Compounds for SHP2 protein degradation and medical uses thereof

Abstract

The present disclosure provides a compound of a specific chemical structure having excellent activity in SHP2 protein degradation, an optical isomer, a stereoisomer, an isotope variant, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt thereof. The disclosure also provides compositions comprising such compounds, optical isomers, stereoisomers, isotopic variants, hydrates or solvates thereof, or pharmaceutically acceptable salts thereof. The present disclosure also provides the medical use of a composition comprising a compound according to the present disclosure, an optical isomer, a stereoisomer, an isotopic variant, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt thereof for the treatment or prevention of an SHP2-related disease (e.g., cancer). The disclosure also provides methods for treating or preventing a SHP2-related disease (e.g., cancer) comprising administering to a subject in need thereof an effective amount of a composition comprising a compound according to the disclosure, an optical isomer, stereoisomer, isotope variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This application claims priority to 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, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to a group of compounds having SHP2 proteolytic activity. Specifically, the present disclosure relates to a group of compounds having a specific structure and having the activity of degrading SHP2 protein. The present disclosure also relates to a composition for treating SHP2 protein-related diseases or a method for treating SHP2 protein-related diseases using such compounds. In other words, the present disclosure relates to the medical use of the compounds according to the present disclosure for treating or preventing SHP2 protein-related diseases. Background Art

[0003] Src homology 2 domain-containing phosphatase (SHP2) is a protein tyrosine phosphatase. Mutations in SHP2 are prevalent 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 several 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] It is known that SHP2 is involved in multiple signal transduction processes, such as the RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB, and mTOR pathways in cancer cells. In the RAS-ERK pathway, SHP2 acts as a positive regulator upstream to promote RAS-RAF-MEK-ERK kinase cascade signal transduction. Therefore, SHP2 inhibition suppresses the oncogenic function of the RAS-RAF-MEK-ERK pathway, leading to cell growth inhibition and apoptosis in cancer cells. As a key protein in the PD-1 / PD-L1-mediated T cell activation inhibitory signal transduction pathway in immune cells, SHP2 also promotes immune evasion. In summary, SHP2 is a very attractive cancer treatment target. For example, it has been shown that the SHP2 inhibitor SHP099 selectively blocks the phosphatase activity of SHP2, inhibits cancer cell growth in vitro, and inhibits tumor growth in xenograft mouse models (Chen et al., Nature 2016, 535, 148-152; GarciaFortanet et al., J. Med. Chem. 2016, 59, 7773-7782).

[0005] Allosteric SHP2 inhibitors have been shown to be effective in preclinical models of Kirsten rat sarcoma (KRAS)-mutant human cancers. In addition, inactivating SHP2 by CRISPR-Cas9 has been shown to induce senescence and inhibit tumor growth in xenograft models of KRAS mutant tumors.

[0006] Disclosure

[0007] Technical problem

[0008] Deletion of the SHP2 protein can provide an alternative and more effective strategy for inhibiting SHP2 activity. Therefore, the problem to be solved by the present invention is to provide compounds having the activity of degrading the phosphatase with Src homology 2 domain (SHP2), pharmaceutical compositions containing the compounds as active ingredients, and medical uses for treating or preventing SHP2-related diseases (such as cancer, tumors, etc.).

[0009] Another problem to be solved by the present invention is to provide a method for treating or preventing SHP2-related diseases (preferably cancer or tumors), which is characterized in that it degrades SHP2 and thus reduces the SHP2 level, and which comprises administering a compound according to the present invention to a patient in need of treatment, improvement, or prevention of SHP2-related diseases.

[0010] Technical solution

[0011] The present disclosure relates to SHP2-targeted protein degradation (TPD) compounds capable of targeting and degrading SHP2 protein through ubiquitination by an E3 ubiquitin ligase, pharmaceutical compositions comprising the compounds as active ingredients, and methods for using the compounds to treat or prevent SHP2-related diseases.

[0012] The compounds of the present disclosure

[0013] The compound according to one embodiment of the present invention is a target protein degradation compound of "SHP2 binding ligand-linker (-W-L-)-VHL ligand". In one embodiment, the present application relates to a bifunctional compound that can be used to modulate protein activity by inducing target protein degradation. In some embodiments, the bifunctional compound comprises a VHL ligand and a target protein binding moiety, the VHL ligand being an E3 ubiquitin ligase binding moiety, and the target protein binding moiety being preferably linked through a linker moiety as described herein. An E3 ubiquitin ligase refers to a family of proteins that target substrate proteins for degradation by transferring ubiquitin. VHL is an E3 ubiquitin ligase protein that combines with an E2 ubiquitin-conjugating enzyme to link ubiquitin to lysine on the target protein, thereby inducing proteasomal degradation. Thus, the bifunctional compound binds to both VHL and the target protein, thereby inducing degradation via ubiquitination by bringing the target protein near VHL, and thus inhibiting / repressing the activity of the target protein. In certain embodiments, the bifunctional compound comprises an SHP2 binding ligand and a VHL ligand covalently, directly or indirectly linked to, for example, a chemical linker -W-L-.

[0014] One embodiment of the present invention provides a compound of Formula 1 below, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts.

[0015] [Formula 1]

[0016]

[0017] In Formula 1,

[0018] R 1 is or

[0019] 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 one or more hydrogens in the aryl and heteroaryl are optionally and independently replaced by C 1-6Alkyl, hydroxy, halogen, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl or C 1-3 substituted by alkoxy,

[0020] R 12 is amino, C 1-6 Aminoalkyl or C 1-6 alkylamino,

[0021] R 13a and R 13b are each independently H, C 1-6 alkyl (preferably methyl), hydroxy, halogen, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl or C 1-6 substituted by alkoxy,

[0022] R 14 are each independently H, C 1-6 alkyl, hydroxy, halogen or CN,

[0023] Z are each independently -O-, -S-, -NH- or -CH 2 -,

[0024] Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine),

[0025] n is an integer from 0 to 5,

[0026] R 2 is H, C 1-6 alkyl or -NH 2 ,

[0027] R 3 is H, C 1-6 alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, -C(O)R 9a , -C(O)OR 9a , -C(O)NR 9a R 9b or CN,

[0028] R 4 is H, C 1-6 alkyl, halogen (preferably Cl), C 1-6 Halogenated alkyl or C 1-6 substituted by alkoxy, or R 4 is connected to R of W 9a to form a heterocycle (preferably pyrrolidine, morpholine) or heteroaryl (preferably pyrrole), where W is -N(R 9a ), and one or more hydrogens in the heterocycle and heteroaryl are optionally and each independently replaced by C 1-6alkyl, halogen or C 1-3 substituted by haloalkyl,

[0029] R 5 is H, C 1-6 alkyl, C 2-6 alkynyl (preferably ethynyl), halogen, -CN or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole or triazole), wherein one or more hydrogens in the heteroaryl are optionally substituted by C 1-6 alkyl (preferably methyl, ethyl), halogen or C 1-3 substituted by haloalkyl,

[0030] R 6 is -NHC(O)R 7 or heteroaryl (preferably triazole, pyrazole, iso oxazole), wherein one or more hydrogens in the heteroaryl are optionally substituted by C 1-6 alkyl, halogen, C 1-3 substituted by haloalkyl or C 3-6 substituted by cycloalkyl, and wherein R 7 is C 1-6 alkyl, C 1-6 substituted by haloalkyl, C 1-6 substituted by hydroxyalkyl, C 1-6 substituted by cyanoalkyl, C 3-10 substituted by cycloalkyl or heterocycle, wherein one or more hydrogens in the cycloalkyl and heterocycle are optionally and independently substituted by C 1-6 alkyl, halogen or -CN,

[0031] R 8a is H, C 1-6 alkyl or C 3-6 substituted by cycloalkyl,

[0032] R 8b and R 8c are each independently H, C 1-6 alkyl, C 1-6 substituted by alkoxy or halogen,

[0033] X is -S-, -O-, -N(R 9a ), -CH 2 (substituted by -), -CHCH-, -CC-, -CH 2 substituted by O- or -OCH 2 (substituted by -),

[0034] Y is CH or N,

[0035] W is a direct bond, -O- or -N(R 9a ),

[0036] R 9a and R 9bEach independently is H, C 1-6 alkyl or C 1-6 haloalkyl,

[0037] L is the following Chemical Formula 2,

[0038] [Chemical Formula 2]

[0039]

[0040] In Chemical Formula 2,

[0041] A 1 and A 2 each independently is a direct bond, C 3-10 cycloalkyl (preferably cyclohexane, cyclobutane), heterocycle (preferably piperidine, piperazine, azetidine, 7-azaspiro[3.5]nonane), aryl or heteroaryl, wherein one or more hydrogens in the cycloalkyl, heterocycle, aryl or heteroaryl are optionally and independently replaced by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or ═O,

[0042] B 1 and B 2 each independently is a direct bond, -O-, -N(R 10 )--C(O)-, -C(O)N(R 10 )-, or -N(R 10 )C(O)-, wherein R 10 each independently is H or C 1-6 alkyl, and

[0043] q 1 、q 2 、q 3 、q 4 and q 5 each independently is an integer from 0 to 10.

[0044] A preferred embodiment of the present invention provides a compound represented by Chemical Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, wherein

[0045] R 1 is or

[0046] R 11 is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl or C 1-6 haloalkyl,

[0047] R 12is amino, C 1-6 aminoalkyl or C 1-6 alkylamino,

[0048] R 13a and R 13b are each independently H, C 1-6 alkyl (preferably methyl), hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl or C 1-6 alkoxy,

[0049] R 14 are each independently H, C 1-6 alkyl, hydroxy, halogen or CN,

[0050] Z are each independently -O-, -S-, -NH- or -CH 2 ]-,

[0051] Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine),

[0052] n is an integer from 0 to 5,

[0053] R 2 is H, C 1-6 alkyl or -NH 2 ],

[0054] R 3 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, -C(O)NR 9a R 9b or CN,

[0055] R 4 is H, C 1-6 alkyl, halogen (preferably Cl), C 1-6 haloalkyl or C 1-6 alkoxy, or R 4 is connected to R 9a of W to form a heterocycle (preferably pyrrolidine, morpholine) or heteroaryl (preferably pyrrole), where W is -N(R 9a ), and one or more hydrogens in the heterocycle and heteroaryl are optionally and each independently substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl,

[0056] R 5 is H, C 1-6 alkyl, C 2-6 alkynyl (preferably ethynyl), halogen, -CN or heteroaryl (preferably thiazole, pyrazole, pyrrole, azole or triazole), wherein one or more hydrogens in the heteroaryl are optionally replaced by C 1-6 alkyl (preferably methyl, ethyl), halogen or C 1-3 haloalkyl substitution,

[0057] R 6 is -NHC(O)R 7 or heteroaryl (preferably triazole, pyrazole, iso azole), wherein one or more hydrogens in the heteroaryl are optionally replaced by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl substitution, and wherein 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 one or more hydrogens in the cycloalkyl and heterocycle are optionally and independently replaced by C 1-6 alkyl, halogen or -CN substitution,

[0058] R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl,

[0059] R 8b and R 8c are each independently H, C 1-6 alkyl, C 1-6 alkoxy or halogen,

[0060] X is -S-, -O-, -N(R 9a )- or -CH 2 -,

[0061] Y is CH or N,

[0062] W is a direct bond, -O- or -N(R 9a )-,

[0063] R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-6 haloalkyl,

[0064] L is the following Chemical Formula 2,

[0065] [Chemical Formula 2]

[0066]

[0067] In Chemical Formula 2,

[0068] A 1 and A 2 each independently is a direct bond, C 3-10 cycloalkyl (preferably cyclohexane, cyclobutane), heterocycle (preferably piperidine, piperazine, azetidine, 7-azaspiro[3.5]nonane), aryl or heteroaryl, wherein one or more hydrogens in the cycloalkyl, heterocycle, aryl or heteroaryl are optionally and each independently substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or ═O,

[0069] B 1 and B 2 each independently is a direct bond, -O-, -N(R 10 ), -, -C(O)-, -C(O)N(R 10 ), - or -N(R 10 )C(O)-, wherein R 10 each independently is H or C 1-6 alkyl, and

[0070] q 1 、q 2 、q 3 、q 4 and q 5 each independently is an integer from 0 to 10.

[0071] The compounds of the present disclosure have desirable characteristics in terms of SHP2 degradation activity, stability in plasma, metabolic stability in vivo, stability during storage, pharmacological properties, physicochemical aspects, etc.

[0072] In addition, in addition to the aspects of the compounds of the present invention described above, the compounds of the present invention also have advantageous characteristics in terms of cancer cell proliferation inhibitory activity, (aqueous) solubility, cell permeability, dosage requirements (exhibiting good effects even at low doses due to good activity, solubility, etc.), bioavailability, in vivo distribution, cancer tissue distribution, pharmacodynamic properties, pharmacodynamic activity, duration of action, drug interactions, etc.

[0073] More preferably, one embodiment of the present invention provides a compound represented by Chemical Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, wherein:

[0074] R 1 is or

[0075] R 11 is H, C 1-6 alkyl, hydroxy, halogen, C 1-3Hydroxyalkyl or C 1-3 haloalkyl,

[0076] R 12 is amino, C 1-3 aminoalkyl or C 1-3 alkylamino,

[0077] R 13a and R 13b are each independently H, C 1-6 alkyl (preferably methyl), hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 alkoxy,

[0078] R 14 are each independently H, C 1-3 alkyl, hydroxy, halogen or CN,

[0079] Z is each independently -O-, -NH- or -CH 2 -,

[0080] Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine),

[0081] n is an integer from 0 to 3,

[0082] R 2 is H, C 1-6 alkyl or -NH 2 ,

[0083] R 3 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, -C(O)NR 9a R 9b or CN,

[0084] R 4 is H, C 1-6 alkyl, halogen (preferably Cl), C 1-6 haloalkyl or C 1-6 alkoxy, or R 4 is connected to the R of W 9a to form a heterocycle (preferably pyrrolidine, morpholine) or heteroaryl (preferably pyrrole), where W is -N(R 9a ), and one or more hydrogens in the heterocycle and heteroaryl are optionally and each independently substituted by C 1-3 alkyl, halogen or C 1-3 haloalkyl,

[0085] R 5 is H, C 1-6alkyl, ethynyl, halogen, -CN or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole or triazole), wherein one or more hydrogens in the heteroaryl are optionally replaced by C 1-6 alkyl (preferably methyl, ethyl), halogen or C 1-3 haloalkyl,

[0086] R 6 is -NHC(O)R 7 or heteroaryl (preferably triazole, pyrazole, iso oxazole), wherein one or more hydrogens in the heteroaryl are optionally replaced by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein R 7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl or C 3-10 cycloalkyl, wherein one or more hydrogens in the cycloalkyl are optionally and independently replaced by C 1-3 alkyl, halogen or -CN,

[0087] R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl,

[0088] R 8b and R 8c are each independently H, C 1-6 alkyl or halogen,

[0089] X is -S-, -O-, -N(R 9a )- or -CH 2 -,

[0090] Y is CH or N,

[0091] W is a direct bond, -O- or -N(R 9a )-,

[0092] R 9a and R 9b are each independently H, C 1-6 alkyl or C 1-6 haloalkyl,

[0093] L is the following Chemical Formula 2,

[0094] [Chemical Formula 2]

[0095]

[0096] In Chemical Formula 2,

[0097] A 1 and A 2 are each independently a direct bond, C 3-10 cycloalkyl (preferably cyclohexane, cyclobutane) or heterocycle (preferably piperidine, piperazine, azetidine, 7-azaspiro[3.5]nonane), wherein one or more hydrogens in the cycloalkyl and heterocycle are optionally and each independently substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or ═O,

[0098] B 1 and B 2 are each independently a direct bond, -O-, -N(R 10 )-, or -C(O)-, wherein R 10 is each independently H or C 1-6 alkyl, and

[0099] q 1 、q 2 、q 3 、q 4 and q 5 are each independently an integer from 0 to 5.

[0100] Even more preferably, one embodiment of the present invention provides a compound represented by Chemical Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, wherein:

[0101] R 1 is or

[0102] R 11 is H, C 1-6 alkyl, hydroxy or C 1-3 hydroxyalkyl,

[0103] R 12 is amino or C 1-3 aminoalkyl,

[0104] R 13a and R 13b are each independently H, C 1-6 alkyl (preferably methyl), hydroxy, C 1-3 hydroxyalkyl or C 1-3 alkoxy,

[0105] R 14 are each independently H, C 1-3 alkyl, hydroxy, halogen or CN,

[0106] Z is independently -O-, -NH- or -CH 2 -,

[0107] Ring C is aryl (preferably benzene) or heteroaryl (preferably pyridine),

[0108] n is an integer from 0 to 3,

[0109] R 2 is H, C 1-6 alkyl or -NH 2 ,

[0110] R 3 is H, C 1-6 alkyl or C 1-6 hydroxyalkyl,

[0111] R 4 is H, C 1-6 alkyl, halogen (preferably Cl), C 1-6 haloalkyl or C 1-6 alkoxy, or R 4 is connected to the R of W 9a to form a heterocycle (preferably pyrrolidine, morpholine) or heteroaryl (preferably pyrrole), where W is -N(R 9a ), and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently substituted by C 1-3 alkyl, halogen or C 1-3 haloalkyl,

[0112] R 5 is H, C 1-6 alkyl, ethynyl, halogen, -CN, thiazole, pyrazole, pyrrole, oxazole or triazole, where one or more hydrogens in thiazole, pyrazole, pyrrole, oxazole and triazole are optionally substituted by C 1-6 alkyl (preferably methyl, ethyl), halogen or C 1-3 haloalkyl,

[0113] R 6 is -NHC(O)R 7 , triazole, pyrazole or iso oxazole, where one or more hydrogens in triazole, pyrazole and iso oxazole are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and where R 7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl or C3-6 A cycloalkyl group, wherein one or more hydrogens in the cycloalkyl group are optionally and independently replaced by C 1-3 alkyl, halogen, or -CN,

[0114] R 8a is H, C 1-6 alkyl, or C 3-6 cycloalkyl,

[0115] R 8b and R 8c are each independently H, C 1-3 alkyl, or halogen,

[0116] X is -S- or -O-,

[0117] Y is CH or N,

[0118] W is a direct bond, -O-, or -N(R 9a )-,

[0119] R 9a and R 9b are each independently H, C 1-3 alkyl, or C 1-3 haloalkyl,

[0120] L is the following Chemical Formula 2,

[0121] [Chemical Formula 2]

[0122]

[0123] In Chemical Formula 2,

[0124] A 1 and A 2 are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine, or 7-azaspiro[3.5]nonane, wherein one or more hydrogens in cyclohexane, cyclobutane, piperidine, piperazine, azetidine, and 7-azaspiro[3.5]nonane are optionally and independently replaced by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH, or =O,

[0125] B 1 and B 2 are each independently a direct bond, -O-, or -C(O)-, and

[0126] q 1 、q 2 、q 3 、q 4 and q 5 are each independently an integer from 0 to 5.

