsilyl)ethyl 4-bromo-2-hydroxybenzylcarbamate (1.79 g, 5.17 mmol) and 4-methylthiazole (0.94 mL, 10.34 mmol) were suspended in DMAC (7.3 mL), followed by the addition of KOAc (1.02 g, 10.34 mmol) and Pd(OAc)2 (58 mg, 0.26 mmol). The mixture was heated to reflux for 16 hours. Distilled water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to yield 546 mg (30%) of an ivory solid.

[0291] Step 4: Synthesis of tert-butyl 4-(5-(4-methylthiazol-5-yl)-2-((((2-(trimethylsilyl)ethoxy)carbonyl)amino)methyl)phenoxy)piperidine-1-carboxylate 2-(Trimethylsilyl)ethyl 2-hydroxy-4-(4-methylthiazol-5-yl)benzylcarbamate (700 mg, 1.92 mmol), tert-butyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate (2.23 g, 5.76 mmol), and Cs2CO3 (1.36 g, 3.84 mmol) were suspended in DMF (4 mL) and stirred at 50 °C for 16 h. Distilled water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (0-30% EtOAc / hexane) to give 927 g (88%) of a white solid.

[0292] Step 5: Synthesis of tert-butyl 4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(5-(4-methylthiazol-5-yl)-2-((((2-(trimethylsilyl)ethoxy)carbonyl)amino)methyl)phenoxy)piperidine-1-carboxylate (150 mg, 0.27 mmol) and TBAF (1.0 M in THF, 0.8 mL, 0.82 mmol) were suspended in THF (2.7 mL) and stirred at 50°C for 2 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL). The organic layer was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to yield 110 mg of a crude ivory solid.

[0293] Step 6: Synthesis of (2S,4R)-benzyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (2S,4R)-Benzyl 4-hydroxypyrrolidine-2-carboxylate (10 g, 38.8 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethyldimethylbutanoate (8.97 g, 38.8 mmol), EDCI (8.93 g, 45.56 mmol), HOBt (6.29 g, 45.56 mmol), and DIPEA (25 mL, 194 mmol) were suspended in DCM (60 mL) and stirred at room temperature for 16 h. The reaction mixture was washed with distilled water (100 mL), extracted with DCM (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to give 9.42 g (56%) of an ivory solid.

[0294] Step 7: Synthesis of (2S,4R)-benzyl 1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (2S,4R)-Benzyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (4.83 g, 11.1 mmol) was suspended in DCM (80 ml), and then 4 M HCl in dioxane (22 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3.7 g (crude) of a white solid.

[0295] Step 8: Synthesis of (2S,4R)-benzyl 1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (2S,4R)-Benzyl 1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (3.7 g, 11.1 mmol), 2-cyanoacetic acid (58 mg, 0.69 mmol), EDCI (159 mg, 0.83 mmol), HOBt (112 mg, 0.83 mmol), and DIPEA (0.6 mL, 3.45 mmol) were suspended in DCM (1.4 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (100 mL), extracted with DCM (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% MeOH / DCM) to give 112 mg (41%) of a white solid.

[0296] Step 9: Synthesis of (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2S,4R)-Benzyl 1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (112 mg, 0.28 mmol) and LiOH (23 mg, 0.56 mmol) were suspended in a HO:THF:MeOH mixture (1:1:1, 0.52 mL) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 1-2 with 1 M HCl (aq.) and then concentrated under reduced pressure to yield 151 mg of a crude ivory solid.

[0297] Step 10: Synthesis of tert-butyl 4-(2-(((2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (140 mg, 0.28 mmol), (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (151 mg, 0.28 mmol), EDCI (64 mg, 0.34 mmol), HOBt (45 g, 0.34 mmol), and DIPEA (0.24 mL, 1.40 mmol) were suspended in DMF (0.2 mL) and DCM (0.56 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (10 mL), extracted with DCM (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 79 mg (41%) of an ivory solid.

[0298] Step 11: Synthesis of (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide tert-Butyl 4-(2-(((2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (79 mg, 0.11 mmol) was suspended in DCM (1.1 ml), and then 4 M HCl in dioxane (0.29 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 68 mg of a crude ivory solid.

[0299] Intermediates 81 to 83 were synthesized in the same manner as in the synthesis of Intermediate 80.

[0300] [Table 16]

[0301] Intermediate 84. (2S,4R)-4-Hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1)

[0302] [ka]

[0303] Step 1: Synthesis of benzyl (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylate (P1) 3-Methyl-2-(3-methylisoxazol-5-yl)dimethylbutanoate (4.50 g, 24.60 mmol) and benzyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (6.96 g, 27.00 mmol) were suspended in DMF (27 mL). HATU (9.34 g, 24.60 mmol) and DIPEA (4.28 mL, 24.60 mmol) were added at 0 °C and the mixture was stirred at room temperature for 12 h. 1 M HCl (aq.) was added to the reaction mixture, which was then extracted with EtOAc (200 mL x 2). The organic layer was washed with saturated NaHCO3 (aq.) (200 mL) and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-100% EtOAc / petroleum ether) to obtain a mixture. The resulting mixture was subjected to SFC (column: REGIS(S,S)WHELK-O1 (250 mm × 25 mm × 10 μm); mobile phase: [CO₂-EtOH (0.1% NH₄OH)]; B%: 25%, isocratic elution mode) to give 1.50 g of a yellow solid, P1 (16%, 100% ee), and 2.00 g of its isomer, P2 (20%, 98.8% ee).

[0304] Step 2: Synthesis of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid (P1) Benzyl (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylate (P1) (1.52 g, 3.88 mmol) was suspended in MeOH (15 mL), and Pd / C (150 mg, 10% purity) was added. The mixture was stirred under a hydrogen atmosphere (15 psi) at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 995 mg (65%) of a pale yellow solid.

[0305] Step 3: Synthesis of tert-butyl 4-(2-(((2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (P1) tert-Butyl 4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (357 mg, 0.88 mmol), (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid (P1) (262 mg, 0.88 mmol), EDCI (203 mg, 1.06 mmol), HOBt (143 mg, 1.06 mmol), and DIPEA (0.46 mL, 2.65 mmol) were suspended in DM (2.2 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (50 mL), extracted with DCM (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 488 mg (81%) of an ivory solid.

[0306] Step 4: Synthesis of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) tert-Butyl 4-(2-(((2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (P1) (488 mg, 0.72 mmol) was suspended in DCM (7.2 mL), followed by addition of 4 M HCl in dioxane (1.8 mL) and stirring at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO3 (aq.) (20 mL), extracted with DCM (20 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-5% MeOH / DCM) to yield 375 mg (90%) of a yellow solid. Intermediate 85 was synthesized in the same manner as intermediate 84.

[0307] [Table 17]

[0308] Intermediate 86. (2S,4R)-4-Hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1)

[0309] [ka]

[0310] Step 1: Synthesis of ethyl 3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoate Ethyl 2-bromo-3-methylbutanoate (500 mg, 2.39 mmol) and 4-methylpyrazole (255 mg, 3.11 mmol) were suspended in THF (4 mL), followed by the slow addition of NaH (60% dispersion in mineral oil, 124 mg, 3.11 mmol) at 0°C and stirring for 48 hours. Distilled water (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-20% EtOAc / hexane) to give 311 mg (62%) of a colorless oil.

[0311] Step 2: Synthesis of 3-methyl-2-(4-methyl-1H-pyrazol-1-yl)dimethylbutanoic acid Ethyl 3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoate (295 mg, 1.40 mmol) and LiOH (88 mg, 2.10 mmol) were suspended in a 1:1 HO:THF mixture (6 mL) and stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 1-2 with 1 M HCl (aq.) and then extracted with EtOAc (15 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 278 mg of a colorless crude oil.

[0312] Step 3: Synthesis of (2S,4R)-methyl 4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxylate 3-Methyl-2-(4-methyl-1H-pyrazol-1-yl)dimethylbutanoate (105 mg, 0.57 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (83 g, 0.57 mmol), EDCI (132 mg, 0.69 mmol), HOBt (93 mg, 0.69 mmol), and DIPEA (0.5 mL, 2.88 mmol) were suspended in DCM (2 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (15 mL) and then extracted with DCM (15 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-5% MeOH / DCM) to give 71 mg (40%) of a colorless oil.

[0313] Step 4: Synthesis of (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (2S,4R)-Methyl 4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxylate (94 mg, 0.30 mmol) and 2M NaOH (aq.) (0.2 mL) were suspended in THF (1 mL) and stirred at 50°C for 2 hours. The reaction mixture was adjusted to pH 1-2 with 1M HCl (aq.) and then extracted with EtOAc (10 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 21 mg (crude) of a colorless oil.

[0314] Step 5: Synthesis of (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (P1) 2-(Aminomethyl)-5-(4-methylthiazol-5-yl)phenol (16 mg, 0.07 mmol), (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (21 g, 0.07 mmol), EDCI (16 mg, 0.08 mmol), HOBt (11 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.36 mmol) were suspended in DCM (0.2 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (10 mL) and extracted with DCM (10 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 14 mg (40%) of white solid P1 and 9 mg (25%) of its isomer P2.

[0315] Step 6: Synthesis of tert-butyl 4-(2-(((2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (P1) (2S,4R)-4-Hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (P1) (54 mg, 0.11 mmol), tert-butyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate (127 mg, 0.33 mmol), and CsCO (72 mg, 0.22 mmol) were suspended in DMF (1.1 mL) and stirred at 50 °C for 16 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to give 62 mg (80%) of an ivory solid.

[0316] Step 7: Synthesis of (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) tert-Butyl 4-(2-(((2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (P1) (62 mg, 0.09 mmol) was suspended in DCM (0.91 mL), followed by the addition of 4M HCl in dioxane (0.23 mL) and stirring at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO3 (aq.) (15 mL) and then extracted with DCM (15 mL × 2). The mixture was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield 50 mg of a crude ivory solid.

[0317] Intermediate 87 was synthesized in the same manner as intermediate 86.

[0318] [Table 18]

[0319] Intermediate 88. (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide

[0320] [ka]

[0321] Step 1: Synthesis of benzyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine-2-carboxylate Benzyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (300 mg, 1.16 mmol), (tert-butoxycarbonyl)-L-valine (253 mg, 1.16 mmol), EDCI (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DIPEA (0.8 mL, 4.66 mmol) were suspended in DCM (2.3 mL) and stirred at room temperature for 16 hours. Distilled water (15 mL) was added to the reaction mixture, followed by extraction with DCM (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to give 249 mg (51%) of an ivory solid.

[0322] Step 2: Synthesis of benzyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylate hydrochloride Benzyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine-2-carboxylate (120 mg, 0.29 mmol) was suspended in DCM (2.8 ml), and then 4 M HCl in dioxane (0.71 ml) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 114.7 mg (quantity) of a white solid.

[0323] Step 3: Synthesis of trifluoromethanesulfonyl azide Sodium azide (56 mg, 0.86 mmol) was suspended in pyridine (0.84 ml), and then trifluoromethanesulfonic anhydride (0.14 ml, 0.86 mmol) was added at 0° C. and stirred at room temperature for 1 hour. The reaction solution was immediately used in the next reaction.

[0324] Step 4: Synthesis of benzyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate Copper(II) sulfate pentahydrate (10.7 mg, 0.04 mmol) and benzyl (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (114.7 mg, 0.29 mmol) were suspended in HO (0.2 mL), trifluoromethanesulfonyl azide (0.86 mmol) was added, and the mixture was stirred at room temperature for 16 hours. 1M HCl (aq.) (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL). The organic layer was washed with distilled water (10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to yield 101 mg (quant.) of a colorless oil.

[0325] Step 5: Synthesis of benzyl (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate Benzyl (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (101 mg, 0.28 mg), ethynylcyclopropane (36 μL, 0.43 mmol), copper(II) sulfate pentahydrate (93 mg, 0.37 mmol), and sodium L-ascorbate (226 mg, 1.14 mmol) were suspended in a 2:1:1 mixture of HO:DCM:DMSO (3 mL) and stirred at room temperature for 2 h. Distilled water (10 mL) was added to the reaction mixture, followed by extraction with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-3% MeOH / DCM) to yield 83.5 mg (71%) of a white solid.

[0326] Step 6: Synthesis of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid Benzyl (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (83.5 mg, 0.20 mmol) was suspended in MeOH (0.5 mL), and then Pd / C (2.4 mg, 5% purity) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 71 mg (quantity) of a white solid.

[0327] Step 7: Synthesis of tert-butyl 4-(2-(((2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (51 mg, 0.10 mmol), (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (19 mg, 0.10 mmol), EDCI (23 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol), and DIPEA (0.05 mL, 0.30 mmol) were suspended in DCM (0.3 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (10 mL), extracted with DCM (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 54 mg (76%) of a white solid.

[0328] Step 8: Synthesis of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide tert-Butyl 4-(2-(((2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (54 mg, 0.08 mmol) was suspended in DCM (0.8 mL), followed by the addition of 4 M HCl in dioxane (0.19 mL) and stirring at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO3 (aq.) (10 mL) and then extracted with DCM (10 mL × 2). The mixture was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield 45 mg (97%) of an ivory solid.

[0329] Intermediate 89 was synthesized in the same manner as intermediate 88.

[0330] [Table 19]

[0331] Intermediate 90. (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide

[0332] [ka]

[0333] Step 1: Synthesis of N'-(1,1-dimethoxypropan-2-ylidene)-4-methylbenzenesulfonohydrazide 1,1-Dimethoxypropan-2-one (34 g, 287 mmol) and 4-methylbenzenesulfonohydrazide (48.7 g, 261 mmol) were suspended in MeOH (340 mL), degassed, and purged with N2 three times. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was immediately used in the next reaction.

[0334] Step 2: Synthesis of ethyl (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoate N'-(1,1-Dimethoxypropan-2-ylidene)-4-methylbenzenesulfonohydrazide (74.92 g, 261 mmol) was suspended in MeOH (340 mL), followed by the addition of ethyl L-valinate hydrochloride (57 g, 313 mmol) and TEA (36.4 mL, 261 mmol). The mixture was degassed and purged with N2 three times. The mixture was then stirred at 75 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by MPLC (2-20% EtOAc / petroleum ether) to give 39.20 g (69%) of a yellow liquid.

[0335] Step 3: Synthesis of (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)dimethylbutanoic acid Ethyl (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoate (10 g, 47.3 mmol) was suspended in distilled water (50 ml), and then concentrated HCl (50 ml) was added and stirred for 5 hours at 50° C. The reaction solution was concentrated under reduced pressure to obtain 12.80 g (crude) of a yellow gum.

[0336] Step 4: Synthesis of benzyl (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylate (S)-3-Methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)dimethylbutanoate (6.20 g, 27.2 mmol), benzyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (7.03 g, 27.2 mmol), and DIPEA (14.2 mL, 81.8 mmol) were suspended in DMF (60 mL). The suspension was degassed and purged with N2 three times. HATU (12.4 g, 32.7 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with distilled water (150 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with distilled water (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (2–10% EtOAc / petroleum ether) and the resulting mixture was purified by prep-HPLC (column: Phenomenex Luna C18 (250 mm × 70 mm × 10 μm); mobile phase: [HO(FA)-ACN]; B%: 30–60%, 20 min) to give 1.70 g (16%, 100% ee) of a white solid.

[0337] Step 5: Synthesis of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid Benzyl (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylate (1.70 g, 4.40 mmol) was suspended in MeOH (15 mL), and Pd / C (170 mg, 10% purity) was added. The mixture was stirred under a hydrogen atmosphere (15 psi) at room temperature for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 1.05 g (81%) of a white solid.