[0127] Even more preferably, an embodiment of the present invention provides a compound represented by Chemical Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, wherein:

[0128] R 1 is or

[0129] R 11 is H, C 1-6 alkyl or hydroxy,

[0130] R 12 is amino or C 1-3 aminoalkyl,

[0131] R 13a and R 13b are each independently H, C 1-6 alkyl, hydroxy or C 1-3 hydroxyalkyl,

[0132] R 14 are each independently H, C 1-3 alkyl or halogen,

[0133] Z are each independently -O- or -CH 2 -,

[0134] Ring C is aryl or heteroaryl,

[0135] n is an integer from 0 to 3,

[0136] R 2 is H, C 1-6 alkyl or -NH 2 ,

[0137] R 3 is H, C 1-6 alkyl or C 1-6 hydroxyalkyl,

[0138] R 4 is H, C 1-6 alkyl, halogen, C 1-6 haloalkyl or C 1-6 alkoxy, or R 4 is connected to the R 9a of W to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and each independently substituted by C 1-3 alkyl or halogen,

[0139] R 5 is H, C 1-6Alkyl, ethynyl, halogen, -CN, thiazole, pyrazole or pyrrole, wherein one or more hydrogens in thiazole, pyrazole and pyrrole are optionally replaced by C 1-6 alkyl, halogen or C 1-3 haloalkyl,

[0140] R 6 is -NHC(O)R 7 , triazole, pyrazole or iso azole, wherein one or more hydrogens in triazole, pyrazole and iso azole are optionally replaced by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein 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 hydrogens in cycloalkyl are optionally and independently replaced by C 1-3 alkyl, halogen or -CN,

[0141] R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl,

[0142] R 8b and R 8c are each independently H, C 1-3 alkyl or halogen,

[0143] X is -S- or -O-,

[0144] Y is CH or N,

[0145] W is a direct bond, -O- or -N(R 9a ),

[0146] R 9a and R 9b are each independently H, C 1-3 alkyl or C 1-3 haloalkyl,

[0147] L is the following Chemical Formula 2,

[0148] [Chemical Formula 2]

[0149]

[0150] In Chemical Formula 2,

[0151] A 1 and A2 Each independently is a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine or 7-azaspiro[3.5]nonane, wherein one or more hydrogens in cyclohexane, cyclobutane, piperidine, piperazine, azetidine and 7-azaspiro[3.5]nonane are optionally and each independently replaced by C 1-6 alkyl, halogen, -OH or ═O,

[0152] B 1 and B 2 Each independently is a direct bond or -C(O)-, and

[0153] q 1 、q 2 、q 3 、q 4 and q 5 Each independently is an integer from 0 to 3.

[0154] Even more preferably, one embodiment of the present invention provides a compound represented by Chemical Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, wherein:

[0155] R 1 is or

[0156] R 11 is H or C 1-6 alkyl,

[0157] R 12 is amino or C 1-3 aminoalkyl,

[0158] R 13a and R 13b Each independently is H or C 1-6 alkyl,

[0159] R 14 Each independently is H or C 1-3 alkyl,

[0160] Z each independently is -O- or -CH 2 -,

[0161] Ring C is aryl or heteroaryl,

[0162] n is an integer from 0 to 3,

[0163] R 2 is H, C 1-6 alkyl or -NH 2 ,

[0164] R 3 is H, C1-6 alkyl or C 1-6 hydroxyalkyl,

[0165] R 4 is H, C 1-6 alkyl, halogen or C 1-6 haloalkyl, or R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently replaced by C 1-3 alkyl or halogen,

[0166] R 5 is H, C 1-6 alkyl, halogen, -CN, thiazole or pyrazole, where one or more hydrogens in thiazole and pyrazole are optionally replaced by C 1-6 alkyl, halogen or C 1-3 haloalkyl,

[0167] R 6 is -NHC(O)R 7 triazole, pyrazole or iso azole, where one or more hydrogens in triazole, pyrazole and iso azole are optionally replaced by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and 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 one or more hydrogens in cycloalkyl are optionally and independently replaced by halogen or -CN,

[0168] R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl,

[0169] R 8b and R 8c are each independently H, C 1-3 alkyl or halogen,

[0170] X is -S- or -O-,

[0171] Y is CH or N,

[0172] W is a direct bond or -N(R 9a )-,

[0173] R9a and R 9b are each independently H, C 1-3 alkyl or C 1-3 haloalkyl,

[0174] L is represented by the following Chemical Formula 2,

[0175] [Chemical Formula 2]

[0176]

[0177] In Chemical Formula 2,

[0178] A 1 and A 2 are each independently a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine or 7-azaspiro[3.5]nonane, wherein one or more hydrogens in cyclohexane, cyclobutane, piperidine, piperazine, azetidine and 7-azaspiro[3.5]nonane are optionally and each independently substituted by C 1-6 alkyl, halogen, -OH or ═O,

[0179] B 1 and B 2 are each independently a direct bond or -C(O)-, and

[0180] q 1 、q 2 、q 3 、q 4 and q 5 are each independently an integer from 0 to 3.

[0181] Preferably, in the SHP2 target protein degrading compound according to the present invention, the part (SHP2 ligand) on the left side of the linker (-W-L-) has any of the following structures. When it has the following structures, not only is the SHP2 degrading activity excellent, but it is also suitable for various purposes of the present invention as described above.

[0182]

[0183]

[0184] Preferably, in the SHP2 target protein degrading compound according to the present invention, the linker (-W-L-) is any of the following linkers. When the compound has the linker as described below, not only is the SHP2 degrading activity excellent, but it is also suitable for various purposes of the present invention as described above, particularly metabolic stability, stability during storage, etc.

[0185]

[0186]

[0187] Preferably, in the SHP2 target protein degrading compound according to the present invention, the portion (VHL ligand) on the right side of the linker (-W-L-) has any of the following structures. When it has the following structures, the SHP2 degrading activity is excellent, and it is more suitable for various purposes of the present invention described above.

[0188]

[0189]

[0190]

[0191] One embodiment of the present invention provides various forms of an SHP2 target protein degrading compound, its optical isomers, stereoisomers, isotope variants, hydrates, solvates or pharmaceutically acceptable salts in combination with one of the following: (i) an SHP2 ligand portion, (ii) one of the linker (-W-L-) portions, and (iii) one of the VHL ligand portions.

[0192] Some non-limiting examples of the compounds of Formula 1 according to the present disclosure are the compounds prepared in Examples 1 to 124 below. Each example number corresponds to a compound number. For example, the number of the final compound prepared in Example 101 is Compound 101.

[0193] One embodiment of the present invention provides the compounds described in the following table, their optical isomers, stereoisomers, isotope variants, hydrates, solvates or pharmaceutically acceptable salts.

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] The terms "substituent", "radical", "group", "moiety" and "fragment" as used herein are used interchangeably.

[0209] If a substituent is described as "optionally substituted", this means that the substituent may be unsubstituted or substituted by one or more defined substituents. If the position that may be substituted is unsubstituted, the default substituent is hydrogen.

[0210] Unless the context clearly dictates otherwise, the term "alkyl" as used herein means a saturated straight-chain or branched-chain acyclic hydrocarbon having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms. "Lower alkyl" means an alkyl having from 1 to 4 carbon atoms. Representative saturated straight-chain alkyl groups include: -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, while saturated branched-chain alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, etc. In a preferred embodiment of the present invention, the alkyl is methyl, ethyl or n-propyl.

[0211] Unless the context clearly dictates otherwise, the term "alkynyl" as used herein means a straight-chain or branched-chain acyclic hydrocarbon having from 2 to 10 carbon atoms or from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Representative straight-chain or branched-chain (C 2 -C 10) The alkynyl groups are: -ethynyl, -propargyl, -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. These alkynyl groups may be optionally substituted.

[0212] As used herein, the term "alkoxy" means -O-(alkyl), including -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -OC(CH 3 ) 2 H, -OC(CH 3 ) 3 etc., where the alkyl is as defined above.

[0213] As used herein, when using the terms "C 1-6 ", "C1-6" or "C1-C6", it means the number of carbon atoms is 1 to 6. For example, C 1-6 alkyl means an alkyl having any integer number of carbon atoms from 1 to 6.

[0214] As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine or iodine. In a preferred embodiment of the present invention, the halogen is chlorine or fluorine.

[0215] As used herein, the term "haloalkyl" means an alkyl in which one or more hydrogen atoms are replaced by halogen atoms. For example, haloalkyl includes -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH2 -CBr 3 ,-CH 2 -CHBr 2 ,-CH 2 -CH 2 Br,-CH 2 -CC1 3 ,-CH 2 -CHC1 2 ,-CH 2 -CH 2 CI,-CH 2 -CI 3 ,-CH 2 -CHI 2 ,-CH 2 -CH 2 I, etc., where the alkyl group and the halogen are as described above. In a preferred embodiment of the present invention, the haloalkyl group is -CF 3 .

[0216] The term "hydroxyalkyl" as used herein means a straight-chain or branched-chain C 1-10 alkyl or C 1-6 alkyl substituted by one or more hydroxyl groups. Some examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0217] The term "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon atoms and hydrogen atoms and no carbon-carbon multiple bonds. Some examples of monocyclic rings include, but are not limited to, (C 3 -C 7 ) cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Some examples of polycyclic rings include, but are not limited to: fused bicyclic rings such as octahydroindene and decalin; spiro 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 unsubstituted or optionally substituted. In a preferred embodiment of the present invention, the cycloalkyl group is cyclopropyl.

[0218] The term "heterocyclic" or "heterocycloalkyl" means a 5- to 7-membered monocyclic saturated heterocyclic ring or a 7- to 12-membered bicyclic saturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized. Heterocycles include heteroaryls as defined above. Representative heterocycles include ethylene oxide, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidone, hydantoin, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, morpholine, tetrahydropyridine, and tetrahydropyrimidine. Heterocycles include bicyclic rings wherein a portion of the heterocycle is fused to a benzene or cyclopent-1,3-diene ring. The heterocycle may be attached through any heteroatom or carbon atom. Additionally, heterocycles include fused bicyclic rings, spiro rings, and bridged bicyclic rings wherein one or more carbon atoms of the above polycyclic rings are replaced by nitrogen, oxygen, or sulfur atoms. For example, when the heteroatom is nitrogen, these include but are not limited to: fused heterobicyclic rings such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, and decahydro-2,6-naphthyridine; spiro rings such as 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, 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, and 3,9-diazaspiro[5.5]undecane; 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, and 2,5-diazabicyclo[2.2.2]octane. In a preferred embodiment of the present invention, the heterocycle is any one selected from the following: azetidine, diazetidine, piperidine, piperazine, azaspiro[3.5]nonane, and diazabicyclo[3.2.1]octane.

[0219] The term "aryl" as used herein means a carbocyclic aromatic group containing 5 to 10 ring atoms. Some representative examples include but are not limited to phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthryl, fluorenyl, indenyl, and azulenyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0220] As used herein, the term "heteroaryl" means an aromatic heterocyclic ring having 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom, including both monocyclic rings and bicyclic ring systems. Representative heteroaryls are furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, azole, iso azole, thiazole, isothiazole, diazole, benzofuran, benzothiophene, quinoline, indole, benzo azole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, etc. In a preferred embodiment of the present invention, the heteroaryl is thiazole, pyridine, or pyrazine.

[0221] In this specification, * or means connected to another part.

[0222] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from the active compounds according to the present disclosure with relatively non-toxic acids or bases (depending on the specific substituents of those compounds). When the compounds of the present disclosure have relatively acidic groups, the base addition salts can be obtained by contacting the neutral compound with a sufficient amount of the desired base and a pure or inert solvent. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, organic amino salts, magnesium salts, etc. When the compounds of the present disclosure have relatively basic groups, the acid addition salts can be obtained by contacting the neutral compound with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include salts derived from non-toxic organic acids and non-toxic inorganic acids. The non-toxic organic acids include, but are not limited to, 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. The non-toxic inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc. In addition, pharmaceutically acceptable salts include salts of amino acids, such as arginine salts or their analogs, and pharmaceutically acceptable salts also include analogs of organic acids such as glucuronic acid or galacturonic acid. Some specific compounds of the present disclosure have both basic and acidic functional groups for the conversion of compounds having basic or acidic moieties (addition) salts. Other examples of salts are known from the literature known in the art to which the present invention pertains.

[0223] As used herein, the term "compound of the present disclosure" means not only each compound of Formula 1, but also its optical isomers, stereoisomers, isotopic variants, hydrates or solvates. And, even if the term "compound of the present invention" does not mention its pharmaceutically acceptable salts, the term also includes its salts. In one embodiment, the compounds of the present disclosure include stereochemically pure compounds, such as compounds that are substantially free (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee or greater than 99% ee) of other stereoisomers. In other words, if the compound or its salt according to Formula 1 of the present disclosure is a tautomer and / or stereoisomer (e.g., geometric isomer and conformational isomer), such separated isomers and their mixtures are also included within the scope of the present disclosure. If the compounds or their salts of the present disclosure have asymmetric carbons in their structures, their active optical isomers and their racemic mixtures are also included within the scope of the present disclosure.

[0224] As used herein, the term "isomer" means a compound having the same molecular formula but different in the nature or order of its atomic bonds or in the arrangement of its atoms in space.

[0225] As used herein, the term "stereoisomer" means an isomer in which its atoms have different arrangements in space.

[0226] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". For example, if a compound has an asymmetric center, an enantiomeric pair can be bonded to four different groups. Enantiomers can be characterized by the absolute configuration of the asymmetric center, described by the R and S sequence rules, or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (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".

[0227] The pure enantiomeric compounds used herein are those that are substantially free of the other enantiomer or stereoisomer of the compound. This state is referred to as enantiomeric excess. In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0228] Unless otherwise indicated, the term "enantiomerically pure (R)-compound" as used herein means at least about 95% by weight of the (R)-compound, no more than about 5% by weight of the (S), at least about 99% by weight of the (R)-compound and at most about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (R)-compound and at most about 0.1% by weight of the (S)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0229] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition may contain, for example, greater than or equal to about 95% by weight of the (R)-compound and at most about 5% by weight of the (S)-compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound may contain, for example, about 90% excipient by total weight and about 10% by weight of the enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such a composition may contain, for example, greater than or equal to about 95% by weight of the (S)-compound and at most about 5% by weight of the (R)-compound. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.

[0230] Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to cover both its individual enantiomers and mixtures, racemates, or other substances.

[0231] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and their corresponding mixtures. All geometric forms of the compounds described herein are contemplated and are within the scope of the present disclosure.

[0232] In certain embodiments, the compounds described herein have one or more chiral centers, each in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. All diastereomeric, enantiomeric, and epimeric forms of the compounds described herein are contemplated and are within the scope of the present disclosure.

[0233] In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used in 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 optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociation of the complex is preferred. In certain embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In certain embodiments, the diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on solubility differences. In certain embodiments, the optically pure enantiomers are recovered with the resolving agent.

[0234] In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the chemical formulas described herein.

[0235] Tautomers are compounds that are interconvertible by the movement of a hydrogen atom, which movement includes the conversion of a single bond to an adjacent double bond. In the bonding arrangements where tautomerism is possible, there is a chemical equilibrium of the tautomers. The tautomeric forms may be related to the optimal chemical reactivity and biological activity of the desired compound. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure. The exact ratio of tautomers varies according to several factors, including temperature, solvent, and pH.

[0236] As used herein, the term "isotope variant" means a compound that contains an unusual proportion of isotopes at one or more atoms that make up the compound. For example, an isotope variant of a compound can be radioactively labeled. For example, a hydrogen atom can be selected from hydrogen, deuterium, and tritium, and can include carbon-13( 13 C), nitrogen-15( 15 N), etc.

[0237] As used herein, the term "solvate" means a compound or a salt thereof according to the present disclosure, which further contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and acceptable for administration to humans in trace amounts.

[0238] As used herein, the term "hydrate" means a compound or a salt thereof according to the present disclosure, which further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0239] As used herein, the term "purified" means that when separated, the purity of the isolate is greater than 90%, in one embodiment greater than 95%, in another embodiment greater than 99%, and in another embodiment greater than 99.9%.

[0240] Medical uses and treatment methods of the compounds according to the present invention

[0241] One aspect of the present invention also provides a method for treating a disease or disorder in a subject suffering from or susceptible to a disease or disorder by administering to the subject a therapeutically effective amount of one or more of the compounds described above. In one embodiment, the treatment is prophylactic treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.

[0242] As used herein, the term "prevention" and its variants describe preventing the onset of symptoms or complications of a disease, disorder, or condition.

[0243] 1. Disease or disorder

[0244] The compounds of the present disclosure can be used for a variety of therapeutic or prophylactic uses (e.g., cancer). These compounds can be used to degrade SHP2 to reduce SHP2 activity and can also be used to treat SHP2-related diseases or prevent the progression of these diseases. Accordingly, one aspect of the present disclosure provides a method for degrading SHP2 in a cell. In this method, a cell is contacted with an effective amount of a compound of the present disclosure. In one embodiment, the cell is present in a subject. The method of the present disclosure includes administering to a subject in need of treatment or prophylaxis a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to the present disclosure.

[0245] In one embodiment, one aspect of the present invention provides a method for degrading SHP2 in a cell of an SHP2-related disease. For example, one embodiment of the present invention may provide a method for reducing SHP2 activity by degrading SHP2 in a cell of a subject suffering from an SHP2-related disease, which will be described later. In another embodiment of the present invention, the compounds of the present disclosure can be used to degrade SHP2 in cells of cancer, 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.