[0338] Step 6: Synthesis of tert-butyl 4-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate tert-Butyl 4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (228 mg, 0.57 mmol), (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (140 mg, 0.47 mmol), EDCI (109 mg, 0.57 mmol), HOBt (77 mg, 0.57 mmol), and DIPEA (0.41 mL, 2.36 mmol) were suspended in DCM (1.6 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with distilled water (15 mL) and then extracted with DCM (15 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 268 mg (83%) of an ivory solid.

[0339] Step 7: Synthesis of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide tert-Butyl 4-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (266 mg, 0.39 mmol) was suspended in DCM (4 mL), followed by the addition of 4M HCl in dioxane (0.98 mL) and stirring at room temperature for 1 hour. The reaction mixture was neutralized with saturated NaHCO3 (aq.) (20 mL) and then extracted with DCM (20 mL × 2). The mixture was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield 226 mg of a crude ivory solid.

[0340] Intermediates 91 to 93 were synthesized in the same manner as in the synthesis of Intermediate 90.

[0341] [Table 20]

[0342] Example 1. (2S,4R)—N-(2-((6-(4-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)piperidin-1-yl)hexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0343] [ka]

[0344] Step 1: Synthesis of tert-butyl ((1-(5-((2-chloro-3-(((1-(6-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)hexyl)piperidin-4-yl)methyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate tert-Butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 19, 33 mg, 0.06 mmol) and (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 69, 46 mg, 0.07 mmol) were suspended in DMF (0.1 mL), and then KI (13 mg, 0.12 mmol) and KCO (24 mg, 0.17 mmol) were added and the mixture was stirred at 70 °C for 16 hours. Distilled water (10 ml) was added to the reaction mixture, which was then extracted with EtOAc (10 ml x 2). The organic layer was washed with brine (10 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-2% MeOH / DCM) to give 49 mg (72%) of an ivory solid.

[0345] Step 2: Synthesis of (2S,4R)—N-(2-((6-(4-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)piperidin-1-yl)hexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide tert-Butyl ((1-(5-((2-chloro-3-(((1-(6-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)hexyl)piperidin-4-yl)methyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (43 mg, 0.04 mmol) was suspended in DCM (1.0 ml), and then 4 M HCl in dioxane (0.1 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was neutralized with sat. NaHCO3 (aq.) (10 ml) and extracted with DCM (10 ml × 2). The organic layer was washed with brine (10 ml × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (amine-silica, 0-5% MeOH / DCM) to give 30 mg (78%) of an ivory solid.

[0346] Example 2. (2S,4R)—N-(2-(2-(4-(2-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)ethyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0347] [ka]

[0348] Instead of tert-butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 19), tert-butyl ((1-(5-((2-chloro-3-((2-(piperazin-1-yl)ethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 20) was used, and (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazol-5-yl)methyl)carbamate (Intermediate 21) was used. Example 2 was synthesized in a manner similar to that of Example 1, except that (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 68) was used in place of (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 69).

[0349] Example 3. (2S,4R)—N-(2-(2-(4-(2-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)ethyl)-3-oxopiperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0350] [ka]

[0351] (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazole) using tert-butyl ((1-(5-((2-chloro-3-((2-(2-oxopiperazin-1-yl)ethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 21) instead of tert-butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 19). Example 3 was synthesized in the same manner as in Example 1, except that (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 68) was used in place of (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 69).

[0352] Example 4 (2S,4R)—N-(2-(2-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0353] [ka]

[0354] Step 1: Synthesis of methyl (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycinate tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1, 30 mg, 0.06 mmol), methyl bromoacetate (33 mg, 0.21 mmol), K2CO3 (27 mg, 0.19 mmol), and KI (21 mg, 0.13 mmol) were suspended in DMF (0.4 mL) and stirred at 70 °C for 16 h. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (1-30% EtOAc / hexane) to give 28.6 mg (82%) of an ivory solid.

[0355] Step 2: Synthesis of (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycine Methyl (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycinate (28.6 mg, 0.05 mmol) and LiOH (4.5 mg, 0.11 mmol) were suspended in a 2:1 HO:THF mixture (0.4 mL) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 2 with 1 M HCl (aq.) and then extracted with DCM (10 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-12% MeOH / DCM) to give 20.3 mg (73%) of an ivory solid.

[0356] Step 3: Synthesis of tert-butyl ((1-(5-((2-chloro-3-((2-(4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycine (19 mg 0.04 mmol), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl Thiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 71, 24.5 mg, 0.04 mmol), EDCI (8.4 mg, 0.04 mmol), HOBt (5.9 mg, 0.04 mmol), and DIPEA (0.02 mL, 0.11 mmol) were suspended in DMF (0.12 mL) and stirred at room temperature for 16 hours. Distilled water (7 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL). The organic layer was washed with brine (7 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-7% MeOH / DCM) to give 24 mg (57%) of an ivory solid.

[0357] Step 4: Synthesis of (2S,4R)—N-(2-(2-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide tert-Butyl ((1-(5-((2-chloro-3-((2-(4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (24 mg, 0.02 mmol) was suspended in DCM (2.1 ml), and then 4 M HCl in dioxane (0.052 ml) was added and the mixture was stirred at room temperature for 2 hours. After adding 5 ml of saturated aqueous NaHCO3 to the reaction mixture, the mixture was extracted with 2 x 10 ml DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to give 17.3 mg (79%) of an ivory solid.

[0358] Example 5. (2S,4R)—N-(2-(((1R,4S)-4-((3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidin-1-yl)methyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0359] [ka]

[0360] Step 1: Synthesis of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(((1R,4S)-4-(hydroxymethyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Methyl (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylate (100 mg, 0.15 mmol) was suspended in THF (2 mL). LAH (2.0 M in THF, 82 μL, 0.16 mmol) was added at 0°C and the mixture was stirred at room temperature for 30 minutes. 10% NaOH (aq.) (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (15 mL). The organic layer was washed with distilled water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 72.5 mg (76%) of an ivory solid.

[0361] Step 2: Synthesis of ((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(((1R,4S)-4-(hydroxymethyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (72.5 mg, 0.11 mmol) was suspended in DCM (0.48 mL) and added with TEA (23 μL, 0.17 mmol), DMAP (1.4 mg, 0.01 mmol), and 4-toluenesulfonyl chloride (25.7 mg, 0.13 mmol) at 0°C. The mixture was stirred at room temperature for 3 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 55.8 mg (62%) of an ivory solid.

[0362] Step 3: Synthesis of tert-butyl ((1-(5-((2-chloro-3-((1-(((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11, 26.4 mg, crude), ((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate (25 mg, 0.3 mmol), KCO (13 mg, 0.09 mmol), and KI (10 mg, 0.06 mmol) were suspended in DMF (0.1 mL) and stirred at 70 °C for 16 hours. Distilled water (7 ml) was added to the reaction mixture, which was then extracted with EtOAc (10 ml). The organic layer was washed with brine (7 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-7% MeOH / DCM) to give 11.6 mg (32%) of an ivory solid.

[0363] Step 4: Synthesis of (2S,4R)-N-(2-(((1R,4S)-4-((3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidin-1-yl)methyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide tert-Butyl ((1-(5-((2-chloro-3-((1-(((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (11.6 mg, 0.01 mmol) was suspended in DCM (1 ml), and then 4 M HCl in dioxane (25 μl) was added and stirred at room temperature for 1 hour. After adding 3 ml of saturated aqueous NaHCO3 to the reaction mixture, the mixture was extracted with 2 x 5 ml of DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to give 7.6 mg (72%) of an ivory solid.