[0246] In another embodiment, the present disclosure provides a method for treating an SHP2-related disease, which includes administering to a subject a therapeutically effective amount of a compound of Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts. Such a method includes administering to a subject in need of treatment an amount of a compound of the present disclosure sufficient to degrade SHP2 (i.e., a therapeutically effective amount). In such a method, the compounds of the present disclosure can be administered to the subject in the form of a pharmaceutical composition as described herein.

[0247] In one embodiment of the present invention, the SHP2-related disease can be cancer, cancer metastasis, cardiovascular disease, immune disorder, or eye disorder.

[0248] In one embodiment of the present invention, the SHP2-related disease is cancer. For example, it can be any of the cancers described in Table 2 of International Patent Application Publication No. WO 2021 / 236775, but is not limited thereto. Specifically, the cancer can be at least one selected from the following: blood cancer, acute lymphoblastic 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, colon cancer, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma, sarcoma, papillary thyroid cancer, and combinations thereof. The disclosure of Table 2 of WO 2021 / 236775 is hereby incorporated by reference in its entirety. In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is a blood cancer. Exemplary blood cancers include, but are not limited to, the cancers listed in Table 3 of WO 2021 / 236775. The disclosure of Table 3 of WO 2021 / 236775 is hereby incorporated by reference in its entirety. In another embodiment, the blood cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia) or acute myeloid leukemia. In another embodiment, the cancer is leukemia, such as leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the cancer is NUT midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is head and neck cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is gastric cancer. In another embodiment, the cancer is pancreatic cancer. In another embodiment, the cancer is liver cancer. In another embodiment, the cancer is melanoma. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0249] In another embodiment, cancers according to the present invention are selected from 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 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 carcinoma.

[0250] That is, aspects of the present invention provide the medical use of the compound of Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts for treating or preventing the above diseases.

[0251] 2. Subjects

[0252] Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., and encompass mammals in utero.

[0253] In one embodiment, a suitable subject to be treated according to the present invention is a human.

[0254] 3. Administration and Dosage

[0255] The compounds of the present disclosure are generally administered in a therapeutically effective amount.

[0256] As used herein, "effective amount" refers to an amount of the compound of the present disclosure that is sufficient to prevent SHP2-related diseases, slow or minimize the progression of SHP2-related diseases, or provide a therapeutic benefit in the treatment or management of SHP2-related diseases. "Effective amount" also refers to an amount sufficient to inhibit or reduce SHP2 activity in vitro or in vivo.

[0257] The compounds of the present disclosure can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such a route, and in a dose effective for the intended treatment. In single or divided doses, an effective dose is generally about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg / day. Depending on age, species, and the disease or condition to be treated, dose levels below the lower limit of this range may be appropriate. In other cases, even larger doses may be used without harmful side effects. Larger doses can also be divided into several smaller doses for administration throughout the day.

[0258] 4. Some Other Embodiments Related to Medical Use

[0259] Based on the foregoing description, one embodiment of the present invention provides a method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts.

[0260] Based on the foregoing description, one embodiment 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, which comprises contacting the patient or the biological sample with a compound according to the present invention, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts.

[0261] Based on the foregoing description, one embodiment of the present invention provides the use of a compound according to the present invention, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts for producing a medicament for degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample.

[0262] Based on the foregoing description, one embodiment of the present invention provides the use of a compound according to the present invention, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts for producing a medicament for treating diseases related to Src homology 2 domain-containing phosphatase (SHP2).

[0263] The pharmaceutical composition of the compounds of the present disclosure

[0264] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or excipient. In one embodiment of the present invention, the pharmaceutical composition is for treating or preventing SHP2-related diseases, especially cancer, as described above.

[0265] The term "pharmaceutically acceptable" means suitable for use in pharmaceutical formulations and is generally considered safe for such use. The term also means that it has been officially approved by a national regulatory agency for such use, or is included in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0266] Pharmaceutical compositions, dosage forms and routes of administration

[0267] For treating the above diseases or conditions, the compounds described herein can be administered as follows:

[0268] 1. Oral administration

[0269] The compounds of the present disclosure can be administered orally (including by swallowing) such that the compound enters the gastrointestinal tract or is absorbed directly into the bloodstream from the mouth (e.g., buccally or sublingually).

[0270] Suitable compositions for oral administration include solid, liquid, gel, or powder formulations and have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0271] The compositions for oral administration can optionally be enteric-coated and can exhibit delayed or sustained release via the enteric coating. In other words, the compositions for oral administration according to the present invention can be formulations with an immediate release or modified release pattern.

[0272] Liquid formulations can include solutions, syrups, and suspensions, which can be used in soft or hard gelatin capsules. Such formulations can contain pharmaceutically acceptable carriers, e.g., water, ethanol, polyethylene glycol, cellulose, or oil. The formulations can also contain one or more emulsifiers and / or suspending agents.

[0273] In tablet dosage form, the amount of drug, the active ingredient, can be from about 0.05 wt% to about 95 wt% of the dosage form, more typically from about 2 wt% to about 50 wt%. Additionally, the tablets can contain a disintegrant, which accounts for from about 0.5 wt% to about 35 wt% of the dosage form, more typically about 2 wt% to about 25 wt%. Some examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0274] Suitable lubricants for tablets can be present in an amount from about 0.1 wt% to about 5 wt% and include, but are not limited to, talc, silica, stearic acid, calcium stearate, zinc stearate, or magnesium stearate, sodium stearyl fumarate, etc.

[0275] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0276] Suitable solubilizers for tablets can be present in an amount from about 0.1 wt% to about 3 wt% and include, but are not limited to, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR TM (Nikkol), fatty acid esters, Gelucire TM 、mono / diglycerides of caprylic / capric acid, sorbitan fatty acid esters, and Solutol HSTM

[0277] 2. Parenteral administration

[0278] The compounds of the present disclosure can be administered directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous, intra-arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needles and needleless syringes) and infusion methods.

[0279] Most parenteral preparations are liquid compositions, and the liquid compositions are aqueous solutions containing the active ingredient, salts, buffers, isotonic agents, etc. according to the present invention.

[0280] Parenteral preparations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These preparations can be used with suitable carriers such as sterile water.

[0281] 3. Topical administration

[0282] The compounds of the present disclosure can be topically applied to the skin or administered transdermally. Preparations for such topical administration can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration preparations can include water, alcohols, mineral oils, glycerin, polyethylene glycols, etc. Topical administration can also be carried out by electroporation, iontophoresis, phonophoresis, etc.

[0283] The terms "combined administration" and "co-administration step" or "combination therapy" refer to simultaneous administration (administering two or more therapeutic agents simultaneously) and staggered administration (administering one or more therapeutic agents at a different time from the administration of additional therapeutic agents or medicaments), provided that the therapeutic agents are present in the patient's body to a certain extent, preferably in an effective amount, simultaneously. In certain preferred embodiments, one or more of the compounds of the present disclosure described herein are co-administered in combination with at least one additional bioactive agent, particularly a bioactive agent including an anticancer agent. In certain preferred embodiments, the co-administration of the compounds results in synergistic activity and / or therapy, including anticancer therapy.

[0284] Beneficial effects

[0285] The present disclosure provides compounds capable of exhibiting various pharmacological activities due to very good SHP2 degradation activity, pharmaceutical compositions containing the compounds as active ingredients, their medical uses (especially for cancer or tumors), and methods of treatment or prevention, which include administering the compounds to a subject in need of such treatment or prevention. The compounds according to the present disclosure can provide compounds having excellent SHP2 degradation activity by introducing an SHP2 binding ligand to a VHL ligand via a linker of the present disclosure, and thus can provide an effective treatment option for tumor cells, especially cancers having a KRAS mutation. In addition, the compounds according to the present disclosure are excellent in various aspects, such as SHP2 degradation activity, plasma stability, metabolic stability, stability during storage, pharmacological properties, and physicochemical properties. Detailed Description of the Invention

[0286] Hereinafter, examples and the like will be described in detail to assist in understanding the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following embodiments. The embodiments of the present invention are provided to more fully illustrate the present invention to those of ordinary skill in the art to which the present invention pertains.

[0287] Preparation of the compounds of the present invention

[0288] Hereinafter, methods for synthesizing some compounds of the present disclosure will be described, and other compounds not mentioned below can be prepared in a similar manner by replacing starting materials, intermediates, and / or reactants.

[0289] Intermediate 1. tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0290]

[0291] Step 1: Synthesis of 3-(tert-butylthio)-2-chloroaniline

[0292] 2-Chloro-3-fluoroaniline (5 g, 34.34 mmol), 2-methylpropan-2-thiol (11.6 ml, 103.02 mmol), and Cs 2 CO 3 (22 g, 68.68 mmol) were suspended in DMF (60 ml) and then stirred at 20 °C for 16 hours. The reaction solution was diluted with EtOAc (400 ml) and washed with distilled water (150 ml × 3) and brine (150 ml × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7.8 g (quantitative) of a brown oil.

[0293] Step 2: Synthesis of 3-Amino-2-chlorobenzenethiol

[0294] Suspend 3-(tert-butylthio)-2-chloroaniline (7.8 g, 34.34 mmol) in concentrated HCl (126 ml), and then stir at 90 °C for 6 hours. Cool the reaction solution, filter the resulting solid and dry it to obtain 5.3 g (97%) of a milky white solid.

[0295] Step 3: Synthesis of 2-Chloro-3-((5-chloropyrazin-2-yl)thio)aniline

[0296] Suspend 3-Amino-2-chlorobenzenethiol (5.3 g, 33.20 mmol), 2-Bromo-5-chloropyrazine (6.4 g, 33.20 mmol), Pd 2 (dba) 3 (304 mg, 0.33 mmol), Xantphos (384 mg, 0.66 mmol) and DIPEA (11.6 ml, 66.40 mmol) in 1,4-dioxane (60 ml), and then stir at 95 °C for 1 hour. Filter the reaction solution and concentrate the filtrate under reduced pressure. Subject the resulting residue to MPLC (3% to 15% EtOAc / hexane) to obtain 5.93 g (66%) of a milky white solid.

[0297] Step 4: Synthesis of tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0298] Suspend 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) in NMP (9 ml), and then stir at 130 °C for 16 hours. Add distilled water (150 ml) to the reaction solution, and then extract with EtOAc (150 ml). Wash the organic layer with brine (150 ml), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Subject the resulting residue to MPLC (3% to 30% EtOAc / hexane) to obtain 3.84 g (90%) of a milky white solid.

[0299] Intermediates 2 to 5 were synthesized using the same method as used for the synthesis of Intermediate 1.

[0300]

[0301]

[0302] Intermediate 6. ((1-(5-(3-Amino-2-chlorophenoxy)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0303]

[0304] Step 1: Synthesis of 2-Chloro-5-(2-chloro-3-nitrophenoxy)pyrazine

[0305] Suspend 2,5-dichloropyrazine (1.72 g, 11.50 mmol), 2-chloro-3-nitrophenol (2.00 g, 11.50 mmol) and K 2 CO 3 (3.19 g, 23.00 mmol) in DMF (20 ml), and then stir at 100 °C for 4 hours. Terminate the reaction solution by adding saturated NH 4 Cl (aqueous solution), dilute with brine (200 ml), extract with EtOAc (400 ml), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 20% EtOAc / hexane) to obtain 1.91 g (58%) of a white solid.

[0306] Step 2: Synthesis of 2-Chloro-3-((5-chloropyrazin-2-yl)oxy)aniline

[0307] Suspend 2-chloro-5-(2-chloro-3-nitrophenoxy)pyrazine (1.91 g, 6.68 mmol) in THF (100 ml), add saturated NH 4 Cl (aqueous solution), and stir the mixture at 60 °C for 48 hours. Cool the reaction solution to room temperature, filter the resulting dark suspension, and dilute with EtOAc (100 ml). Extract the organic layer, wash with brine (50 ml × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 50% EtOAc / hexane) to obtain 1.28 g (75%) of an off-white solid.

[0308] Step 3: Synthesis of ((1-(5-(3-Amino-2-chlorophenoxy)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0309] 2-Chloro-3-((5-chloropyrazin-2-yl)oxy)aniline (500 mg, 1.95 mmol) was suspended in NMP (2.5 ml). Then, ((4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (535 mg, 2.34 mmol) and DIPEA (3.40 ml, 19.50 mmol) were added, and the mixture was stirred at 130 °C for one day. The reaction solution 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 subjected to MPLC (0% to 50% EtOAc / hexane) to give 316 mg (36%) of a white solid.

[0310] Intermediate 7. (R)-N-((3S,4S)-8-(5-(Indolin-4-ylthio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide

[0311]

[0312] Step 1: Synthesis of 4-bromoindoline

[0313] 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 solution was concentrated under reduced pressure to give a residue. After adjusting the pH to 10 with 2M NaOH (aqueous solution), distilled water (50 ml) was added, and then the mixture was extracted with EtOAc (50 ml × 3). The organic layer was washed with brine (50 ml × 2) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to give 1.90 g (crude) of a yellow oil.

[0314] Step 2: Synthesis of tert-butyl 4-bromoindoline-1-carboxylate

[0315] 4-Bromoindoline (1.90 g, 9.59 mmol) was suspended in DCM (30 ml), di-tert-butyl dicarbonate (3.14 g, 14.39 mmol) and TEA (4.01 ml, 28.78 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with distilled water (30 ml) and brine (30 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 6% EtOAc / petroleum ether) to give 2.80 g (91%) of a yellow oil.

[0316] 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-mercaptopropionate (3.05 ml, 28.17 mmol), TEA (3.92 ml, 28.17 mmol), Xantphos (1.09 g, 1.88 mmol), and Pd 2 (dba) 3 (0.86 g, 0.94 mmol) were suspended in toluene (56 ml). And, degassing and N 2 2 purging were repeated three times, and then the mixture was stirred at 100 °C for 16 h. Distilled water (100 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (80 ml × 3), and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 10% EtOAc / petroleum ether) to give 1.46 g (46%) of a yellow solid.

[0317] Step 4: Synthesis of potassium 1-(tert-butoxycarbonyl)indoline-4-thiolate

[0318] tert-Butyl 4-((3-methoxy-3-oxopropyl)thio)indoline-1-carboxylate (1.45 g, 4.30 mmol) was suspended in THF (29 ml), t-BuOK (1 M, 8.59 ml) was added at -65 °C, and the mixture was stirred at the same temperature for 2 h. The reaction solution was concentrated under reduced pressure to give 1.20 g (crude) of a yellow liquid.

[0319] Step 5: Synthesis of tert-butyl 4-((5-chloropyrazin-2-yl)thio)indoline-1-carboxylate

[0320] 2,5-Dichloropyrazine (1.30 g, 8.73 mmol) was suspended in THF (12 ml), potassium 1-(tert-butoxycarbonyl)indoline-4-thiolate (1.20 g, 4.15 mmol) was added, and the mixture was stirred at room temperature for 2 h. After saturated NH 4 4Cl (aqueous solution) (30 ml) was added to the reaction solution, the mixture was extracted with EtOAc (20 ml × 3), and 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 subjected to MPLC (0% to 15% EtOAc / petroleum ether) to give 601 mg (40%) of a white solid.

[0321] Step 6: Synthesis of tert-butyl 4-((5-((3S,4S)-4-(((R)-tert-butanesulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)indoline-1-carboxylate

[0322] Suspend (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)propan-2-sulfinamide (181 mg, 0.66 mmol) in NMP (2 ml), add DIPEA (0.23 ml, 1.32 mmol), and add tert-butyl 4-((5-chloropyrazin-2-yl)thio)indoline-1-carboxylate (120 mg, 0.33 mmol). Stir the mixture at 130 °C for 5 h. After adding saturated NH 4 Cl (aqueous solution) to the reaction solution, extract it with EtOAc (30 ml × 3), wash the organic layer with brine (20 ml × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 100% EtOAc / hexane) to obtain 116 mg (58%) of a colorless oil.

[0323] Step 7: Synthesis of (R)-N-((3S,4S)-8-(5-(indoline-4-ylthio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropan-2-sulfinamide

[0324] Suspend tert-butyl 4-((5-((3S,4S)-4-(((R)-tert-butanesulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)indoline-1-carboxylate (116 mg, 0.19 mmol) in DCM (10 ml), add TFA (2.5 ml), and stir the mixture at room temperature for 1 h. Concentrate the reaction solution under reduced pressure, dilute with EtOAc (50 ml), and basify the organic layer with 1 M NaOH (aqueous solution), wash with brine (30 ml), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 10% MeOH / DCM + 0.1% NH 4 OH) to obtain 71 mg (73%) of a colorless oil.

[0325] Intermediate 8. ((1-(5-((3,4-dihydro-2H-benzo[b][1,4] oxazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0326]

[0327] Step 1: Synthesis of tert-Butyl 8-bromo-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-carboxylate

[0328] 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), and TEA (5.85 ml, 42.04 mmol) and DMAP (171 mg, 1.40 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was washed with distilled water (30 ml) and brine (30 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 20% EtOAc / petroleum ether) to give 3.40 g (77%) of a yellow oil.

[0329] Step 2: Synthesis of tert-Butyl 8-((3-methoxy-3-oxopropyl)thio)-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-carboxylate

[0330] 8-Bromo-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-carboxylate tert-butyl ester (3 g, 9.55 mmol), methyl 3-mercaptopropionate (2.59 ml, 23.87 mmol), TEA (3.99 ml, 28.65 mmol), Xantphos (1.11 g, 1.91 mmol), and Pd 2 (dba) 3 (0.87 g, 0.95 mmol) were suspended in toluene (30 ml), degassed, and N 2 2 purge was repeated three times, and the mixture was stirred at 100 °C for 12 hours. Distilled water (40 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (30 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% to 25% EtOAc / petroleum ether) to give 2.40 g (68%) of a yellow oil.

[0331] Step 3: Synthesis of Potassium 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine-8-thiolate

[0332] 8-((3-Methoxy-3-oxopropyl)thio)-2,3-dihydro-4H-benzo[b][1,4] Tert-butyl oxazine-4-carboxylate (1.45 g, 4.30 mmol) was suspended in THF (29 ml), t-BuOK (1 M, 8.59 ml) was added at -65°C, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1.20 g (crude) of a yellow liquid.

[0333] Step 4: 8-((5-chloropyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4] Synthesis of tert-Butyl Oxazine-4-carboxylate

[0334] 2,5-Dichloropyrazine (3.51 g, 23.57 mmol) was suspended in THF (20 ml), and 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4] Oxazine-8-thiol potassium (2.40 g, 7.86 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Distilled water (20 ml) was added to the reaction solution, and extracted with EtOAc (20 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 subjected to MPLC (0% to 30% EtOAc / petroleum ether) to obtain 1.70 g (56%) of a yellow solid.

[0335] Step 5: 8-((5-(4-(((tert-Butyloxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4] Synthesis of tert-Butyl Oxazine-4-carboxylate

[0336] N-[(4-methyl-4-piperidinyl)methyl]carbamic acid tert-butyl ester (1.12 g, 4.92 mmol), 8-((5-chloropyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4] Oxazine-4-carboxylic acid tert-butyl ester (1.70 g, 4.48 mmol) and K 2 CO 3 (1.86 g, 13.43 mmol) was suspended in DMSO (20 ml), degassed and N 2 The purging was repeated three times, and the mixture was stirred at 80°C for 3 hours. 4After adding Cl (aqueous solution) to the reaction solution, it was extracted with EtOAc (20 ml × 2). Then, 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 subjected to MPLC (0% to 30% EtOAc / hexane) to obtain 2.00 g (80%) of a yellow solid.

[0337] Step 6: Synthesis of (1-(5-((3,4-dihydro-2H-benzo[b][1,4] piperazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methanamine

[0338] 8-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2,3-dihydro-4H-benzo[b][1,4] piperazine-4-carboxylic acid tert-butyl ester (2 g, 3.50 mmol) was suspended in MeOH (25 ml), 4M HCl in MeOH (8.75 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with EtOAc (80 ml), and the organic layer was basified with 1M NaOH (aqueous solution), washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (20% to 70% EtOAc / petroleum ether) to obtain 780 mg (60%) of a yellow solid.

[0339] Step 7: Synthesis of ((1-(5-((3,4-dihydro-2H-benzo[b][1,4] piperazin-8-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0340] (1-(5-((3,4-dihydro-2H-benzo[b][1,4] piperazin-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 solution was concentrated under reduced pressure, saturated NH 4 Cl (aqueous solution) was added, and extraction was carried out 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 subjected to preparative HPLC (column: Waters Xbridge PrepOBD C18 150 mm × 40 mm × 10 um; mobile phase: [H2 O(0.1% NH 4 HCO 3 )-ACN]; B%: 40% to 70%, 15 minutes), to obtain 290 mg (32%) of a yellow solid.

[0341] Intermediate 9 was synthesized using the same method as that used for the synthesis of Intermediate 8.

[0342]

[0343] Intermediate 10. ((1-(5-((3-Fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0344]

[0345] Step 1: Synthesis of ethyl 3-((5-chloropyrazin-2-yl)thio)propionate

[0346] 2,5-Dichloropyrazine (500 mg, 3.36 mmol) and ethyl 3-mercaptopropionate (455 mg, 3.39 mmol) were suspended in DMF (2.5 ml), K 2 CO 3 (464 mg, 3.36 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Distilled water (10 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (5 ml × 5). The organic layer was washed with brine (5 ml × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 25% EtOAc / petroleum ether) to obtain 593 mg (68%) of a colorless oil.

[0347] Step 2: Synthesis of potassium 5-chloropyrazine-2-thiol

[0348] Ethyl 3-((5-chloropyrazin-2-yl)thio)propionate (1.60 g, 6.49 mmol) was suspended in THF (25 ml), and t-BuOK (1.46 g, 12.97 mmol) was added at -30 °C, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1.20 g (crude) of an orange solid.

[0349] Step 3: Synthesis of 3,3-difluoro-4-iodoindolin-2-one

[0350] 4-Iodoindoline-2,3-dione (10 g, 36.63 mmol) was suspended in DCM (350 ml), DAST (17.71 g, 109.88 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 24 h. Distilled water (100 ml) was added to the reaction solution, and the mixture was extracted with DCM (50 ml × 3). The organic layer was washed with brine (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. At room temperature, the resulting residue was recrystallized from PE for 30 min to give 11.20 g (93%) of a brown solid.

[0351] Step 4: Synthesis of 3,3-difluoro-4-iodoindoline

[0352] 3,3-Difluoro-4-iodoindolin-2-one (5 g, 16.95 mmol) was suspended in THF (30 ml), and BH 3 -THF (1 M, 59.32 ml) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 h. 10% Citric acid (aqueous solution) (100 ml) was added to the reaction solution at 0 °C, distilled water (200 ml) was added, and the mixture was then extracted 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 give 4.76 g (crude) of a yellow oil.

[0353] Step 5: Synthesis of 1-(3,3-difluoro-4-iodoindolin-1-yl)ethan-1-one

[0354] 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, and the mixture was stirred at the same temperature for 2 h. Distilled water (150 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (80 ml × 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 subjected to MPLC (0% to 25% EtOAc / petroleum ether) to give 2.87 g (51%) of a green solid.

[0355] Step 6: Synthesis of 1-(4-((5-chloropyrazin-2-yl)thio)-3,3-difluoroindolin-1-yl)ethan-1-one

[0356] 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 2 (dba) 3 (213 mg, 0.23 mmol) were suspended in 1,4-dioxane (25 ml), degassed and purged with N 2 three times, and then the mixture was stirred at 70 °C for 5 h. Distilled water (80 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (30 ml × 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 subjected to MPLC (0% to 25% EtOAc / petroleum ether) to give 830 mg (42%) of a yellow solid.

[0357] 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

[0358] 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), and K 2 CO 3 (1.01 g, 7.29 mmol) was added, and the mixture was stirred at 80 °C for 12 h. Distilled water (20 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (10 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 subjected to MPLC (0% to 40% EtOAc / petroleum ether) to give 510 mg (39%) of a yellow solid.

[0359] Step 8: Synthesis of tert-butyl ((1-(5-((3-fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0360] 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 H 2In O (2.7 ml), NaOH (134.91 mg, 3.37 mmol) was added and stirred at 50 °C for 4 h. The reaction solution was concentrated under reduced pressure, saturated NH 4 Cl (aqueous solution) (5 ml) was added, extracted with EtOAc (5 ml × 3), and 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% to 45% EtOAc / petroleum ether) to give 250 mg (62%) of a yellow solid.

[0361] Intermediate 11. ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0362]

[0363] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 3-hydroxyazetidine-1-carboxylate

[0364] 3-Hydroxyazetidine hydrochloride (1 g, 9.13 mmol) and Na 2 CO 3 (2.9 g, 27.38 mmol) were suspended in a mixed solvent of H 2 O:1,4-dioxane (1:1 (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 solution and 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 subjected to MPLC (1% to 60% EtOAc / hexane) to give 2.52 g (93%) of a white solid.

[0365] Step 2: Synthesis of (9H-fluoren-9-yl)methyl 3-oxoazetidine-1-carboxylate

[0366] (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 h. After adding saturated Na 2 S 2 O 3After adding the aqueous solution (40 ml) to the reaction solution, it was extracted 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 subjected to MPLC (1% to 25% EtOAc / hexane) to give 1.1 g (100%) of a white solid.

[0367] 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

[0368] ((1-(5-((3-Amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (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) 4 (1.9 ml, 6.47 mmol) were suspended in THF (12 ml), and the mixture was stirred at 70 °C for 16 h. NaBH 4 (306 mg, 8.08 mmol) and MeOH (4 ml) were added, and the mixture was stirred at room temperature for 1 h. Distilled water (50 ml) was added to the reaction solution, extracted with DCM (50 ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 15% EtOAc / DCM) to give 1.62 g (68%) of an off-white solid.

[0369] Step 4: Synthesis of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0370] (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 Et 2 NH (6.3 ml, 60.70 mmol) were suspended in DCM (6.3 ml), and the mixture was stirred at room temperature for 3 h. Distilled water (20 ml) was added to the reaction mixture, and it was extracted with DCM (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 739 mg (crude) of an off-white solid.

[0371] Intermediates 12 to 16 were synthesized using the same method as that used for the synthesis of Intermediate 11.

[0372]

[0373]

[0374] Intermediate 17. tert-Butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0375]

[0376] Step 1: Synthesis of (9H-fluoren-9-yl)methyl 4-hydroxypiperidine-1-carboxylate

[0377] 4-Hydroxypiperidine (1 g, 9.89 mmol) and Na 2 CO 3 were suspended in a mixed solvent of H 2 O:1,4-dioxane (1:1, 82 ml), and the mixture was stirred at 0 °C for 10 minutes. Fmoc-Cl (2.56 g, 9.89 mmol) was added and the mixture was stirred at room temperature for 16 hours. Distilled water (30 ml) was added to the reaction solution and the mixture was 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 subjected to MPLC (20% to 70% EtOAc / hexane) to give 2.95 g (92%) of a white solid.

[0378] Step 2: Synthesis of (9H-fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate

[0379] (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 the mixture was stirred at room temperature for 3 hours. After saturated Na 2 S 2 O 3 (aqueous solution) (40 ml) was added to the reaction mixture, the mixture was extracted 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 subjected to MPLC (0% to 35% EtOAc / hexane) to give 2.76 g (quantitative) of a white solid.

[0380] 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

[0381] ((1-(5-((3-Amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 1, 150 mg, 0.32 mmol), (9H-Fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate (260 mg, 0.81 mmol), NaBH(OAc) 3 (206 mg, 0.97 mmol) and acetic acid (0.3 ml) were suspended in a mixed solvent of ACN:DCM (1:1, 2.1 ml), and the mixture was stirred at room temperature for 4 hours. After adding saturated NaHCO 3 (aqueous solution) (10 ml) to the reaction solution, it was extracted with DCM (10 ml × 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (1% to 40% EtOAc / hexane) to obtain 334 mg (crude) of a milky white solid.

[0382] Step 4: Synthesis of ((1-(5-((2-Chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0383] (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 the mixture was stirred at room temperature for 2 hours. Distilled water (10 ml) was added to the reaction solution, and the mixture was 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 subjected to MPLC (amine-silica, 0% to 3% MeOH / DCM) to obtain 80.1 mg (45%, two steps) of a milky white solid.

[0384] Intermediates 18 to 24 were synthesized using the same method as used for the synthesis of Intermediate 17.

[0385]

[0386]

[0387] Intermediate 25. ((4-Methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4] tert-Butyl ((4-methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]pyrazin-8-yl)thio)pyrazin-2-yl)piperidin-4-yl)methyl)carbamate

[0388]

[0389] 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] pyrazin-4-yl)piperidine-1-carboxylate

[0390] ((1-(5-((3,4-Dihydro-2H-benzo[b][1,4] (tert-Butyl ((1-(5-((3,4-dihydro-2H-benzo[b][1,4]pyrazin-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 h. After adding saturated NaHCO 3 (aqueous solution) (5 ml) to the reaction solution, it was 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% to 40% EtOAc / hexane) to give 37 mg (75%) of a milky solid.

[0391] Step 2: Synthesis of tert-Butyl ((4-methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4] pyrazin-8-yl)thio)pyrazin-2-yl)piperidin-4-yl)methyl)carbamate

[0392] ((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] (40 mg, 0.05 mmol) of piperidine-1-carboxylate (4-(piperidin-4-yl)piperidine-1-carboxylate) was suspended in DCM (0.8 ml), and piperidine (0.1 ml, 1.03 mmol) was added. The mixture was stirred at room temperature for 2 hours. Distilled water (10 ml) was added to the reaction solution, and the mixture was 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 subjected to MPLC (amine-silica, 0% to 3% MeOH / DCM) to obtain 24 mg (84%) of a white solid.

[0393] Intermediate 26 was synthesized using the same method as that used for the synthesis of Intermediate 25.

[0394]

[0395] 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

[0396]

[0397] Step 1: Synthesis of tert-Butyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate

[0398] 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 the mixture was stirred at room temperature for 3 hours. Distilled water (50 ml) was added to the reaction solution, and the 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 subjected to MPLC (0% to 30% EtOAc / hexane) to obtain 5.89 g (61%) of a white solid.

[0399] Step 2: Synthesis of Piperidin-4-yl 2-nitrobenzenesulfonate Hydrochloride

[0400] tert-Butyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate (300 mg, 0.78 mmol) was suspended in DCM (5.2 ml), 4 M HCl in dioxane (1.9 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 243 mg (quantitative) of a white solid.

[0401] Step 3: Synthesis of 2-(Trimethylsilyl)ethyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate

[0402] 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), 1-[2-(Trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (221 mg, 0.85 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Distilled water (20 ml) was added to the reaction solution, and the mixture was extracted with DCM (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 40% EtOAc / hexane) to give 327 mg (98%) of a white solid.

[0403] 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

[0404] ((1-(5-((3-Fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 10, 10 mg, 0.02 mmol), 2-(Trimethylsilyl)ethyl 4-(((2-nitrophenyl)sulfonyl)oxy)piperidine-1-carboxylate (27 mg, 0.06 mmol) and Cs 2 CO 3 (14 mg, 0.04 mmol) were suspended in DMF (0.05 ml), and the mixture was stirred at 70 °C for 16 hours. Distilled water (5 ml) was added to the reaction solution, and it was 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% to 40% EtOAc / hexane), (0% to 10% EtOAc / DCM) to give 10.6 mg (crude) of an off-white solid.

[0405] Step 5: Synthesis of ((1-(5-((3-Fluoro-1-(piperidin-4-yl)-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0406] 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), TBAF (1.0 M in THF, 30 μl, 0.03 mmol) was added, and the mixture was stirred at 50 °C for 1 h. Distilled water (5 ml) was added to the reaction solution, and the mixture 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 (amine-silica, 0% to 5% MeOH / DCM) to afford 3.7 mg (25%, two steps) of an off-white solid.

[0407] Intermediate 28. ((1-(5-((2-(Azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0408]

[0409] Step 1: Synthesis of tert-Butyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate

[0410] 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 the mixture was stirred at 100 °C for 2 h. Distilled water (30 ml) was added to the reaction solution, and the mixture 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 subjected to MPLC (1% to 15% EtOAc / hexane) to afford 540 mg (68%) of a white solid.

[0411] Step 2: Synthesis of N-(Azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine

[0412] 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), TFA (2.6 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to afford 800 mg (quantitative) of a brown oil.

[0413] Step 3: Synthesis of 2-(Trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate

[0414] Suspend N-(Azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine (800 mg, 1.07 mmol) and TEA (0.60 ml, 4.30 mmol) in DCM (3.8 ml), add 1-[2-(Trimethylsilyl)ethoxycarbonyl-oxy]pyrrolidine-2,5-dione (279 mg, 1.07 mmol) at 0 °C, and stir the mixture at room temperature for 1 h. Add distilled water (15 ml) to the reaction solution, and extract the mixture with DCM (20 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (1% to 15% EtOAc / hexane) to afford 468 mg (96%) of a colorless oil.

[0415] Step 4: Synthesis of tert-Butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0416] Suspend 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) in NMP (2 ml), and stir at 130 °C for 1 h. Add distilled water (20 ml) to the reaction solution and extract with EtOAc (30 ml). Wash the organic layer with brine (20 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (1% to 15% EtOAc / hexane) to afford 705 mg (87%) of a yellow solid.

[0417] Step 5: Synthesis of Methyl 3-((5-(4-(((tert-Butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propionate

[0418] Suspend 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), Pd 2 (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 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (1% to 35% EtOAc / hexane) to afford 680 mg (88%) of a yellow oil.

[0419] Step 6: Synthesis of sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate

[0420] Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propionate (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. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to afford 278 mg (crude) of a yellow solid.

[0421] 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

[0422] 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 2 (dba) 3 (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 solution and the mixture was 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 resulting residue was subjected to MPLC (1% to 40% EtOAc / hexane) to afford 278 mg (95%) of a yellow solid.

[0423] 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

[0424] Suspend 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) in THF (0.43 ml) and stir the mixture at 50 °C for 2 h. Add distilled water (5 ml) to the reaction solution, extract with DCM (5 ml), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give 28.5 mg (96%) of a milky white solid.

[0425] Intermediates 29 to 34 are synthesized using the same method as used for the synthesis of Intermediate 28.

[0426]

[0427]

[0428] 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

[0429]

[0430] Step 1: Synthesis of (1S,3S)-Methyl 3-((3-chloro-4-iodopyridin-2-yl)amino)cyclobutane-1-carboxylate

[0431] Suspend 3-chloro-2-fluoro-4-iodopyridine (1 g, 3.88 mmol), (1S,3S)-methyl 3-aminocyclobutane-1-carboxylate hydrochloride (644 mg, 3.88 mmol), and DIPEA (2 ml, 11.65 mmol) in DMSO (12 ml) and stir the mixture at 100 °C for 4 h. Add distilled water (30 ml) to the reaction solution and extract with EtOAc (30 ml × 2). Wash the organic layer with brine (30 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 10% EtOAc / hexane) to give 600 mg (42%) of a yellow solid.

[0432] 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

[0433] 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), Pd 2 (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 solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 50% EtOAc / hexane) to give 680 mg (94%) of an off-white solid.

[0434] 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

[0435] (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 mixed solvent of THF:H 2 O:MeOH (4:1:1, 2 ml) and stirred at room temperature for 2 h. The reaction solution was adjusted to pH 1 to 2 with 1 M HCl (aqueous solution) and 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 subjected to MPLC (0% to 66% EtOAc / hexane) to give 241 mg (66%) of an orange solid.

[0436] Intermediates 36 to 48 were synthesized using the same method as used for the synthesis of intermediate 35.

[0437]

[0438]

[0439]

[0440] 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

[0441]

[0442] Step 1: Synthesis of methyl 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylate

[0443] Suspend 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) in DMF (75 ml) and stir at 80 °C for 2 h. Add distilled water (50 ml) to the reaction solution and extract with EtOAc (50 ml × 2). Wash the organic layer with brine (50 ml × 2), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 15% EtOAc / hexane) to give 7.18 g (96%) of a yellow solid.