[0364] Example 6 (2S,4R)—N-(2-(((1R,4S)-4-((4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidin-1-yl)methyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0365] [ka]

[0366] Example 6 was synthesized in the same manner as in Example 5, except that tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 17) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0367] Example 7 (2S,4R)—N-(2-((1-(((1R,4S)-4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0368] [ka]

[0369] Step 1: Synthesis of tert-butyl ((1-(5-((3-chloro-2-(((1R,4R)-4-(hydroxymethyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexane-1-carboxylic acid (Intermediate 38, 42 mg, 0.07 mmol) was suspended in THF (0.24 mL). LAH (2.0 M in THF, 0.03 mL, 0.07 mmol) was added at 0 °C and stirred at room temperature for 1 hour. Distilled water (0.01 mL) was added to the reaction mixture, which was then stirred at room temperature for 5 minutes and extracted with DCM (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-5% MeOH / DCM) to give 14 mg (34%) of an ivory solid.

[0370] Step 2: Synthesis of ((1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl 2-nitrobenzenesulfonate tert-Butyl ((1-(5-((3-chloro-2-(((1R,4R)-4-(hydroxymethyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (16 mg, 0.03 mmol), TEA (0.007 mL, 0.06 mmol), and DMAP (0.13 mg, 0.001 mmol) were suspended in DCM (0.14 mL). The mixture was stirred at 0°C for 10 minutes, and then 2-nitrobenzenesulfonyl chloride (20 mg, 0.09 mmol) was added. The mixture was then stirred at room temperature for 4 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL × 2). The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to give 15 mg (quantity) of an ivory solid.

[0371] Step 3: Synthesis of tert-butyl ((1-(5-((3-chloro-2-(((1S,4R)-4-((4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidin-1-yl)methyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate ((1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl 2-Nitrobenzenesulfonate (14 mg, 0.02 mmol) was suspended in DMF (0.2 mL), followed by the addition of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75, 14 mg, 0.02 mmol) and CsCO (12 mg, 0.04 mmol) and the mixture was stirred at 50 °C for 16 hours. Distilled water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 2). The organic layer was washed with brine (10 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to give 6.8 mg (32%) of an ivory solid.

[0372] Step 4: Synthesis of (2S,4R)—N-(2-((1-(((1R,4S)-4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide tert-Butyl ((1-(5-((3-chloro-2-(((1S,4R)-4-((4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidin-1-yl)methyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (6 mg, 0.005 mmol) was suspended in DCM (1.0 ml), and then 4 M HCl in dioxane (0.01 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 ml of saturated aqueous NaHCO3 and then extracted with 2 x 5 ml DCM. The organic layer was washed with 2 x 5 ml brine solutions, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (amine-silica, 0-5% MeOH / DCM) to give 3.5 mg (65%) of an ivory solid.

[0373] Example 8 (2S,4R)—N-(2-(2-(4-((1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0374] [ka]

[0375] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of (1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexane-1-carboxylic acid (Intermediate 38), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxylic acid) Example 8 was synthesized in a manner similar to that of Example 7 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 71) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0376] Example 9 (2S,4R)—N-(2-((1-((1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0377] [ka]

[0378] Example 9 was synthesized in a manner similar to that of Example 7, using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of (1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexane-1-carboxylic acid (Intermediate 38).

[0379] Example 10 (2S,4R)—N-(2-((1-((1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0380] [ka]

[0381] Example 10 was synthesized in a manner similar to that of Example 7, except that 2-(1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetic acid (Intermediate 48) was used instead of (1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexane-1-carboxylic acid (Intermediate 38). Example 11 (2S,4R)—N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0382] [ka]

[0383] Step 1: Synthesis of tert-butyl ((1-(5-((2-chloro-3-((1-((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carbonyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11,278 mg, crude), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4- Hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (intermediate 65, 205 mg, 0.31 mmol), EDCI (72 mg, 0.37 mmol), HOBt (54 mg, 0.37 mmol), and DIPEA (0.16 mL, 0.93 mmol) were suspended in DMF (1 mL) and stirred at room temperature for 16 hours. Distilled water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-7% MeOH / DCM) to yield 144 mg (40%) of an ivory solid.

[0384] Step 2: Synthesis of (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide tert-Butyl ((1-(5-((2-chloro-3-((1-((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carbonyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (100 mg, 0.09 mmol) was suspended in DCM (8.6 ml), and then 4 M HCl in dioxane (0.22 ml) was added and the mixture was stirred at room temperature for 1 hour. After adding 5 ml of saturated aqueous NaHCO3 to the reaction mixture, the mixture was extracted with 2 x 10 ml DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to give 80.7 mg (88%) of an ivory solid.

[0385] Example 12 (2S,4R)—N-(2-(((1R,4S)-4-(3-((3-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0386] [ka]

[0387] Example 12 was synthesized in a manner similar to that of Example 11, except that tert-butyl (1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 12) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0388] Example 13 (2S,4R)—N-(2-(((1R,4S)-4-(3-((3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0389] [ka]

[0390] Example 13 was synthesized in a manner similar to that of Example 11 using tert-butyl ((3S,4S)-8-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate 13) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0391] Example 14 (2S,4R)—N-(2-(((1R,4S)-4-(3-((3-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0392] [ka]

[0393] Example 14 was synthesized in a manner similar to that of Example 11, using (S)-tert-butyl (1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate (Intermediate 14) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0394] Example 15 (2S,4R)—N-(2-(((1R,4S)-4-(3-((3-((5-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-1′-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0395] [ka]

[0396] Example 15 was synthesized in a manner similar to that of Example 11 using N-((S)-1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate 15) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0397] Example 16 (2S,4R)—N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)oxy)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0398] [ka]

[0399] Example 16 was synthesized in the same manner as in Example 11, except that tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 16) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0400] Example 17 (2S,4R)—N-(2-(((1R,4S)-4-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0401] [ka]

[0402] Example 17 was synthesized in the same manner as in Example 11, except that tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 17) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0403] Example 18 (2S,4R)—N-(2-(((1R,4S)-4-(3-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0404] [ka]

[0405] Example 18 was synthesized in a manner similar to that of Example 11, using tert-butyl ((1-(5-((3-(azetidin-3-ylmethyl)amino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 18) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylmethyl)amino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0406] Example 19 (2S,4R)—N-(2-(((1R,4S)-4-(4-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0407] [ka]

[0408] Example 19 was synthesized in a manner similar to that of Example 11, using tert-butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 19) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0409] Example 20 (2S,4R)—N-(2-(((1R,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0410] [ka]

[0411] Example 20 was synthesized in a manner similar to that of Example 11, using tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 28) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0412] Example 21 (2S,4R)—N-(2-(((1R,4S)-4-(3-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0413] [ka]

[0414] Example 21 was synthesized in a manner similar to that of Example 11, using tert-butyl (1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0415] Example 22 (2S,4R)—N-(2-(((1R,4S)-4-(3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0416] [ka]

[0417] Example 22 was synthesized in a manner similar to that of Example 11 using tert-butyl ((3S,4S)-8-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate 30) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0418] Example 23 (2S,4R)—N-(2-(((1R,4S)-4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0419] [ka]

[0420] Example 23 was synthesized in a manner similar to that of Example 11, using tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 31) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0421] Example 24 (2S,4R)—N-(2-(((1R,4S)-4-(4-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0422] [ka]

[0423] Example 24 was synthesized in a manner similar to that of Example 11, using tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 32) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0424] Example 25 (2S,4R)—N-(2-(((1R,4S)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0425] [ka]

[0426] Example 25 was synthesized in a manner similar to that of Example 11 using tert-butyl ((3S,4S)-8-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate 33) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0427] Example 26 (2S,4R)—N-(2-(((1R,4S)-4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperazine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0428] [ka]

[0429] Example 26 was synthesized in the same manner as in Example 11, except that tert-butyl ((1-(5-((3-chloro-2-(piperazin-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 34) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0430] Example 27 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0431] [ka]

[0432] Example 27 was synthesized in a manner similar to that of Example 11, using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0433] Example 28 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0434] [ka]

[0435] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3- Example 28 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0436] Example 29 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(3-((3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0437] [ka]

[0438] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl)methyl)methyl)carbamate (Intermediate 13) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11). Example 29 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0439] Example 30 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0440] [ka]

[0441] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbazin-2-yl)methyl)methyl)carbamate (Intermediate 11) was replaced with (S)-tert-butyl(1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate (Intermediate 14). Example 30 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used in place of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0442] Example 31 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0443] [ka]

[0444] N-((S)-1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate 15) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 31 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used in place of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0445] Example 32 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)indolin-1-yl)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0446] [ka]

[0447] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane)-2-yl)-4-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (Intermediate 22) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11). Example 32 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0448] Example 33 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)indolin-1-yl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0449] [ka]

[0450] Using (R)-2-methyl-N-((3S,4S)-3-methyl-8-(5-((1-(piperidin-4-yl)indolin-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (Intermediate 23) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane Example 33 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0451] Example 34 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-(8-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0452] [ka]

[0453]

[0123] Using tert-butyl ((1-(5-((4-(azetidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 24) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamate) Example 34 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0454] Example 35 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(4-(8-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0455] [ka]

[0456]

[0123] Using tert-butyl ((4-methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)piperidin-4-yl)methyl)carbamate (Intermediate 25) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamate) Example 35 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0457] Example 36 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-(8-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0458] [ka]

[0459] Using tert-butyl ((3S,4S)-3-methyl-8-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate 26) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclohexane) Example 36 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used in place of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0460] Example 37 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-fluoro-1H-indol-1-yl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0461] [ka]

[0462] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)) using tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 27) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11). Example 37 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0463] Example 38 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0464] [ka]

[0465] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 28) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)- Example 38 was synthesized in a manner similar to that of Example 11, using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) instead of (3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0466] Example 39 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0467] [ka]

[0468] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl (1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3, Example 39 was synthesized in a manner similar to that of Example 11, using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) instead of (3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0469] Example 40 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0470] [ka]

[0471] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl ((3S,4S)-8-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate 30) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1- Example 40 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0472] Example 41 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0473] [ka]

[0474] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 31) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)- Example 41 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0475] Example 42 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0476] [ka]

[0477] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 32) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3, Example 42 was synthesized in a manner similar to that of Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0478] Example 43 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0479] [ka]

[0480] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl ((3S,4S)-8-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (Intermediate 33) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1- Example 43 was synthesized in a manner similar to that of Example 11, except that (1S,4r)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used instead of (1S,4r)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0481] Example 44 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0482] [ka]

[0483] Using tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 49) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl) Example 44 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used in place of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0484] Example 45 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0485] [ka]

[0486] Using tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 50) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl) Example 45 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) was used in place of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0487] Example 46 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(4-(3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0488] [ka]

[0489] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-yl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 55) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3- Example 46 was synthesized in a manner similar to that of Example 11, using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0490] Example 47 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0491] [ka]

[0492] Using tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 56) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3 Example 47 was synthesized in a manner similar to that of Example 11, using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 66) instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0493] Example 48 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0494] [ka]

[0495] Example 48 was synthesized in a manner similar to that of Example 11 using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 67) instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0496] Example 49 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(2-(((1R,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0497] [ka]

[0498] Using tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 28) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3 Example 49 was synthesized in the same manner as in Example 11, except that (1S,4R)-4-(2-((S)-1-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 67) was used in place of (1S,4R)-4-(2-((S)-1-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)ethyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0499] Example 50 (2S,4R)—N-(2-(2-(4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)piperidin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0500] [ka]

[0501] Example 50 was synthesized in a manner similar to that of Example 11 using 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65) instead of 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (Intermediate 70).

[0502] Example 51 (2S,4R)—N-(2-(2-(4-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carbonyl)piperidin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0503] [ka]

[0504] Instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 17) was used, and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoic acid) Example 51 was synthesized in a manner similar to that of Example 11, using 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (Intermediate 70) instead of 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)cyclohexane-1-carboxylic acid (Intermediate 65).

[0505] Example 52 (2S,4R)—N-(2-(2-(4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0506] [ka]

[0507] Using tert-butyl ((1-(5-((3-chloro-2-(piperazin-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 34) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutadiene) Example 52 was synthesized in a manner similar to that of Example 11, using 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (Intermediate 70) instead of 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (Intermediate 70).

[0508] Example 53 (2S,4R)—N-(2-(2-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0509] [ka]

[0510]

[0111] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carboxylic acid (Intermediate 39) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3 Example 53 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (intermediate 71) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (intermediate 65).

[0511] Example 54 (2S,4R)—N-(2-(2-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0512] [ka]

[0513] 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3 Example 54 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (intermediate 71) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (intermediate 65).

[0514] Example 55 (2S,4R)—N-(2-(2-(1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonyl)piperidin-4-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0515] [ka]

[0516]

[0111] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carboxylic acid (Intermediate 39) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3 Example 55 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperidin-4-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (intermediate 72) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (intermediate 65).

[0517] Example 56 (2S,4R)—N-(2-(2-(1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0518] [ka]

[0519] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3 Example 56 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperidin-4-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (intermediate 72) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (intermediate 65).

[0520] Example 57 (2S,4R)—N-(2-((7-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0521] [ka]

[0522] 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3- Example 57 was synthesized in a manner similar to that of Example 11 using (2S,4R)—N-(2-((7-azaspiro[3.5]nonan-2-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 73) instead of (dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0523] Example 58 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)methoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0524] [ka]

[0525] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide) Example 58 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-ylmethoxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 74) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-ylmethoxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 74).

[0526] Example 59 (2S,4R)—N-(2-((1-((1s,3R)-3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0527] [ka]

[0528] (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutene-1-carboxylic acid (Intermediate 35) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxylic acid) Example 59 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0529] Example 60 (2S,4R)—N-(2-((1-((1S,3R)-3-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0530] [ka]

[0531] Using (1S,3S)-3-((4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylic acid (Intermediate 36) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide) Example 60 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0532] Example 61 (2S,4R)—N-(2-((1-((1r,3S)-3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0533] [ka]

[0534] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-yl)methyl)methyl)cyclobutene-1-carboxylic acid (Intermediate 37) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11). Example 61 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0535] Example 62 (2S,4R)—N-(2-((1-((1R,4S)-4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0536] [ka]

[0537] (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-yl)-2-carboxylic acid))-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexane-1-carboxylic acid (Intermediate 38) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11). Example 62 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0538] Example 63 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0539] [ka]

[0540] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carboxylic acid (Intermediate 39) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide) Example 63 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0541] Example 64 (2S,4R)—N-(2-((1-(2-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidin-3-yl)acetyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0542] [ka]

[0543] Using 2-(1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidin-3-yl)acetic acid (Intermediate 40) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido) Example 64 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0544] Example 65 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0545] [ka]

[0546] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide) Example 65 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0547] Example 66 (2S,4R)—N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0548] [ka]

[0549] 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 42) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3 Example 66 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0550] Example 67 (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0551] [ka]

[0552] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane- Example 67 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0553] Example 68 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0554] [ka]

[0555] tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) was replaced with 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-methylpiperidine-4-carboxylic acid (Intermediate 44), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxy Example 68 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0556] Example 69 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-fluoropiperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0557] [ka]

[0558] 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-fluoropiperidine-4-carboxylic acid (Intermediate 45) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxy Example 69 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0559] Example 70 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0560] [ka]

[0561] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 46) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 70 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0562] Example 71 (2S,4R)—N-(2-((1-(2-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0563] [ka]

[0564] Using 2-(1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)acetic acid (Intermediate 47) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido) Example 71 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0565] Example 72 (2S,4R)—N-(2-((1-(2-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0566] [ka]

[0567] Using 2-(1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetic acid (Intermediate 48) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carbamoyl) Example 72 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75).