[0444] Step 2: Synthesis of tert-Butyl ((1-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0445] Suspend methyl 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylate (3 g, 6.77 mmol) in EtOH (16 ml) and add NaBH 4 (640 mg, 16.92 mmol) and CaCl 2 (1.5 mg, 13.53 mmol) at 0 °C and stir the mixture at room temperature for 16 h. After adding saturated NH 4 Cl (aqueous solution) (40 ml) to the reaction solution, extract it with EtOAc (40 ml). Wash the organic layer with brine (40 ml), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Subject the resulting residue to MPLC (1% to 20% EtOAc / hexane) to give 1.08 g (39%) of a yellow solid.

[0446] Step 3: Synthesis of Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propionate

[0447] ((1-(5-Bromo-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)tert-butyl carbamate (1.07 g, 2.58 mmol), methyl 3-mercaptopropionate (0.31 ml, 2.83 mmol), Pd 2 (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 solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (1% to 40% EtOAc / hexane) to give 1.07 g (82%) of a yellow oil.

[0448] Step 4: Synthesis of Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiol

[0449] Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propionate (167 mg, 0.37 mmol) was suspended in THF (1.2 ml) and NaOEt (approx. 20% in EtOH, 0.16 ml, 0.40 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to give 143 mg (crude) of a yellow solid.

[0450] 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

[0451] 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-thiol (143 mg, crude, 0.37 mmol), Pd 2 (dba) 3(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 the mixture was stirred at 90 °C for 16 hours. Distilled water (15 ml) was added to the reaction solution, and the mixture was 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 resulting residue was subjected to MPLC (1% to 20% EtOAc / hexane) to afford 71 mg (55%) of a yellow solid.

[0452] Step 6: Synthesis of ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0453] 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 the mixture was stirred at 50 °C for 2 hours. Distilled water (5 ml) was added to the reaction solution, extracted with DCM (5 ml), and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 51 mg (crude) of an off-white solid was obtained.

[0454] Intermediate 50 was synthesized using the same method as that used for the synthesis of Intermediate 49.

[0455]

[0456] 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

[0457]

[0458] 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

[0459] 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), Pd 2 (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 the mixture was stirred at 90 °C for 16 h. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 50% EtOAc / hexane) to give 104 mg (74%) of an off-white solid.

[0460] 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

[0461] 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 mixed solvent of THF:H 2 O (3:1, 0.72 ml), and the mixture was stirred at room temperature for 2 h. The reaction solution was adjusted to pH 1 to 2 with 1 M HCl (aqueous solution) and 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.

[0462] Intermediates 52 to 54 were synthesized using the same method as that used for the synthesis of Intermediate 51.

[0463]

[0464] Intermediate 55. tert-Butyl ((1-(5-((2-chloro-3-(piperidin-4-yl)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0465]

[0466] Step 1: Synthesis of tert-butyl 4-(3-amino-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0467] 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) 2 (79 mg, 0.10 mmol) and Cs 2 CO 3 (631 mg, 1.94 mmol) were suspended in a mixed solvent of 1,4-dioxane:H 2 O (4:1, 4 ml) and stirred at 90 °C for 2 h. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (1% to 10% EtOAc / hexane) to afford 270 mg (90%) of a yellow gum.

[0468] Step 2: Synthesis of tert-butyl 4-(3-amino-2-chlorophenyl)piperidine-1-carboxylate

[0469] 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), Pd / C (23 mg, 10% purity) was added, and the mixture was stirred at room temperature under a hydrogen stream for 3.5 h. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (1% to 10% EtOAc / hexane) to afford 41.8 mg (21%) of a colorless oil.

[0470] Step 3: Synthesis of tert-butyl 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylate

[0471] tert-Butyl 4-(3-amino-2-chlorophenyl)piperidine-1-carboxylate (41.8 mg, 0.13 mmol) was suspended in a mixed solvent of 2 M HCl (aqueous solution):dioxane (2:1, 0.87 ml), sodium nitrite (10 mg, 0.15 mmol) and H 2 O (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 solution and the mixture was stirred at room temperature for 10 min. Distilled water (5 ml) was added to the reaction solution and then the mixture was 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% to 10% EtOAc / hexane) to afford 24.2 mg (43%) of a brown oil.

[0472] Step 4: Synthesis of 4-(2-chloro-3-iodophenyl)piperidine hydrochloride

[0473] Suspend 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylic acid tert-butyl ester (24.2 mg, 0.06 mmol) in DCM (0.57 ml), add 4 M HCl in dioxane (0.14 ml), and stir the mixture at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure to obtain 19.8 mg (quantitative) of a white solid.

[0474] Step 5: Synthesis of 2-(trimethylsilyl)ethyl 4-(2-chloro-3-iodophenyl)piperidine-1-carboxylate

[0475] Suspend 4-(2-chloro-3-iodophenyl)piperidine hydrochloride (19.8 mg, 0.06 mmol) and TEA (32 μl, 0.23 mmol) in DCM (0.2 ml), add 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (14.9 mg, 0.06 mmol), and stir the mixture at room temperature for 1 hour. Add distilled water (5 ml) to the reaction solution, and extract the mixture with DCM (5 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 10% EtOAc / hexane) to obtain 22.6 mg (85%) of a brown oil.

[0476] 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

[0477] Suspend 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), Pd 2 (dba) 3 (2.2 mg, 0.002 mmol), Xantphos (2.8 mg, 0.04 mmol) and DIPEA (17 μl, 0.10 mmol) in 1,4-dioxane (0.11 ml), and stir at 90 °C for 1 hour. Add distilled water (5 ml) to the reaction solution, and extract the mixture with EtOAc (5 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 30% EtOAc / hexane) to obtain 16.5 mg (50%) of a milky white solid.

[0478] 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

[0479] Suspend 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) in THF (0.05 ml), add TBAF (1.0 M in THF, 30 μl, 0.03 mmol), and stir the mixture at 50 °C for 1 hour. Add distilled water (5 ml) to the reaction solution and then extract with DCM (5 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 16 mg (quantitative) of an off-white solid.

[0480] 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

[0481]

[0482] Step 1: Synthesis of tert-butyl (2,3-dichloropyridin-4-yl)carbamate

[0483] Suspend 2,3-dichloro-4-iodopyridine (500 mg, 1.83 mmol), tert-butyl carbamate (257 mg, 2.19 mmol), Pd 2 (dba) 3 (84 mg, 0.09 mmol), Xantphos (106 mg, 0.18 mmol) and Cs 2 CO 3 (1.19 g, 3.65 mmol) in toluene (8 ml) and stir it at 90 °C for 16 hours. Add distilled water (30 ml) to the reaction solution and extract with EtOAc (30 ml). Wash the organic layer with brine (30 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 5% EtOAc / hexane) to obtain 380 mg (79%) of an off-white solid.

[0484] Step 2: Synthesis of tert-butyl 4-(3-amino-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0485] 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) 2 (220 mg, 0.27 mmol) and Cs 2 CO 3 (882 mg, 2.71 mmol) were suspended in a mixed solvent of 1,4-dioxane:H 2 O (4:1, 5.6 ml) and the reaction was carried out in a microwave reactor at 130 °C for 1.5 h. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 30% EtOAc / hexane) to give 369 mg (67%) of a brown gum.

[0486] Step 3: Synthesis of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)piperidine-1-carboxylate

[0487] 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), platinum(IV) oxide (21 mg) was added, and the mixture was stirred under a hydrogen stream at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 10% EtOAc / hexane) to give 204 mg (55%) of a white solid.

[0488] Step 4: Synthesis of 4-(2-chloro-3-iodophenyl)piperidine trifluoroacetate

[0489] 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), TFA (1.86 ml) was added, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to give 415 mg (quantitative) of a brown oil.

[0490] Step 5: Synthesis of tert-butyl 4-(4-amino-3-chloropyridin-2-yl)piperidine-1-carboxylate

[0491] 4-(2-Chloro-3-iodophenyl)piperidine trifluoroacetate (415 mg, 0.50 mmol) and TEA (0.28 ml, 1.98 mmol) were suspended in DCM (1.8 ml), di-tert-butyl dicarbonate (113 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Distilled water (10 ml) was added to the reaction solution, and the mixture was 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% to 40% EtOAc / hexane) to give 147 mg (95%) of a white solid.

[0492] Step 6: Synthesis of 3-chloro-4-iodo-2-(piperidin-4-yl)pyridine

[0493] 4-(4-Amino-3-chloropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.19 mmol) was suspended in 50% sulfuric acid (aqueous solution) (0.96 ml), sodium nitrite (14.6 mg, 0.21 mmol) and H 2 O (0.1 ml) were added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. KI (160 mg, 0.96 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was adjusted to pH 8 with saturated NaHCO 3 (aqueous solution) and 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 subjected to MPLC (amine-silica, 0% to 3% MeOH / DCM) to give 29.8 mg (48%) of an off-white solid.

[0494] Step 7: Synthesis of 2-(trimethylsilyl)ethyl 4-(3-chloro-4-iodopyridin-2-yl)piperidine-1-carboxylate

[0495] 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), 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (28.3 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 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 subjected to MPLC (0% to 15% EtOAc / hexane) to give 34.9 mg (72%) of a white solid.

[0496] 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

[0497] 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), Pd 2 (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 h. Distilled water (5 ml) was added to the reaction solution and the mixture was 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% to 40% EtOAc / hexane) to give 43 mg (83%) of an off-white solid.

[0498] Step 9: Synthesis of ((1-(5-((3-chloro-2-(piperidin-4-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester

[0499] 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), TBAF (1.0 M in THF, 0.19 ml, 0.19 mmol) was added and the mixture was stirred at 50 °C for 2 h. Distilled water (5 ml) was added to the reaction solution and 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 subjected to MPLC (amine-silica, 0% to 3% MeOH / DCM) to give 32 mg (97%) of an off-white solid.

[0500] Intermediate 57. 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid

[0501]

[0502] Step 1: Synthesis of tert-Butyl (3-Bromo-2-chlorophenyl)(tert-butoxycarbonyl)carbamate

[0503] Suspend 3-bromo-2-chloroaniline (300 mg, 1.45 mmol) and DMAP (18 mg, 0.14 mmol) in THF (2.6 ml), add di-tert-butyl dicarbonate (951 mg, 4.36 mmol), and heat the mixture under reflux for 1 hour. Add distilled water (20 ml) to the reaction mixture and extract the mixture with EtOAc (20 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 15% EtOAc / hexane) to obtain 582 mg (98%) of a white solid.

[0504] Step 2: Synthesis of tert-Butyl (3-Bromo-2-chlorophenyl)carbamate

[0505] Suspend tert-butyl (3-bromo-2-chlorophenyl)(tert-butoxycarbonyl)carbamate (550 mg, 1.35 mmol) and K 2 CO 3 (561 mg, 4.06 mmol) in MeOH (2.4 ml) and heat under reflux for 2 hours. Add distilled water (20 ml) to the reaction solution and extract it with EtOAc (20 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 5% EtOAc / hexane) to obtain 582 mg (75%) of a milky white solid.

[0506] Step 3: Synthesis of Ethyl 1-(3-((tert-butoxycarbonyl)amino)-2-chlorophenyl)piperidine-4-carboxylate

[0507] Suspend 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 Cs 2 CO 3 (516 mg, 1.59 mmol) in 1,4-dioxane (2.6 ml) and stir it at 90 °C for 16 hours. Add distilled water (20 ml) to the reaction solution and extract the mixture with EtOAc (20 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 10% EtOAc / hexane) to obtain 254 mg (84%) of a milky white solid.

[0508] Step 4: Synthesis of Ethyl 1-(3-amino-2-chlorophenyl)piperidine-4-carboxylate

[0509] Suspend ethyl 1-(3-((tert-butoxycarbonyl)amino)-2-chlorophenyl)piperidine-4-carboxylate (254 mg, 0.66 mmol) in DCM (6.6 ml), add TFA (1.65 ml), and stir the mixture at room temperature for 1 h. Adjust the reaction solution to pH 8 with saturated NaHCO 3 (aqueous solution), and extract with DCM (10 × 2 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 185 mg (99%) of a milky white solid.

[0510] Step 5: Synthesis of Ethyl 1-(2-chloro-3-iodophenyl)piperidine-4-carboxylate

[0511] Suspend ethyl 1-(3-amino-2-chlorophenyl)piperidine-4-carboxylate (100 mg, 0.35 mmol) in a mixed solvent of 2 M HCl (aqueous solution):dioxane (2:1, 2.29 ml), and add sodium nitrite (26.8 mg, 0.39 mmol) and H 2 O (0.08 ml) at 0 °C, and stir the mixture at 0 °C for 15 min. Add NaI (58 mg, 0.39 mmol) to the reaction solution, and stir the mixture at room temperature for 30 min. Add distilled water (5 ml) to the reaction solution, and extract the mixture with EtOAc (5 ml). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 5% EtOAc / hexane) to obtain 86 mg (62%) of a brown oil.

[0512] 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

[0513] Suspend 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), Pd 2 (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 the mixture was stirred at 90 °C for 1 hour. Distilled water (5 ml) was added to the reaction solution, and the mixture was 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% to 30% EtOAc / hexane) to give 88 mg (67%) of a milky white solid.

[0514] 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

[0515] 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:H 2 O (3:2:1, 1 ml), LiOH·H 2 O (12 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 2 with 1 M HCl (aqueous solution), and 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 a milky white solid.

[0516] Intermediates 58 to 60 were synthesized using the same method as used for the synthesis of Intermediate 57.

[0517]

[0518] 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

[0519]

[0520] Step 1: Synthesis of (2S,4R)-methyl 1 - ((S)-2 - ((tert - butoxycarbonyl)amino)-3,3 - dimethylbutanoyl)-4 - hydroxypyrrolidine - 2 - carboxylate

[0521] (2S,4R)-Methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (7.85 g, 43.23 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic 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 h. The reaction solution was washed with saturated NH 4 Cl (aqueous solution) (300 ml) and saturated NaHCO 3 (aqueous solution) (300 ml), and 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% to 5% MeOH / DCM) to give 11 g (71%) of an off-white solid.

[0522] Step 2: Synthesis of (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid

[0523] (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 mixed solvent of H 2 O:THF (1:1, 10 ml), and it was stirred at room temperature for 3 h. The reaction solution was adjusted to pH 1 to 2 with 1 M HCl (aqueous solution) and extracted with EtOAc (15 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 680 mg (91%) of a white solid.

[0524] Step 3: Synthesis of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile

[0525] 4-Bromo-2-hydroxybenzonitrile (2 g, 10.15 mmol) and 4-methylthiazole (1.83 ml, 20.20 mmol) were suspended in DMAC (40 ml), KOAc (1.98 g, 20.20 mmol) and Pd(OAc) 2(45 mg, 0.20 mmol), and the mixture was heated and refluxed for 16 h. Distilled water (100 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (50 ml × 2). The organic layer was washed with brine (50 ml × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0% to 50% EtOAc / hexane) to give 980 mg (45%) of an off-white solid.

[0526] Step 4: Synthesis of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

[0527] 2-Hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (864 mg, 3.99 mmol) was suspended in THF (22 ml), LAH (2.0 M in THF, 8 ml, 15.98 mmol) was added dropwise at 0 °C, and the mixture was heated and refluxed for 3 h. After the temperature of the reaction solution was cooled to 0 °C, distilled water (0.5 ml) was added dropwise, neutralized with Rochelle salt solution (20 ml), and filtered through a Celite filter. The filtrate was subjected to MPLC (DCM:MeOH:NH4OH = 15:1:0.1) to give 416 mg (47%) of a yellow solid.

[0528] 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

[0529] 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 solution, and the mixture 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 subjected to MPLC (0% to 20% MeOH / DCM) to give 898 mg (87%) of a pale yellow solid.

[0530] 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

[0531] Suspend ((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)carbamic acid tert-butyl ester (885 mg, 1.62 mmol) in DCM (30 ml), add 4 M HCl in dioxane (8 ml), and stir the mixture at room temperature for 2 h. Neutralize the reaction solution by adding saturated NaHCO 3 (aqueous solution) (20 ml), and then extract with DCM (10 ml × 2). Wash the organic layer with brine (10 ml × 2), dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Subject the resulting residue to MPLC (amine-silica, 0% to 10% MeOH / DCM) to obtain 522 mg (72%) of a yellow solid.

[0532] Step 7: Synthesis of (2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0533] Suspend (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-fluorocyclopropanecarboxylic acid (92.6 mg, 0.89 mmol), HATU (381 mg, 0.89 mmol) and DIPEA (0.8 ml, 4.47 mmol) in DMF (4 ml), and stir at room temperature for 16 h. Add distilled water (10 ml) to the reaction solution and extract with EtOAc (11 ml × 2). Wash the organic layer with brine (10 ml × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (0% to 10% MeOH / DCM) to obtain 377 mg (79%) of a white solid.

[0534] Intermediates 62 to 64 were synthesized using the same method as used for the synthesis of Intermediate 61.

[0535]

[0536] 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

[0537]

[0538] Step 1: Synthesis of (1S,4S)-methyl 4-(((2-nitrophenyl)sulfonyl)oxy)cyclohexane-1-carboxylate

[0539] (1S,4S)-Methyl 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) was dissolved in DCM (25 ml), and this solution was slowly added to the above suspension at 0 °C and stirred at room temperature for 2 hours. Distilled water (200 ml) was added to the reaction solution, and the 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 subjected to MPLC (0% to 20% EtOAc / hexane) to give 7.14 g (82%) of a colorless oil.

[0540] 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

[0541] (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 Cs 2 CO 3(1.8 g, 5.63 mmol) was suspended in DMF (60 ml) and stirred at 50 °C for 16 h. Distilled water (100 ml) was added to the reaction solution, and the mixture was 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% to 5% MeOH / DCM) to afford 1.3 g (70%) of a milky solid.

[0542] 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

[0543] (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 mixed solvent of THF:H 2 O:MeOH (4:1:1, 12 ml), and the mixture was stirred at room temperature for 4 h. The reaction solution was adjusted to pH 1 to 2 with 1 M HCl (aqueous solution), and 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 subjected to MPLC (0% to 20% MeOH / DCM) to afford 896 mg (49%) of a milky solid.

[0544] Intermediates 66 and 67 were synthesized using the same method as that used for the synthesis of Intermediate 65.