[0568] Example 73 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0569] [ka]

[0570] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide) Example 73 was synthesized in a manner similar to that of Example 11, using (2S,4R)-N-(2-(azetidin-3-yloxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (intermediate 76) instead of (2S,4R)-N-(2-(azetidin-3-yloxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (intermediate 76).

[0571] Example 74 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-((1S,3R)-3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0572] [ka]

[0573] Using (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylic acid (Intermediate 35) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutane-1-carboxylic acid (Intermediate 35) Example 74 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of chloropropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0574] Example 75 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0575] [ka]

[0576] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane- Example 75 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (1-carboxyamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxyamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0577] Example 76 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0578] [ka]

[0579] Using 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 42) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-yl) Example 76 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0580] Example 77 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0581] [ka]

[0582] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorophenyl)-2-fluoro-2-fluoro-1 ... Example 77 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0583] Example 78 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0584] [ka]

[0585] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 51) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclohexane) Example 78 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0586] Example 79 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0587] [ka]

[0588] Using 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 52) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanediol) Example 79 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0589] Example 80 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0590] [ka]

[0591] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2 Example 80 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of -(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0592] Example 81 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0593] [ka]

[0594] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 54) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluoro- Example 81 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0595] Example 82 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0596] [ka]

[0597] Using 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid (Intermediate 57) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-yl)methyl) Example 82 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0598] Example 83 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0599] [ka]

[0600] Using 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid (Intermediate 58) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanediol) Example 83 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0601] Example 84 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(3-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0602] [ka]

[0603] Using 1-(3-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid (Intermediate 59) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane Example 84 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77).

[0604] Example 85 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0605] [ka]

[0606] Using 1-(3-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid (Intermediate 60) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-( Example 85 was synthesized in a manner similar to that of Example 11 using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 77) instead of 1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0607] Example 86 (2S,4R)—N—((S)-1-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0608] [ka]

[0609] 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3- Example 86 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 78) instead of (dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0610] Example 87 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0611] [ka]

[0612] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 87 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)phenyl)ethyl)pyrrolidine-2-carboxamide (Intermediate 79) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0613] Example 88 (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0614] [ka]

[0615] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1 Example 88 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 80) instead of (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 80).

[0616] Example 89 (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-2-(2-hydroxyacetamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide

[0617] [ka]

[0618] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1- Example 89 was synthesized in a manner similar to that of Example 11 using (2S,4R)-4-hydroxy-1-((S)-2-(2-hydroxyacetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 81) instead of (fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0619] Example 90 (2S,4R)-1-(acetyl-L-valyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0620] [ka]

[0621] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane Example 90 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 82) instead of (2S,4R)-1-((S)-2-acetamido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 82).

[0622] Example 91 (2S,4R)-1-((S)-2-acetamido-2-cyclopropylacetyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0623] [ka]

[0624] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane- Example 91 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-acetamido-2-cyclopropylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 83) instead of (1-carboxyamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxyamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0625] Example 92 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P1)

[0626] [ka]

[0627] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 92 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) (Intermediate 84) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) (Intermediate 84).

[0628] Example 93 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0629] [ka]

[0630] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 93 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85).

[0631] Example 94 (2S,4R)—N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0632] [ka]

[0633] Using 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 42) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxylate) Example 94 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85).

[0634] Example 95. (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0635] [ka]

[0636] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 95 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85).

[0637] Example 96 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0638] [ka]

[0639] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 51) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane Example 96 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85).

[0640] Example 97. (2S,4R)—N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0641] [ka]

[0642] Using 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 52) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1- Example 97 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85).

[0643] Example 98. (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2

[0644] [ka]

[0645] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fu Example 98 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85).

[0646] Example 99 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (P1)

[0647] [ka]

[0648] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 99 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) (Intermediate 86) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) (Intermediate 86).

[0649] Example 100. (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0650] [ka]

[0651] tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) was replaced with 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxy Example 100 was synthesized in a manner similar to that of Example 11 using (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 87) instead of (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 87).

[0652] Example 101 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0653] [ka]

[0654] 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)- Example 101 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88) instead of (3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0655] Example 102 (2S,4R)—N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0656] [ka]

[0657] 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 42) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3 Example 102 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88) instead of ...).

[0658] Example 103 (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0659] [ka]

[0660] 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) was used in place of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 103 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88) instead of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88).

[0661] Example 104 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0662] [ka]

[0663] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 51) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), Example 104 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88) instead of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88).

[0664] Example 105 (2S,4R)—N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0665] [ka]

[0666] 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 11) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) Example 105 was synthesized in a manner similar to that of Example 11 using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65) instead of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88).

[0667] Example 106 (2S,4R)—N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0668] [ka]

[0669] 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 11) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) Example 106 was synthesized in a manner similar to that of Example 11 using (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65) instead of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 88).

[0670] Example 107 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0671] [ka]

[0672] 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide)-3, Example 107 was synthesized in a manner similar to that of Example 11, using (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 89) instead of (3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0673] Example 108 (2S,4R)—N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0674] [ka]

[0675] Using 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 51) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamide) Example 108 was synthesized in a manner similar to that of Example 11, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 90) instead of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-t...

Claims

1. A compound of the following chemical formula 1, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof: 【Chemistry 1】 In the above Chemical Formula 1, R １ teeth, 【Chemistry 2】 and R １１ is H, C １－６ Alkyl, hydroxy, halogen, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, heterocycle, aryl or heteroaryl, wherein aryl and heteroaryl are independently and optionally, one or more hydrogen atoms in the ring are replaced by C １－６ Alkyl, hydroxy, halogen, C １－３ Hydroxyalkyl, C １－３ Haloalkyl or C １－３ alkoxy-substituted, R １２ is amino, C １－６ Aminoalkyl or C １－６ alkylamino, R １３ａ and R １３ｂ are independently H, C １－６ Alkyl, hydroxy, halogen, C １－６ Hydroxyalkyl, C １－６ Haloalkyl or C １－６ is an alkoxy; R １４ are independently H, C １－６ alkyl, hydroxy, halogen or CN; Z's are each independently —O—, —S—, —NH—, or —CH ２ - and Ring C is aryl or heteroaryl; n is an integer from 0 to 5, R ２ is H, C １－６ Alkyl or -NH ２ and R ３ is H, C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, —C(O)R ９ａ , -C(O)OR ９ａ , —C(O)NR ９ａ R ９ｂ or CN, R ４ is H, C １－６ Alkyl, halogen, C １－６ Haloalkyl or C １－６ Alkoxy or —N(R ９ａ )-W's R ９ａ and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ５ is H, C １－６ Alkyl, C ２－６ alkynyl, halogen, —CN, or heteroaryl, where heteroaryl optionally replaces one or more hydrogens in the ring with C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ６ is -NHC(O)R ７ or heteroaryl, wherein the heteroaryl is optionally substituted with one or more hydrogen atoms in the ring. １－６ Alkyl, halogen, C １－３ Haloalkyl or C ３－６ cycloalkyl-substituted, where R ７ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Cyanoalkyl, C ３－１０ cycloalkyl or heterocycle, wherein the cycloalkyl and heterocycle are independently and optionally, one or more hydrogens in the ring are replaced by C １－６ substituted with alkyl, halogen or —CN; R ８ａ is H, C １－６ Alkyl or C ３－６ is cycloalkyl, R ８ｂ and R ８ｃ are independently H, C １－６ Alkyl, C １－６ alkoxy or halogen; X is -S-, -O-, -N(R ９ａ ) -, -CH ２ -, -CHCH-, -CC-, -CH ２ O- or -OCH ２ - and Y is CH or N; W is a direct bond, —O— or —N(R ９ａ ) - and R ９ａ and R ９ｂ are independently H, C １－６ Alkyl or C １－６ is haloalkyl, L is represented by the following chemical formula 2: 【Transformation 3】 In Chemical Formula 2, A １ and A ２ are each independently a direct bond, C ３－１０ cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl optionally has one or more hydrogen atoms in the ring replaced by C １－６ Alkyl, halogen, C １－３ substituted with haloalkyl, —OH or ═O; B １ and B ２ are each independently a direct bond, —O—, —N(R １０ )-, -C(O)-, -C(O)N(R １０ )- or -N(R １０ )C(O)—, where R １０ are each independently H or C １－６ is alkyl, q １ , q ２ , q ３ , q ４ and q ５ are each independently an integer from 0 to 10.

2. R １ teeth, 【Chemistry 4】 and R １１ is H, C １－６ Alkyl, hydroxy, halogen, C １－６ Hydroxyalkyl or C １－６ is haloalkyl, R １２ is amino, C １－６ Aminoalkyl or C １－６ alkylamino, R １３ａ and R １３ｂ are independently H, C １－６ Alkyl, hydroxy, halogen, C １－６ Hydroxyalkyl, C １－６ Haloalkyl or C １－６ is an alkoxy; R １４ are independently H, C １－６ alkyl, hydroxy, halogen or CN; Z's are each independently —O—, —S—, —NH—, or —CH ２ - and Ring C is aryl or heteroaryl; n is an integer from 0 to 5, R ２ is H, C １－６ Alkyl or -NH ２ and R ３ is H, C １－６ Alkyl, C １－６ Hydroxyalkyl, —C(O)NR ９ａ R ９ｂ or CN, R ４ is H, C １－６ Alkyl, halogen, C １－６ Haloalkyl or C １－６ Alkoxy or —N(R ９ａ )-W's R ９ａ and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ５ is H, C １－６ Alkyl, C ２－６ alkynyl, halogen, —CN, or heteroaryl, where heteroaryl optionally replaces one or more hydrogens in the ring with C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ６ is -NHC(O)R ７ or heteroaryl, wherein the heteroaryl is optionally substituted with one or more hydrogen atoms in the ring. １－６ Alkyl, halogen, C １－３ Haloalkyl or C ３－６ cycloalkyl-substituted, where R ７ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Cyanoalkyl, C ３－１０ cycloalkyl or heterocycle, wherein the cycloalkyl and heterocycle are independently and optionally, one or more hydrogens in the ring are replaced by C １－６ substituted with alkyl, halogen or —CN; R ８ａ is H, C １－６ Alkyl or C ３－６ is cycloalkyl, R ８ｂ and R ８ｃ are independently H, C １－６ Alkyl, C １－６ alkoxy or halogen; X is -S-, -O-, -N(R ９ａ )- or -CH ２ - and Y is CH or N; W is a direct bond, —O— or —N(R ９ａ ) - and R ９ａ and R ９ｂ are independently H, C １－６ Alkyl or C １－６ is haloalkyl, L is represented by the following chemical formula 2: 【Transformation 5】 In Chemical Formula 2, A １ and A ２ are each independently a direct bond, C ３－１０ cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl optionally has one or more hydrogen atoms in the ring replaced by C １－６ Alkyl, halogen, C １－３ substituted with haloalkyl, —OH or ═O; B １ and B ２ are each independently a direct bond, —O—, —N(R １０ )-, -C(O)-, -C(O)N(R １０ )- or -N(R １０ )C(O)—, where R １０ are each independently H or C １－６ is alkyl, q １ , q ２ , q ３ , q ４ and q ５ are each independently an integer from 0 to 10. The compound of formula 1 according to claim 1, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof.

3. R １ teeth, 【Transformation 6】 and R １１ is H, C １－６ Alkyl, hydroxy, halogen, C １－３ Hydroxyalkyl or C １－３ is haloalkyl, R １２ is amino, C １－３ Aminoalkyl or C １－３ alkylamino, R １３ａ and R １３ｂ are independently H, C １－６ Alkyl, hydroxy, halogen, C １－３ Hydroxyalkyl, C １－３ Haloalkyl or C １－３ is an alkoxy; R １４ are independently H, C １－３ alkyl, hydroxy, halogen or CN; Z's are each independently -O-, -NH- or -CH ２ - and Ring C is aryl or heteroaryl; n is an integer from 0 to 3, R ２ is H, C １－６ Alkyl or -NH ２ and R ３ is H, C １－６ Alkyl, C １－６ Hydroxyalkyl, —C(O)NR ９ａ R ９ｂ or CN, R ４ is H, C １－６ Alkyl, halogen, C １－６ Haloalkyl or C １－６ Alkoxy or —N(R ９ａ )-W's R ９ａ and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C １－３ Alkyl, halogen or C １－３ substituted with haloalkyl, R ５ is H, C １－６ alkyl, acetylenyl, halogen, —CN, or heteroaryl, where the heteroaryl optionally has one or more hydrogens in the ring replaced by C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ６ is -NHC(O)R ７ or heteroaryl, wherein the heteroaryl is optionally substituted with one or more hydrogen atoms in the ring. １－６ Alkyl, halogen, C １－３ Haloalkyl or C ３－６ cycloalkyl-substituted, where R ７ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Cyanoalkyl or C ３－１０ cycloalkyl, where cycloalkyl optionally has one or more hydrogens in the ring replaced by C １－３ substituted with alkyl, halogen or —CN; R ８ａ is H, C １－６ Alkyl or C ３－６ is cycloalkyl, R ８ｂ and R ８ｃ are independently H, C １－６ alkyl or halogen; X is -S-, -O-, -N(R ９ａ )- or -CH ２ - and Y is CH or N; W is a direct bond, —O— or —N(R ９ａ ) - and R ９ａ and R ９ｂ are independently H, C １－６ Alkyl or C １－６ is haloalkyl, L is represented by the following chemical formula 2: 【Transformation 7】 In Chemical Formula 2, A １ and A ２ are each independently a direct bond, C ３－１０ cycloalkyl or heterocycle, wherein cycloalkyl and heterocycle optionally have one or more hydrogen atoms in the ring replaced by C １－６ Alkyl, halogen, C １－３ substituted with haloalkyl, —OH or ═O; B １ and B ２ are each independently a direct bond, —O—, —N(R １０ )- or -C(O)-, where R １０ are each independently H or C １－６ is alkyl, q １ , q ２ , q ３ , q ４ and q ５ are each independently an integer from 0 to 5. The compound of formula 1 according to claim 2, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof.

4. R １ teeth, 【Transformation 8】 and R １１ is H, C １－６ Alkyl, hydroxy or C １－３ is a hydroxyalkyl, R １２ is amino or C １－３ is an aminoalkyl, R １３ａ and R １３ｂ are independently H, C １－６ Alkyl, hydroxy, C １－３ Hydroxyalkyl or C １－３ is an alkoxy; R １４ are independently H, C １－３ alkyl, hydroxy, halogen or CN; Z's are each independently -O-, -NH- or -CH ２ - and Ring C is aryl or heteroaryl; n is an integer from 0 to 3, R ２ is H, C １－６ Alkyl or -NH ２ and R ３ is H, C １－６ Alkyl or C １－６ is a hydroxyalkyl, R ４ is H, C １－６ Alkyl, halogen, C １－６ Haloalkyl or C １－６ Alkoxy or —N(R ９ａ )-W's R ９ａ and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C １－３ Alkyl, halogen or C １－３ substituted with haloalkyl, R ５ is H, C １－６ alkyl, acetylenyl, halogen, —CN, thiazole, pyrazole, pyrrole, oxazole or triazole, wherein the thiazole, pyrazole, pyrrole, oxazole or triazole optionally has one or more hydrogen atoms in the ring replaced by a C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ６ is -NHC(O)R ７ , triazole, pyrazole or isoxazole, wherein the triazole, pyrazole or isoxazole is optionally selected such that one or more hydrogen atoms in the ring are replaced by C １－６ Alkyl, halogen, C １－３ Haloalkyl or C ３－６ cycloalkyl-substituted, where R ７ is C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Cyanoalkyl or C ３－６ cycloalkyl, where cycloalkyl optionally has one or more hydrogens in the ring replaced by C １－３ substituted with alkyl, halogen or —CN; R ８ａ is H, C １－６ Alkyl or C ３－６ is cycloalkyl, R ８ｂ and R ８ｃ are independently H, C １－３ alkyl or halogen; X is —S— or —O—; Y is CH or N; W is a direct bond, —O— or —N(R ９ａ ) - and R ９ａ and R ９ｂ are independently H, C １－３ Alkyl or C １－３ is haloalkyl, L is represented by the following chemical formula 2: 【Chemistry 9】 In Chemical Formula 2, A １ and A ２ are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane optionally has one or more hydrogen atoms in the ring replaced with a C １－６ Alkyl, halogen, C １－３ substituted with haloalkyl, —OH or ═O; B １ and B ２ are each independently a direct bond, —O— or —C(O)—, q １ , q ２ , q ３ , q ４ and q ５ are each independently an integer from 0 to 5. The compound of formula 1 according to claim 3, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof.