[0545]

[0546] 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

[0547]

[0548] (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), and K 2 CO 3 (272 mg, 1.971 mmol) and KI (218 mg, 1.314 mmol) were added, and the mixture was stirred at 70 °C for 16 h. Distilled water (20 ml) was added to the reaction solution, and the mixture 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% to 5% MeOH / DCM) to give 234 mg (60%) of an off-white solid.

[0549] Intermediate 69 was synthesized using the same method as that used for the synthesis of Intermediate 68.

[0550]

[0551] 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

[0552]

[0553] 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

[0554] (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 K 2 CO 3(46 mg, 0.37 mmol) was suspended in DMF (0.15 ml) and stirred at 70 °C for 16 h. Distilled water (10 ml) was added to the reaction solution, and then it was 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% to 5% MeOH / DCM) to give 67 mg (84%) of an off-white solid.

[0555] 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

[0556] 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 mixed solvent of THF:MeOH:H 2 O (3:2:1, 0.26 ml) and stirred at room temperature for 2 h. The reaction solution was adjusted to pH 2 with 1 M HCl (aqueous solution) and concentrated under reduced pressure to afford 87 mg (crude) of an off-white solid.

[0557] 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

[0558]

[0559] Step 1: Synthesis of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate

[0560] 1-(2-Hydroxyethyl)piperazine (2.8 ml, 23.04 mmol) was suspended in THF (23 ml), Boc 2 O (5.8 ml, 25.35 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction solution was quenched by adding saturated NH 4It was neutralized with Cl (aqueous solution) (50 ml), extracted with DCM (50 ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 5.6 g (quantitative) of a colorless oil.

[0561] Step 2: Synthesis of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate

[0562] 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), and 2-nitrobenzenesulfonyl chloride (5.4 g, 24.66 mmol) dissolved in DCM (25 ml) was slowly added at 0 °C, and the mixture was stirred at room temperature for 2 hours. Distilled water (200 ml) was added to the reaction solution, and it 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 subjected to MPLC (0% to 50% EtOAc / hexane) to obtain 2.9 g (49%) of a yellow solid.

[0563] 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

[0564] 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 Cs 2 CO 3 (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 solution, and it was 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% to 5% MeOH / DCM) to obtain 833 mg (57%) of a milky white solid.

[0565] 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

[0566] Suspend 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) in DCM (9 ml), add 4 M HCl in dioxane (2 ml), and stir the mixture at room temperature for 1 h. Neutralize the reaction solution by adding saturated NaHCO 3 (aqueous solution) (30 ml), extract with DCM (3 ml × 2), and dry the organic layer over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the resulting residue to MPLC (amine-silica, 0% to 5% MeOH / DCM) to give 739 mg (quantitative) of an off-white solid.

[0567] Intermediates 72 to 79 were synthesized using the same method as used for the synthesis of Intermediate 71. In the case of Intermediates 72 to 79, o-nosylate was obtained as a result of Step 2.

[0568]

[0569]

[0570]

[0571] 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

[0572]

[0573] Step 1: Synthesis of 2-(trimethylsilyl)ethyl carbamate

[0574] Suspend 2-(trimethylsilyl)ethanol (3 g, 25.4 mmol) in toluene (42 ml), add 1,1'-carbonyldiimidazole (8.23 g, 30.48 mmol), and stir the mixture at room temperature for 5 h. Add ammonium hydroxide (H 228% in O (8.3 mL), and the mixture was stirred at room temperature for 16 h. Distilled water (50 mL) was added to the reaction solution, and it was extracted with EtOAc (50 mL). The organic layer was washed with 1 M HCl (aqueous solution) (30 mL) and saturated NH 4 Cl (aqueous solution) (30 mL), and dried over anhydrous magnesium sulfate. The residue was filtered and concentrated under reduced pressure to afford 4.17 g (100%) of a white solid.

[0575] 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 h. After adding saturated NaHCO 3 (aqueous solution) (50 mL) to the reaction solution, it was extracted with DCM (50 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0 to 15% EtOAc / hexane) to give 1.79 g (83%) of a white solid.

[0576] Step 3: Synthesis of 2-(trimethylsilyl)ethyl 2-hydroxy-4-(4-methylthiazol-5-yl)benzylcarbamate

[0577] 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), KOAc (1.02 g, 10.34 mmol) and Pd(OAc) 2 (58 mg, 0.26 mmol) were added, and the mixture was heated and refluxed for 16 h. Distilled water (50 mL) was added to the reaction mixture, and it was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL × 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0 to 40% EtOAc / hexane) to give 546 mg (30%) of an off-white solid.

[0578] Step 4: Synthesis of tert-butyl 4-(5-(4-methylthiazol-5-yl)-2-((((2-(trimethylsilyl)ethoxy)carbonyl)amino)methyl)phenoxy)piperidine-1-carboxylate

[0579] 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 Cs 2 CO 3 (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 solution and the mixture was 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 obtained was subjected to MPLC (0 to 30% EtOAc / hexane) to give 927 g (88%) of a white solid.

[0580] Step 5: Synthesis of tert-butyl 4-(2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate

[0581] 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 h. Distilled water (10 ml) was added to the reaction mixture and the mixture was extracted with DCM (10 ml). The organic layer was dried over anhydrous sodium sulfate. The resulting mixture was filtered and concentrated under reduced pressure to give 110 mg (crude) of an off-white solid.

[0582] Step 6: Synthesis of (2S,4R)-benzyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0583] (2S,4R)-Benzyl 4-hydroxypyrrolidine-2-carboxylate (10 g, 38.8 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (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 solution was washed with distilled water (100 ml), extracted with DCM (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0 to 50% EtOAc / hexane) to give 9.42 g (56%) of an off-white solid.

[0584] Step 7: Synthesis of (2S,4R)-benzyl 1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0585] (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), 4M HCl in dioxane (22 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to give 3.7 g (crude) of a white solid.

[0586] Step 8: Synthesis of (2S,4R)-benzyl 1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0587] (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 h. The reaction solution was washed with distilled water (100 ml), extracted with DCM (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0 to 10% MeOH / DCM) to give 112 mg (41%) of a white solid.

[0588] Step 9: Synthesis of (2S,4R)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid

[0589] Suspend (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) in a mixed solvent of H 2 O:THF:MeOH (1:1:1, 0.52 ml), and stir at room temperature for 2 hours. Adjust the reaction solution to pH 1 to 2 with 1 M HCl (aqueous solution), and concentrate under reduced pressure to obtain 151 mg (crude) of a milky white solid.

[0590] 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

[0591] Suspend 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) in DMF (0.2 ml) and DCM (0.56 ml), and stir at room temperature for 16 hours. Wash the reaction solution with distilled water (10 ml), extract with DCM (10 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the obtained residue to MPLC (0 to 5% MeOH / DCM) to obtain 79 mg (41%) of a milky white solid.

[0592] 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

[0593] 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), 4M HCl in dioxane (0.29 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford 68 mg (crude) of an off-white solid.

[0594] Intermediates 81 to 83 were synthesized using the same method as used for the synthesis of Intermediate 80.

[0595]

[0596]

[0597] Intermediate 84. (2S,4R)-4-Hydroxy-1-(3-methyl-2-(3-methylis oxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1)

[0598]

[0599] Step 1: Synthesis of benzyl (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylis oxazol-5-yl)butanoyl)pyrrolidine-2-carboxylate (P1)

[0600] 3-Methyl-2-(3-methylis oxazol-5-yl)butyric acid (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), and 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 hours. 1M HCl (aqueous solution) was added to the reaction solution, and the mixture was extracted with EtOAc (200 ml × 2). The organic layer was washed with saturated NaHCO 3 (aqueous solution) (200 ml) and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0 to 100% EtOAc / petroleum ether) to afford a mixture. The mixture obtained was subjected to SFC (column: REGIS (S,S) WHELK-O1 (250 mm × 25 mm × 10 μm); mobile phase: [CO 2-EtOH (0.1% NH 4 (OH)); B%: 25%, isocratic elution mode) for purification to obtain 1.50 g (16%, 100% ee) of yellow solid P1 and 2.00 g (20%, 98.8% ee) of its isomer P2.

[0601] Step 2: Synthesis of (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylis oxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid (P1)

[0602] Suspend (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylis oxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid benzyl ester (P1) (1.52 g, 3.88 mmol) in MeOH (15 ml), add Pd / C (150 mg, 10% purity), and stir the mixture under a hydrogen stream (15 psi) at room temperature for 2 hours. Filter the reaction solution through celite, and concentrate the filtrate under reduced pressure to obtain 995 mg (65%) of a pale yellow solid.

[0603] Step 3: Synthesis of tert-butyl 4-(2-(((2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylis oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylate (P1)

[0604] Suspend 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-methylis oxazol-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) in DCM (2.2 ml), and stir at room temperature for 16 hours. Wash the reaction solution with distilled water (50 ml), extract with DCM (50 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Subject the obtained residue to MPLC (0 to 5% MeOH / DCM) to obtain 488 mg (81%) of a milky white solid.

[0605] Step 4: (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylis 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)

[0606] 4-(2-(((2S,4R)-4-Hydroxy-1-(3-methyl-2-(3-methylis (pyrazol-5-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester (P1) (488 mg, 0.72 mmol) was suspended in DCM (7.2 ml), 4 M HCl in dioxane (1.8 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized by adding saturated NaHCO 3 (aqueous solution) (20 ml), extracted with DCM (20 ml × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (amine-silica, 0 to 5% MeOH / DCM) to give 375 mg (90%) of a yellow solid.

[0607] Intermediate 85 was synthesized using the same method as used for the synthesis of Intermediate 84.

[0608]

[0609] 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)

[0610]

[0611] Step 1: Synthesis of Ethyl 3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoate

[0612] Ethyl 2-bromo-3-methylbutanoate (500 mg, 2.39 mmol) and 4-methylpyrazole (255 mg, 3.11 mmol) were suspended in THF (4 ml), and NaH (60% dispersion in mineral oil, 124 mg, 3.11 mmol) was slowly added at 0 °C, and the mixture was stirred for 48 hours. Distilled water (30 ml) was added to the reaction solution, and the mixture was extracted with EtOAc (30 ml × 2). Thereafter, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0 to 20% EtOAc / hexane) to give 311 mg (62%) of a colorless oil.

[0613] Step 2: Synthesis of 3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butyric acid

[0614] Ethyl 3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butyrate (295 mg, 1.40 mmol) and LiOH (88 mg, 2.10 mmol) were suspended in a mixed solvent of H 2 O:THF (1:1, 6 ml), and stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 1 to 2 with 1 M HCl (aqueous solution), and extracted with EtOAc (15 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 278 mg (crude) of a colorless oil.

[0615] Step 3: Synthesis of (2S,4R)-methyl 4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxylate

[0616] 3-Methyl-2-(4-methyl-1H-pyrazol-1-yl)butyric acid (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 solution was washed with distilled water (15 ml) and extracted with DCM (15 ml). Then, the solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0 to 5% MeOH / DCM) to obtain 71 mg (40%) of a colorless oil.

[0617] Step 4: Synthesis of (2S,4R)-4-hydroxy-1-(3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid

[0618] (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 2 M NaOH (aqueous solution) (0.2 ml) were suspended in THF (1 ml), and stirred at 50 °C for 2 hours. The reaction solution was adjusted to pH 1 to 2 with 1 M HCl (aqueous solution), and extracted with EtOAc (10 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 21 mg (crude) of a colorless oil.

[0619] 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)

[0620] Suspend 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) in DCM (0.2 ml) and stir at room temperature for 16 h. Wash the reaction solution with distilled water (10 ml) and extract with DCM (10 ml). Then, dry the solution over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Subject the obtained residue to MPLC (0 to 5% MeOH / DCM) to afford 14 mg (40%) of white solid P1 and 9 mg (25%) of its isomer P2.

[0621] 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)

[0622] Suspend (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 Cs 2 CO 3 (72 mg, 0.22 mmol) in DMF (1.1 ml) and stir at 50 °C for 16 h. Add distilled water (10 ml) to the reaction solution and extract with EtOAc (10 ml × 2). Wash the organic layer with brine (10 ml), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Subject the obtained residue to MPLC (0 to 10% MeOH / DCM) to afford 62 mg (80%) of a milky white solid.

[0623] 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)

[0624] Suspend 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) in DCM (0.91 ml), add 4 M HCl in dioxane (0.23 ml), and stir the mixture at room temperature for 1 h. Neutralize the reaction solution by adding saturated NaHCO 3 (aqueous solution) (15 ml), and extract with DCM (15 ml × 2). After drying over anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure, 50 mg (crude) of a milky white solid is obtained.

[0625] Synthesize Intermediate 87 using the same method as used for the synthesis of Intermediate 86.

[0626]

[0627] 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

[0628]

[0629] Step 1: Synthesis of benzyl (2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine-2-carboxylate

[0630] (2S,4R)-4-Hydroxypyrrolidine-2-carboxylic acid benzyl ester 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 h. Distilled water (15 ml) was added to the reaction solution and the mixture was extracted with DCM (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0 to 40% EtOAc / hexane) to give 249 mg (51%) of an off-white solid.

[0631] Step 2: Synthesis of (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester hydrochloride

[0632] (2S,4R)-1-((tert-Butoxycarbonyl)-L-valyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (120 mg, 0.29 mmol) was suspended in DCM (2.8 ml), 4 M HCl in dioxane (0.71 ml) was added and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to give 114.7 mg (quantitative) of a white solid.

[0633] Step 3: Synthesis of trifluoromethanesulfonyl azide

[0634] Sodium azide (56 mg, 0.86 mmol) was suspended in pyridine (0.84 ml), trifluoromethanesulfonic anhydride (0.14 ml, 0.86 mmol) was added at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction solution was used immediately for the next reaction.

[0635] Step 4: Synthesis of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester

[0636] Copper(II) sulfate pentahydrate (10.7 mg, 0.04 mmol) and (2S,4R)-1-(L-valyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester hydrochloride (114.7 mg, 0.29 mmol) were suspended in H 2To O (0.2 ml), trifluoromethanesulfonyl azide (0.86 mmol) was added, and the mixture was stirred at room temperature for 16 hours. 1 M HCl (aqueous solution) (10 ml) was added to the reaction solution, and then it was 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 resulting product was filtered and concentrated under reduced pressure to obtain 101 mg (quantitative) of a colorless oil.

[0637] Step 5: Synthesis of (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester

[0638] (2S,4R)-1-((S)-2-Azido-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (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 mixed solvent of H 2 O:DCM:DMSO (2:1:1, 3 ml), and stirred at room temperature for 2 hours. Distilled water (10 ml) was added to the reaction solution, and then it was 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 obtained residue was subjected to MPLC (0 to 3% MeOH / DCM) to obtain 83.5 mg (71%) of a white solid.

[0639] 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

[0640] (2S,4R)-1-((S)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (83.5 mg, 0.20 mmol) was suspended in MeOH (0.5 ml), Pd / C (2.4 mg, 5% purity) was added, and the mixture was stirred at room temperature under a hydrogen stream for 5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 71 mg (quantitative) of a white solid.

[0641] 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

[0642] 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 h. The reaction solution was washed with distilled water (10 ml), extracted with DCM (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0 to 5% MeOH / DCM) to give 54 mg (76%) of a white solid.

[0643] 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

[0644] 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), 4M HCl in dioxane (0.19 ml) was added and the mixture was stirred at room temperature for 1 h. The reaction solution was neutralized by adding saturated NaHCO 3 (aqueous solution) (10 ml) and extracted with DCM (10 ml × 2). After drying over anhydrous magnesium sulfate, filtering and concentrating under reduced pressure, 45 mg (97%) of the title compound as an off-white solid was obtained.

[0645] Intermediate 89 was synthesized using the same method as that used for the synthesis of Intermediate 88.

[0646]

[0647] 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

[0648]

[0649] Step 1: Synthesis of N'-(1,1-dimethoxypropane-2-ylidene)-4-methylbenzenesulfonylhydrazide

[0650] Suspend 1,1-dimethoxypropan-2-one (34 g, 287 mmol) and 4-methylbenzenesulfonylhydrazide (48.7 g, 261 mmol) in MeOH (340 ml). Repeat degassing and N 2 purging three times, and stir the mixture at room temperature for 1 h. Use the reaction solution immediately for the next reaction.

[0651] Step 2: Synthesis of ethyl (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butyrate

[0652] Suspend N'-(1,1-dimethoxypropane-2-ylidene)-4-methylbenzenesulfonylhydrazide (74.92 g, 261 mmol) in MeOH (340 ml), and add L-valine ethyl ester hydrochloride (57 g, 313 mmol) and TEA (36.4 ml, 261 mmol). Repeat degassing and N2 purging three times. Then, stir the mixture at 75 °C for 12 h. Concentrate the reaction solution under reduced pressure, and subject the residue to MPLC (2% to 20% EtOAc / petroleum ether) to obtain 39.20 g (69%) of a yellow liquid.

[0653] Step 3: Synthesis of (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butyric acid

[0654] Suspend ethyl (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butyrate (10 g, 47.3 mmol) in distilled water (50 ml), add concentrated HCl (50 ml), and stir the mixture at 50 °C for 5 h. Concentrate the reaction solution under reduced pressure to obtain 12.80 g (crude) of a yellow gum.

[0655] 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

[0656] (S)-3-Methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butyric acid (6.20 g, 27.2 mmol), (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester hydrochloride (7.03 g, 27.2 mmol) and DIPEA (14.2 ml, 81.8 mmol) were suspended in DMF (60 ml), and degassing and N 2 purge were repeated three times. HATU (12.4 g, 32.7 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction solution was diluted with distilled water (150 ml) and extracted with EtOAc (100 ml × 3). The organic layer was washed with distilled water (150 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was subjected to MPLC (2% to 10% EtOAc / petroleum ether), and the resulting mixture was purified by preparative HPLC (column: Phenomenex luna C18 (250 mm × 70 mm × 10 μm); mobile phase: [H 2 O(FA)-ACN]; B%: 30% to 60%, 20 min) to obtain 1.70 g (16%, 100% ee) of a white solid.

[0657] 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

[0658] (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid benzyl ester (1.70 g, 4.40 mmol) was suspended in MeOH (15 ml), Pd / C (170 mg, 10% purity) was added, and the mixture was stirred at room temperature under a hydrogen stream (15 psi) for 3 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 1.05 g (81%) of a white solid.

[0659] 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

[0660] 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 h. The reaction solution was washed with distilled water (15 ml) and extracted with DCM (15 ml). After drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, the obtained residue was subjected to MPLC (0 to 5% MeOH / DCM) to afford 268 mg (83%) of an off-white solid.

[0661] 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

[0662] 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), 4 M HCl in dioxane (0.98 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was neutralized by addition of saturated NaHCO 3 (aqueous solution) (20 ml) and extracted with DCM (20 ml × 2). After drying over anhydrous magnesium sulfate, filtering and concentrating under reduced pressure, 226 mg (crude) of an off-white solid was obtained.

[0663] Intermediates 91 to 93 were synthesized using the same method as used for the synthesis of Intermediate 90.

[0664]

[0665]

[0666] 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

[0667]

[0668] 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

[0669] Suspend 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) in DMF (0.1 ml). Add KI (13 mg, 0.12 mmol) and K 2 CO 3 (24 mg, 0.17 mmol), and stir at 70 °C for 16 h. Add distilled water (10 ml) to the reaction solution, and extract the mixture with EtOAc (10 ml × 2). Wash the organic layer with brine (10 ml × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the obtained residue to MPLC (amine-silica, 0 to 2% MeOH / DCM) to give 49 mg (72%) of an off-white solid.

[0670] 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)hexyloxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0671] ((1-(5-((2-Chloro-3-(((1-(6-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-4-hydroxy-1H-pyrrole-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)carbamic acid tert-butyl ester (43 mg, 0.04 mmol) was suspended in DCM (1.0 ml), 4M HCl in dioxane (0.1 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was neutralized by adding saturated NaHCO 3 (aqueous solution) (10 ml), and then 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 resulting residue was subjected to MPLC (amine-silica, 0 to 5% MeOH / DCM) to give 30 mg (78%) of an off-white solid.

[0672] 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

[0673]

[0674] Using 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) and (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) respectively to replace tert-butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 19) 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), Example 2 was synthesized in the same manner as in Example 1.

[0675] 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

[0676]

[0677] 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) and (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) respectively to replace tert-butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 19) 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), Example 3 was synthesized in the same manner as in Example 1.

[0678] 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

[0679]

[0680] Step 1: Synthesis of methyl (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycinate

[0681] ((1-(5-((3-Amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 1, 30 mg, 0.06 mmol), methyl bromoacetate (33 mg, 0.21 mmol), K 2 CO 3 (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 solution, and then it was 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 obtained residue was subjected to MPLC (1% to 30% EtOAc / hexane) to give 28.6 mg (82%) of an off-white solid.

[0682] Step 2: Synthesis of (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycine

[0683] (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycine methyl ester (28.6 mg, 0.05 mmol) and LiOH (4.5 mg, 0.11 mmol) were suspended in H 2In a mixed solvent of THF (2:1, 0.4 ml), and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 2 with 1 M HCl (aqueous solution), and extracted with DCM (10 ml × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0 to 12% MeOH / DCM) to give 20.3 mg (73%) of an off-white solid.

[0684] 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

[0685] (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-methylthiazol-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 solution, and 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 obtained residue was subjected to MPLC (0 to 7% MeOH / DCM) to give 24 mg (57%) of an off-white solid.

[0686] 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

[0687] ((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)carbamic acid tert-butyl ester (24 mg, 0.02 mmol) was suspended in DCM (2.1 ml), 4M HCl in dioxane (0.052 ml) was added, and the mixture was stirred at room temperature for 2 h. After adding saturated NaHCO 3 (aqueous solution) (5 ml), it was extracted with DCM (10 ml × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (amine-silica, 0 to 3% MeOH / DCM) to give 17.3 mg (79%) of an off-white solid.

[0688] 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

[0689]

[0690] 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

[0691] Methyl (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-yl)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylate (100 mg, 0.15 mmol) was suspended in THF (2 ml), and 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 (aqueous solution) (5 ml) was added to the reaction solution, and then it was 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 obtained residue was subjected to MPLC (0 to 5% MeOH / DCM) to give 72.5 mg (76%) of an off-white solid.

[0692] Step 2: Synthesis of ((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-yl)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate

[0693] (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 TEA (23 μl, 0.17 mmol), DMAP (1.4 mg, 0.01 mmol), and 4-toluenesulfonyl chloride (25.7 mg, 0.13 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 3 hours. Distilled water (10 ml) was added to the reaction solution, extracted with DCM (10 ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0 to 5% MeOH / DCM) to give 55.8 mg (62%) of an off-white solid.

[0694] 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

[0695] 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), K 2 CO 3 (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 h. Distilled water (7 ml) was added to the reaction solution and the mixture was 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 obtained residue was subjected to MPLC (0 to 7% MeOH / DCM) to give 11.6 mg (32%) of an off-white solid.

[0696] 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

[0697] ((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)carbamic acid tert-butyl ester (11.6 mg, 0.01 mmol) was suspended in DCM (1 ml), 4 M HCl in dioxane (25 μl) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to saturated. After adding saturated NaHCO 3 (aqueous solution) (3 ml), it was extracted with DCM (5 ml × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (amine-silica, 0 to 3% MeOH / DCM) to give 7.6 mg (72%) of an off-white solid.

[0698] 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

[0699]

[0700] Example 6 was synthesized in the same manner as in Example 5 using ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 17) instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11).

[0701] 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0702]

[0703] 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

[0704] (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 the mixture was stirred at room temperature for 1 hour. Distilled water (0.01 ml) was added to the reaction solution, 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 obtained residue was subjected to MPLC (0 to 5% MeOH / DCM) to give 14 mg (34%) of a milky white solid.

[0705] 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

[0706] ((1-(5-((3-chloro-2-(((1R,4R)-4-(hydroxymethyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (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), stirred at 0 °C for 10 minutes, 2-nitrobenzenesulfonyl chloride (20 mg, 0.09 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Distilled water (10 ml) was added to the reaction solution, and then the mixture was extracted with DCM (10 ml × 2). The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0 to 5% MeOH / DCM) to give 15 mg (quantitative) of an off-white solid.

[0707] Step 3: Synthesis of ((1-(5-((3-chloro-2-(((1S,4R)-4-((4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-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)carbamic acid tert-butyl ester

[0708] ((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 dissolved in DMF (0.2 ml). Then (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 Cs 2 CO 3 (12 mg, 0.04 mmol) were added and the mixture was stirred at 50 °C for 16 hours. Distilled water (10 ml) was added to the reaction solution, and the mixture was 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 obtained residue was subjected to MPLC (0 to 10% MeOH / DCM) to give 6.8 mg (32%) of an off-white solid.

[0709] 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

[0710] Suspend 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) in DCM (1.0 ml), add 4 M HCl in dioxane (0.01 ml), and stir the mixture at room temperature for 1 h. Neutralize the reaction solution by adding saturated NaHCO 3 (aqueous solution) (5 ml), and then extract with DCM (5 ml × 2). Wash the organic layer with brine (5 ml × 2), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Subject the obtained residue to MPLC (amine-silica, 0 to 5% MeOH / DCM) to give 3.5 mg (65%) of an off-white solid.

[0711] 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

[0712]

[0713] 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) and (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) to replace (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) and (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), Example 8 was synthesized in the same manner as in Example 7.

[0714] 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

[0715]

[0716] 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) to replace (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 9 was synthesized in the same manner as in Example 7.

[0717] 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

[0718]

[0719] Example 10 was synthesized in the same manner as in Example 7, 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) in place 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).

[0720] 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

[0721]

[0722] 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

[0723] 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-hydroxypyrrolidin-2-yl)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 h. Distilled water (20 ml) was added to the reaction solution and the mixture was extracted 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 residue obtained was subjected to MPLC (0 to 7% MeOH / DCM) to afford 144 mg (40%) of an off-white solid.

[0724] 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-hydroxypyrrolidin-2-carboxamide

[0725] 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-hydroxypyrrolidin-2-yl)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), 4 M HCl in dioxane (0.22 ml) was added and the mixture was stirred at room temperature for 1 h. After adding saturated NaHCO 3After (aqueous solution) (5 ml), it was extracted with DCM (10 ml × 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (amine - silica, 0 to 3% MeOH / DCM) to give 80.7 mg (88%) of an off - white solid.

[0726] 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 - fluorocyclopropanecarboxamido)-3,3 - dimethylbutanoyl)-4 - hydroxypyrrolidine - 2 - carboxamide

[0727]

[0728] Using tert - butyl ((1-(5-((3-(azetidin - 3 - ylamino)-2 - chlorophenyl)thio)pyrazin - 2 - yl)-4 - methylpiperidin - 4 - yl)amino)carbamate (Intermediate 12) instead of tert - butyl ((1-(5-((3-(azetidin - 3 - ylamino)-2 - chlorophenyl)thio)pyrazin - 2 - yl)-4 - methylpiperidin - 4 - yl)methyl)amino)carbamate (Intermediate 11), Example 12 was synthesized in the same manner as in Example 11.

[0729] Example 13. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-((3S,4S)-4 - amino - 3 - methyl - 2 - oxa - 8 - azaspiro[4.5]dec - 8 - yl)pyrazin - 2 - yl)thio)-2 - chlorophenyl)amino)azetidine - 1 - carbonyl)cyclohexyl)oxy)-4-(4 - methylthiazol - 5 - yl)benzyl)-1-((S)-2-(1 - fluorocyclopropanecarboxamido)-3,3 - dimethylbutanoyl)-4 - hydroxypyrrolidine - 2 - carboxamide

[0730]

[0731] 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]dec - 4 - yl)amino)carbamate (Intermediate 13) instead of tert - butyl ((1-(5-((3-(azetidin - 3 - ylamino)-2 - chlorophenyl)thio)pyrazin - 2 - yl)-4 - methylpiperidin - 4 - yl)methyl)amino)carbamate (Intermediate 11), Example 13 was synthesized in the same manner as in Example 11.

[0732] 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0733]

[0734] Using (S)-tert-butyl (1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate (Intermediate 14) instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11), Example 14 was synthesized in the same manner as in Example 11.

[0735] 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0736]

[0737] Using N-((S)-1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate 15) instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11), Example 15 was synthesized in the same manner as in Example 11.

[0738] 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

[0739]

[0740] Example 16 was synthesized in the same manner as in Example 11, using tert-butyl ((1-(5-(3-(azetidin-3-ylamino)-2-chlorophenoxy)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 16) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0741] 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

[0742]

[0743] Example 17 was synthesized in the same manner as in Example 11, using tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 17) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0744] 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

[0745]

[0746] Example 18 was synthesized in the same manner as in 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-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0747] 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

[0748]

[0749] Example 19 was synthesized in the same manner as in 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).

[0750] 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

[0751]

[0752] Example 20 was synthesized in the same manner as in 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).

[0753] 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

[0754]

[0755] Example 21 was synthesized in the same manner as in 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).

[0756] Example 22. (2S,4R)-N-(2-(((1R,4S)-4-(3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0757]

[0758] Example 22 was synthesized in the same manner as in 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]dec-4-yl)carbamate (Intermediate 30) 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).

[0759] 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0760]

[0761] Example 23 was synthesized in the same manner as in 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) 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).

[0762] Example 24. (2S,4R)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)sulfanyl)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0763]

[0764] Example 24 was synthesized in the same manner as in Example 11 using tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 32) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0765] Example 25. (2S,4R)-N-(2-(((1R,4S)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)sulfanyl)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0766]

[0767] Example 25 was synthesized in the same manner as in Example 11 using tert-butyl ((3S,4S)-8-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)sulfanyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (Intermediate 33) instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11).

[0768] 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)piperazin-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0769]

[0770] Example 26 was synthesized in the same manner as in Example 11, 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).

[0771] 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

[0772]

[0773] Example 27 was synthesized in the same manner as in 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-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0774] 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

[0775]

[0776] Example 28 was synthesized in the same manner as in Example 11, using tert-butyl (1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 12) and (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 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0777] 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]dec-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0778]

[0779] 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]dec-4-yl)carbamate (Intermediate 13) and (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) respectively 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 29 was synthesized in the same manner as in Example 11.

[0780] 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

[0781]

[0782] Use (S)-tert-butyl (1'-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate (Intermediate 14) and (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) to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 30 in the same manner as in Example 11.

[0783] 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[cyclopent[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

[0784]

[0785] Using N-((S)-1’-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4’-piperidine]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate 15) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 31 was synthesized in the same manner as in Example 11.

[0786] 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]dec-8-yl)pyrazin-2-yl)thio)indolin-1-yl)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0787]

[0788] Use (R)-N-((3S,4S)-8-(5-((1-(azetidin-3-yl)indolin-4-yl)sulfanyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide (Intermediate 22) and (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) to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 32 in the same manner as in Example 11.

[0789] 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]dec-8-yl)pyrazin-2-yl)sulfanyl)indolin-1-yl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0790]

[0791] 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]dec-4-yl)propane-2-sulfinamide (Intermediate 23) and (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 ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 33 was synthesized in the same manner as in Example 11.

[0792] 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] azin-4-yl)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0793]

[0794] Using ((1-(5-((4-(azetidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4] tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 24) and (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) were used in place of ((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-fluorocyclopropanecarbonyl)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 34 was synthesized in the same manner as in Example 11.

[0795] 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)piperidin-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0796]

[0797] ((4-Methyl-1-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4] tert-Butyl ((3S,4S)-3-methyl-8-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)thio)pyrazin-2-yl)piperidin-4-yl)methyl)carbamate (Intermediate 25) and (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) were used in place of ((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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 35 was synthesized in the same manner as in Example 11.

[0798] 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]dec-8-yl)pyrazin-2-yl)thio)-2H-benzo[b][1,4] thiazin-4(3H)-yl)piperidin-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0799]

[0800] ((3S,4S)-3-Methyl-8-(5-((4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4] tert-Butyl ((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-carboxamido)(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)methyl)carbamate (Intermediate 26) and (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) were used in place of ((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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 36 was synthesized in the same manner as in Example 11.

[0801] 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)piperidin-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0802]

[0803] ((1-(5-((3-Fluoro-1-(piperidin-4-yl)-1H-indol-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 27) and (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) were used in place of ((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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 37 was synthesized in the same manner as in Example 11.

[0804] 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

[0805]

[0806] Example 38 was synthesized in the same manner as in 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) and (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) 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0807] 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

[0808]

[0809] Using tert-butyl (1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) and (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) respectively instead of tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 39 was synthesized in the same manner as in Example 11.

[0810] 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]dec-8-yl)pyrazin-2-yl)sulfanyl)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0811]

[0812] Using tert-butyl ((3S,4S)-8-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)sulfanyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (Intermediate 30) and (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) respectively to replace tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 40 was synthesized in the same manner as in Example 11.

[0813] 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)sulfanyl)-3-chloropyridin-2-yl)amino)piperidin-1-carbonyl)cyclohexyloxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0814]

[0815] Use tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 31) and (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) respectively to replace tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 41 in the same manner as in Example 11.

[0816] Example 42. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-aminopiperidin-1-yl)pyrazin-2-yl)sulfanyl)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0817]

[0818] Use tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)amino)carbamate (Intermediate 32) and (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) respectively to replace tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 42 in the same manner as in Example 11.

[0819] 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]dec-8-yl)pyrazin-2-yl)sulfanyl)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0820]

[0821] Using ((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]dec-4-yl)carbamic acid tert-butyl ester (Intermediate 33) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 43 was synthesized in the same manner as in Example 11.

[0822] 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

[0823]

[0824] 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) and (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) respectively to replace 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 44 was synthesized in the same manner as in Example 11.

[0825] 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

[0826]

[0827] Use 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) and (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) respectively to replace 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 45 in the same manner as in Example 11.

[0828] 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

[0829]

[0830] Using tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-yl)phenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 55) and (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) respectively to replace tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 46 was synthesized in the same manner as in Example 11.

[0831] 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)sulfanyl)-3-chloropyridin-2-yl)piperidin-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0832]

[0833] Using tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-yl)pyridin-4-yl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 56) and (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 tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)sulfanyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 47 was synthesized in the same manner as in Example 11.

[0834] 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)sulfanyl)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0835]

[0836] Using (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) instead of (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 48 was synthesized in the same manner as in Example 11.

[0837] 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

[0838]

[0839] Example 49 was synthesized in the same manner as in 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) and (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) 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-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0840] 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

[0841]

[0842] Use 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) to replace (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), and synthesize Example 50 in the same manner as in Example 11.

[0843] Example 51. (2S,4R)-N-(2-(2-(4-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidin-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

[0844]

[0845] Use tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 17) and 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) to replace 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-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 51 in the same manner as in Example 11.

[0846] 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)piperazin-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

[0847]

[0848] Example 52 was synthesized in the same manner as in Example 11, 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) and 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) 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-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0849] 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

[0850]

[0851] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 53 was synthesized in the same manner as in Example 11.

[0852] 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

[0853]

[0854] Use 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 (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) to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 54 in the same manner as in Example 11.

[0855] 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

[0856]

[0857] Use 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) and (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) to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 55 in the same manner as in Example 11.

[0858] 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)piperidin-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

[0859]

[0860] 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) and (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) to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 56 was synthesized in the same manner as in Example 11.

[0861] 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

[0862]

[0863] Use 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 (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 57 in the same manner as in Example 11.

[0864] 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

[0865]

[0866] Use 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 (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 58 in the same manner as in Example 11.

[0867] 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

[0868]

[0869] Using (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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 59 was synthesized in the same manner as in Example 11.

[0870] 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

[0871]

[0872] Use (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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 60 in the same manner as in Example 11.

[0873] 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

[0874]

[0875] Use (1R,3R)-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 37) and (2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 61 in the same manner as in Example 11.

[0876] 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0877]

[0878] Using (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) and (2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (Intermediate 75) respectively in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 62 was synthesized in the same manner as in Example 11.

[0879] 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-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0880]

[0881] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 63 was synthesized in the same manner as in Example 11.

[0882] 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

[0883]

[0884] 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) and (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) respectively in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 64 was synthesized in the same manner as in Example 11.