5. R １ teeth 【Chemistry 10】 and R １１ is H, C １－６ alkyl or hydroxy; R １２ is amino or C １－３ is an aminoalkyl, R １３ａ and R １３ｂ are independently H, C １－６ Alkyl, hydroxy or C １－３ is hydroxyalkyl, R １４ are independently H, C １－３ alkyl or halogen; Z's are each independently —O— or —CH ２ - and Ring C is aryl or heteroaryl; n is an integer from 0 to 3, R ２ is H, C １－６ Alkyl or -NH ２ and R ３ is H, C １－６ Alkyl or C １－６ is a hydroxyalkyl, R ４ is H, C １－６ Alkyl, halogen, C １－６ Haloalkyl or C １－６ Alkoxy or —N(R ９ａ )-W's R ９ａ and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C １－３ substituted with alkyl or halogen; R ５ is H, C １－６ alkyl, acetylenyl, halogen, —CN, thiazole, pyrazole or pyrrole, wherein the thiazole, pyrazole or pyrrole optionally has one or more hydrogen atoms in the ring replaced by a C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ６ is -NHC(O)R ７ , triazole, pyrazole or isoxazole, wherein the triazole, pyrazole or isoxazole is optionally selected such that one or more hydrogen atoms in the ring are replaced by C １－６ Alkyl, halogen, C １－３ Haloalkyl or C ３－６ cycloalkyl-substituted, where R ７ is C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Cyanoalkyl or C ３－６ cycloalkyl, where cycloalkyl optionally has one or more hydrogens in the ring replaced by C １－３ substituted with alkyl, halogen or —CN; R ８ａ is H, C １－６ Alkyl or C ３－６ is cycloalkyl, R ８ｂ and R ８ｃ are independently H, C １－３ alkyl or halogen; X is —S— or —O—; Y is CH or N; W is a direct bond, —O— or —N(R ９ａ ) - and R ９ａ and R ９ｂ are independently H, C １－３ Alkyl or C １－３ is haloalkyl, L is represented by the following chemical formula 2: 【Chemistry 11】 In Chemical Formula 2, A １ and A ２ are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane optionally has one or more hydrogen atoms in the ring replaced with a C １－６ substituted with alkyl, halogen, —OH or ═O; B １ and B ２ are each independently a direct bond or —C(O)—, q １ , q ２ , q ３ , q ４ and q ５ are each independently an integer from 0 to 3. The compound of formula 1 according to claim 4, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof.

6. R １ teeth, 【Chemistry 12】 and R １１ is H or C １－６ is alkyl, R １２ is amino or C １－３ is an aminoalkyl, R １３ａ and R １３ｂ are each independently H or C １－６ is alkyl, R １４ are each independently H or C １－３ is alkyl, Z's are each independently —O— or —CH ２ - and Ring C is aryl or heteroaryl; n is an integer from 0 to 3, R ２ is H, C １－６ Alkyl or -NH ２ and R ３ is H, C １－６ Alkyl or C １－６ is hydroxyalkyl, R ４ is H, C １－６ Alkyl, halogen or C １－６ haloalkyl or —N(R ９ａ )-W's R ９ａ and form a heterocycle or heteroaryl, wherein the heterocycle and heteroaryl are each independently and optionally, one or more hydrogens in the ring are replaced by C １－３ substituted with alkyl or halogen; R ５ is H, C １－６ alkyl, halogen, —CN, thiazole or pyrazole, wherein the thiazole or pyrazole optionally has one or more hydrogen atoms in the ring replaced by a C １－６ Alkyl, halogen or C １－３ substituted with haloalkyl, R ６ is -NHC(O)R ７ , triazole, pyrazole or isoxazole, wherein the triazole, pyrazole or isoxazole is optionally selected such that one or more hydrogen atoms in the ring are replaced by C １－６ Alkyl, halogen, C １－３ Haloalkyl or C ３－６ cycloalkyl-substituted, where R ７ is C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Hydroxyalkyl, C １－３ Cyanoalkyl or C ３－６ cycloalkyl, wherein one or more hydrogen atoms in the ring of the cycloalkyl are optionally replaced by halogen or —CN; R ８ａ is H, C １－６ Alkyl or C ３－６ is cycloalkyl, R ８ｂ and R ８ｃ are independently H, C １－３ alkyl or halogen; X is —S— or —O—; Y is CH or N; W is a direct bond or —N(R ９ａ ) - and R ９ａ and R ９ｂ are independently H, C １－３ Alkyl or C １－３ is haloalkyl, L is represented by the following chemical formula 2: 【Chemistry 13】 In Chemical Formula 2, A １ and A ２ are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane optionally has one or more hydrogen atoms in the ring replaced with a C １－６ substituted with alkyl, halogen, —OH or ═O; B １ and B ２ are each independently a direct bond or —C(O)—, q １ , q ２ , q ３ , q ４ and q ５ are each independently an integer from 0 to 3. The compound of formula 1 according to claim 5, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof.

7. The compound of formula 1 according to claim 1, wherein the compound is any one of the following compounds: an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof: Table 1

8. A composition comprising the compound according to any one of claims 1 to 7, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), comprising the compound according to any one of claims 1 to 7, or an optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof, as an active ingredient.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2) is for the treatment or prevention of cancer, metastatic cancer (metastasis), cardiovascular disease, immune disorders, eye disorders, Noonan syndrome, or Leopard syndrome.

11. 11. The pharmaceutical composition of claim 10, wherein the cancer is one or more selected from blood cancer, acute lymphocytic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, lymphoma, cervical cancer, head and neck cancer, head cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, melanoma, colorectal cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma or sarcoma, papillary thyroid cancer, and combinations thereof.

12. A method for treating or preventing a disease associated with Src homology 2 domain-containing phosphatase (SHP2), comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7, or an optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof.

13. The method for treatment or prevention according to claim 12, wherein the Src homology 2 domain-containing phosphatase (SHP2)-associated disease is cancer, metastatic cancer (metastasis), cardiovascular disease, immune disorder, ocular disorder, Noonan syndrome, or Leopard syndrome.

14. 14. The method of claim 13, wherein the cancer is one or more selected from blood cancer, acute lymphocytic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, lymphoma, cervical cancer, head and neck cancer, head cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, melanoma, colorectal cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma or sarcoma, papillary thyroid cancer, and combinations thereof.

15. A method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or a pharmaceutically acceptable salt thereof.

16. A method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or biological sample, comprising contacting the patient or biological sample with a compound described in any one of claims 1 to 7, or an optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof.

17. Use of a compound according to any one of claims 1 to 7, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or a pharmaceutically acceptable salt thereof for producing a drug for the degradation of Src homology 2 domain-containing phosphatase (SHP2) in a patient or biological sample.

18. Use of the compound according to any one of claims 1 to 7, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof for producing a drug for the treatment of Src homology 2 domain-containing phosphatase (SHP2)-associated diseases.

Images