[0885] 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)piperidine-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0886]

[0887] Use 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 (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 65 in the same manner as in Example 11.

[0888] 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

[0889]

[0890] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 66 was synthesized in the same manner as in Example 11.

[0891] Example 67. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-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

[0892]

[0893] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) and (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) respectively instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 67 was synthesized in the same manner as in Example 11.

[0894] 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-methylpiperidin-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

[0895]

[0896] Using 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 (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 68 was synthesized in the same manner as in Example 11.

[0897] 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-fluoropiperidin-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

[0898]

[0899] Using 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 69 was synthesized in the same manner as in Example 11.

[0900] 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

[0901]

[0902] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 70 was synthesized in the same manner as in Example 11.

[0903] 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

[0904]

[0905] 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) and (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) respectively in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 71 was synthesized in the same manner as in Example 11.

[0906] 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

[0907]

[0908] Use 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and synthesize Example 72 in the same manner as in Example 11.

[0909] 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

[0910]

[0911] Use 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 (2S,4R)-N-(2-(azetidin-3-yloxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 76) to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and synthesize Example 73 in the same manner as in Example 11.

[0912] 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

[0913]

[0914] 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) and (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) respectively instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 74 was synthesized in the same manner as in Example 11.

[0915] 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)piperidin-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0916]

[0917] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 75 was synthesized in the same manner as in Example 11.

[0918] 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

[0919]

[0920] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 76 was synthesized in the same manner as in Example 11.

[0921] 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]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidine-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0922]

[0923] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) and (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) respectively instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 77 was synthesized in the same manner as in Example 11.

[0924] 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)piperidine-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0925]

[0926] 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) and (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) respectively in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 78 was synthesized in the same manner as in Example 11.

[0927] 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

[0928]

[0929] 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) and (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) respectively instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 79 was synthesized in the same manner as in Example 11.

[0930] 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]dec-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

[0931]

[0932] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 80 was synthesized in the same manner as in Example 11.

[0933] 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

[0934]

[0935] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 81 was synthesized in the same manner as in Example 11.

[0936] 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

[0937]

[0938] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 82 was synthesized in the same manner as in Example 11.

[0939] 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

[0940]

[0941] Example 83 was synthesized in the same manner as in Example 11, 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) and (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) in place of ((1-(5-((3-(Azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-Fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0942] 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

[0943]

[0944] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 84 was synthesized in the same manner as in Example 11.

[0945] 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]dec-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

[0946]

[0947] Using 1-(3-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid (Intermediate 60) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 85 was synthesized in the same manner as in Example 11.

[0948] 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)piperidin-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

[0949]

[0950] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 86 was synthesized in the same manner as in Example 11.

[0951] 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

[0952]

[0953] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 87 was synthesized in the same manner as in Example 11.

[0954] Example 88. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidine-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0955]

[0956] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 88 was synthesized in the same manner as in Example 11.

[0957] Example 89. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-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

[0958]

[0959] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 89 was synthesized in the same manner as in Example 11.

[0960] 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

[0961]

[0962] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 90 was synthesized in the same manner as in Example 11.

[0963] 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-hydroxy pyrrolidine-2-carboxamide

[0964]

[0965] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 91 was synthesized in the same manner as in Example 11.

[0966] 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-methyliso oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P1)

[0967]

[0968] 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 (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methyliso oxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P1) (Intermediate 84) were respectively used in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), and Example 92 was synthesized in the same manner as in Example 11.

[0969] 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-methyliso oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0970]

[0971] 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 (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methyliso oxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) were used instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 93 was synthesized in the same manner as in Example 11.

[0972] 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-methyliso oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0973]

[0974] 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) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methyliso ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)tert-butylcarbamate (Intermediate 11) and (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) were replaced with (1-(4-((5-((3S,4S)-4-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)methyl)tert-butylcarbamate (Intermediate 43) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisothiazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85), and Example 94 was synthesized in the same manner as in Example 11.

[0975] Example 95. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylis thiazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0976]

[0977] 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylis ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)tert-butylcarbamate (Intermediate 11) and (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) were replaced with (1-(4-((5-((3S,4S)-4-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)methyl)tert-butylcarbamate (Intermediate 43) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methylisothiazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85), and Example 95 was synthesized in the same manner as in Example 11.

[0978] 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)piperidin-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methyliso oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0979]

[0980] 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) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methyliso oxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) respectively instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (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), Example 96 was synthesized in the same manner as in Example 11.

[0981] 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)piperidin-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methyliso oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0982]

[0983] 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) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methyliso oxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (P2) (Intermediate 85) were used instead of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 97 was synthesized in the same manner as in Example 11.

[0984] Example 98. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-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-methyliso oxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide (P2)

[0985]

[0986] 1-(4-((5-((3S,4S)-4-((tert-Butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) and (2S,4R)-4-hydroxy-1-(3-methyl-2-(3-methyliso ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl) tert-butylcarbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65) were replaced with (1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl) tert-butylcarbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 98 was synthesized in the same manner as in Example 11.

[0987] Example 99. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-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)

[0988]

[0989] (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 (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) were respectively used to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl) tert-butylcarbamate (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), and Example 99 was synthesized in the same manner as in Example 11.

[0990] 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)

[0991]

[0992] Example 100 was synthesized in the same manner as in Example 11, 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) and (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 ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[0993] 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-hydroxy pyrrolidine-2-carboxamide

[0994]

[0995] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 101 was synthesized in the same manner as in Example 11.

[0996] 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-hydroxyn pyrrolidine-2-carboxamide

[0997]

[0998] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 102 was synthesized in the same manner as in Example 11.

[0999] Example 103. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidine-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

[1000]

[1001] Example 103 was synthesized in the same manner as in Example 11, using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 43) and (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) in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65).

[1002] 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

[1003]

[1004] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 104 was synthesized in the same manner as in Example 11.

[1005] 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-hydroxyn pyrrolidine-2-carboxamide

[1006]

[1007] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 105 was synthesized in the same manner as in Example 11.

[1008] Example 106. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-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

[1009]

[1010] Using 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 53) and (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) respectively in place of ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 106 was synthesized in the same manner as in Example 11.

[1011] 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

[1012]

[1013] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11) and (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (Intermediate 65), Example 107 was synthesized in the same manner as in Example 11.

[1014] 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

[1015]

[1016] 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) and (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) respectively to replace ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (Intermediate 11...

Claims

1. A compound of Formula 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts: [Formula 1] In Formula 1, R 1 is or 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 one or more hydrogens in said aryl and heteroaryl are optionally and independently replaced by C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 substituted with alkoxy, R 12 is amino, C 1-6 aminoalkyl or C 1-6 alkylamino, R 13a and R 13b each independently is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl or C 1-6 alkoxy, R 14 Each independently is H, C 1-6 alkyl, hydroxy, halogen or CN, Z is independently -O-, -S-, -NH- or -CH 2 -, 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 , 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 R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 5 is H, C 1-6 alkyl, C 2-6 alkynyl, halogen, -CN or heteroaryl, wherein one or more hydrogens in the heteroaryl are optionally substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 6 is -NHC(O)R 7 or heteroaryl, wherein one or more hydrogens in said heteroaryl are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein 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 one or more hydrogens in said cycloalkyl and heterocycle are optionally and independently substituted by C 1-6 alkyl, halogen or -CN, R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl, R 8b and R 8c each independently is 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 -, Y is CH or N, W is a direct bond, -O-, or -N(R 9a )-, R 9a and R 9b each independently is H, C 1-6 alkyl or C 1-6 haloalkyl, L is of the following Formula 2, [Formula 2] In Formula 2, A 1 and A 2 each independently is a direct bond, C 3-10 cycloalkyl, heterocycle, aryl or heteroaryl, wherein one or more hydrogens in said cycloalkyl, heterocycle, aryl or heteroaryl are optionally and each independently substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or =O, B 1 and B 2 each independently is a direct bond, -O-, -N(R 10 )--C(O)-, -C(O)N(R 10 )-, or -N(R 10 )C(O)-, where R 10 each independently is H or C 1-6 alkyl, and q 1 、q 2 、q 3 、q 4 and q 5 each independently is an integer from 0 to 10.

2. The compound of claim 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, in Formula 1, R 1 is or R 11 is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl or C 1-6 haloalkyl, R 12 is amino, C 1-6 aminoalkyl or C 1-6 alkylamino, R 13a and R 13b each independently is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl or C 1-6 alkoxy, R 14 each independently is H, C 1-6 alkyl, hydroxy, halogen or CN, Z is independently -O-, -S-, -NH- or -CH 2 -, 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 , 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 R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently replaced by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 5 is H, C 1-6 alkyl, C 2-6 alkynyl, halogen, -CN or heteroaryl, wherein one or more hydrogens in the heteroaryl are optionally substituted with C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 6 is -NHC(O)R 7 or heteroaryl, wherein one or more hydrogens in said heteroaryl are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein 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 one or more hydrogens in said cycloalkyl and heterocycle are optionally and independently substituted by C 1-6 alkyl, halogen or -CN, R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl, R 8b and R 8c each independently is H, C 1-6 alkyl, C 1-6 alkoxy or halogen, X is -S-, -O-, -N(R 9a )- or -CH 2 -, Y is CH or N, W is a direct bond, -O-, or -N(R 9a )-, R 9a and R 9b each independently is H, C 1-6 alkyl or C 1-6 haloalkyl, L is of the following Formula 2, [Formula 2] In Formula 2, A 1 and A 2 each independently is a direct bond, C 3-10 cycloalkyl, heterocycle, aryl or heteroaryl, wherein one or more hydrogens in the cycloalkyl, heterocycle, aryl or heteroaryl are optionally and each independently substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or =O, B 1 and B 2 each independently is a direct bond, -O-, -N(R 10 )-, -C(O)-, -C(O)N(R 10 )-, or -N(R 10 )C(O)-, where R 10 each independently is H or C 1-6 alkyl, and q 1 、q 2 、q 3 、q 4 and q 5 Each independently is an integer from 0 to 10.

3. The compound of claim 2, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, in Formula 1, R 1 is or R 11 is H, C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl or C 1-3 haloalkyl, R 12 is an amino group, C 1-3 aminoalkyl or C 1-3 alkylamino, R 13a and R 13b each independently is H, C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 alkoxy, R 14 each independently is H, C 1-3 alkyl, hydroxy, halogen or CN, Z is independently -O-, -NH- or -CH 2 -, 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 , 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 R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently replaced by C 1-3 alkyl, halogen or C 1-3 haloalkyl, R 5 is H, C 1-6 alkyl, ethynyl, halogen, -CN or heteroaryl, wherein one or more hydrogens in said heteroaryl are optionally substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 6 is -NHC(O)R 7 or heteroaryl, wherein one or more hydrogens in said heteroaryl are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein R 7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl or C 3-10 cycloalkyl, wherein one or more hydrogens in said cycloalkyl are optionally and independently substituted by C 1-3 alkyl, halogen or -CN, R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl, R 8b and R 8c each independently is H, C 1-6 alkyl or halogen, X is -S-, -O-, -N(R 9a )- or -CH 2 -, Y is CH or N, W is a direct bond, -O-, or -N(R 9a )-, R 9a and R 9b each independently is H, C 1-6 alkyl or C 1-6 haloalkyl, L is of the following Formula 2, [Formula 2] In Formula 2, A 1 and A 2 each independently is a direct bond, C 3-10 cycloalkyl or heterocycle, wherein one or more hydrogens in said cycloalkyl and heterocycle are optionally and each independently substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or =O, B 1 and B 2 each independently is a direct bond, -O-, -N(R 10 )-, or -C(O)-, where R 10 each independently is H or C 1-6 alkyl, and q 1 、q 2 、q 3 、q 4 and q 5 Each independently is an integer from 0 to 5.

4. The compound of claim 3, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, in Formula 1, R 1 is or R 11 is H, C 1-6 alkyl, hydroxy or C 1-3 hydroxyalkyl, R 12 is an amino group or a C 1-3 aminoalkyl, R 13a and R 13b each independently is H, C 1-6 alkyl, hydroxy, C 1-3 hydroxyalkyl or C 1-3 alkoxy, R 14 each independently is H, C 1-3 alkyl, hydroxy, halogen or CN, Z is independently -O-, -NH- or -CH 2 -, 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 , R 3 is H, C 1-6 alkyl or C 1-6 hydroxyalkyl, R 4 is H, C 1-6 alkyl, halogen, C 1-6 haloalkyl or C 1-6 alkoxy, or R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently replaced by C 1-3 alkyl, halogen or C 1-3 haloalkyl, R 5 is H, C 1-6 alkyl, ethynyl, halogen, -CN, thiazole, pyrazole, pyrrole, oxazole or triazole, wherein one or more hydrogens in said thiazole, pyrazole, pyrrole, oxazole and triazole are optionally substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 6 is -NHC(O)R 7 , a triazole, a pyrazole or an iso azole, wherein one or more hydrogens in said triazole, pyrazole and iso azole are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein 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 hydrogens in said cycloalkyl are optionally and independently substituted by C 1-3 alkyl, halogen or -CN, R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl, R 8b and R 8c each independently is 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 )-, R 9a and R 9b each independently is H, C 1-3 alkyl or C 1-3 haloalkyl, L is of the following Formula 2, [Formula 2] In Formula 2, A 1 and A 2 each independently is a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine or 7-azaspiro[3.5]nonane, wherein one or more hydrogens in said cyclohexane, cyclobutane, piperidine, piperazine, azetidine and 7-azaspiro[3.5]nonane are optionally and each independently substituted with C 1-6 alkyl, halogen, C 1-3 haloalkyl, -OH or ═O, B 1 and B 2 each independently is a direct bond, -O-, or -C(O)-, and q 1 、q 2 、q 3 、q 4 and q 5 are each independently an integer from 0 to 5.

5. The compound of claim 4, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, in Formula 1 R 1 is or R 11 is H, C 1-6 alkyl or hydroxyl, R 12 is an amino group or a C 1-3 aminoalkyl, R 13a and R 13b each independently is H, C 1-6 alkyl, hydroxy or C 1-3 hydroxyalkyl, R 14 each independently is H, C 1-3 alkyl or halogen, Z is independently -O- or -CH 2 -, 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 , R 3 is H, C 1-6 alkyl or C 1-6 hydroxyalkyl, R 4 is H, C 1-6 alkyl, halogen, C 1-6 haloalkyl or C 1-6 alkoxy, or R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a )-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently replaced by C 1-3 alkyl or halogen, R 5 is H, C 1-6 alkyl, ethynyl, halogen, -CN, thiazole, pyrazole or pyrrole, wherein one or more hydrogens in said thiazole, pyrazole and pyrrole are optionally substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 6 is -NHC(O)R 7 , a triazole, pyrazole or iso azole, wherein one or more hydrogens in said triazole, pyrazole and iso azole are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein 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 hydrogens in said cycloalkyl are optionally and independently substituted by C 1-3 alkyl, halogen or -CN, R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl, R 8b and R 8c each independently is 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 )-, R 9a and R 9b each independently is H, C 1-3 alkyl or C 1-3 haloalkyl, L is of the following Formula 2, [Formula 2] In Formula 2, A 1 and A 2 each independently is a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine or 7-azaspiro[3.5]nonane, wherein one or more hydrogens in the cyclohexane, cyclobutane, piperidine, piperazine, azetidine and 7-azaspiro[3.5]nonane are optionally and each independently substituted with C 1-6 alkyl, halogen, -OH or ═O, B 1 and B 2 each independently is a direct bond or -C(O)-, and q 1 、q 2 、q 3 、q 4 and q 5 each independently is an integer from 0 to 3.

6. The compound of claim 5, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, in Formula 1 R 1 is or R 11 is H or C 1-6 alkyl group R 12 is an amino group or a C 1-3 aminoalkyl, R 13a and R 13b each independently is H or C 1-6 alkyl R 14 each independently is H or C 1-3 alkyl Z is independently -O- or -CH 2 -, 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 , R 3 is H, C 1-6 alkyl or C 1-6 hydroxyalkyl, R 4 is H, C 1-6 alkyl, halogen or C 1-6 haloalkyl, or R 4 is linked to the R of W 9a to form a heterocycle or heteroaryl, where W is -N(R 9a ))-, and one or more hydrogens in the heterocycle and heteroaryl are optionally and independently substituted by C 1-3 alkyl or halogen, R 5 is H, C 1-6 alkyl, halogen, -CN, thiazole or pyrazole, wherein one or more hydrogens in said thiazole and pyrazole are optionally substituted by C 1-6 alkyl, halogen or C 1-3 haloalkyl, R 6 is -NHC(O)R 7 , triazole, pyrazole or is oxazole, wherein one or more hydrogens in said triazole, pyrazole and is oxazole are optionally substituted by C 1-6 alkyl, halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl, and wherein 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 hydrogens in said cycloalkyl are optionally and independently substituted by halogen or -CN, R 8a is H, C 1-6 alkyl or C 3-6 cycloalkyl, R 8b and R 8c each independently is 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 )-, R 9a and R 9b each independently is H, C 1-3 alkyl or C 1-3 haloalkyl, L is of the following Formula 2, [Formula 2] In Formula 2, A 1 and A 2 each independently is a direct bond, cyclohexane, cyclobutane, piperidine, piperazine, azetidine or 7-azaspiro[3.5]nonane, wherein one or more hydrogens in said cyclohexane, cyclobutane, piperidine, piperazine, azetidine and 7-azaspiro[3.5]nonane are optionally and each independently substituted with C 1-6 alkyl, halogen, -OH or ═O, B 1 and B 2 each independently is a direct bond or -C(O)-, and q 1 、q 2 、q 3 、q 4 and q 5 Each independently is an integer from 0 to 3.

7. The compound of claim 1, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, wherein the compound is any one of the following compounds:

8. A composition comprising the compound of any one of claims 1 to 7, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for degrading or inhibiting Src homology 2 domain-containing phosphatase (SHP2), comprising the compound of any one of claims 1 to 7, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts as an active agent.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition for degrading or inhibiting Src homology 2 domain-containing phosphatase (SHP2) is for treating or preventing cancer, cancer metastasis, cardiovascular diseases, immune disorders, eye disorders, Noonan syndrome or Leopard syndrome.

11. The pharmaceutical composition according to claim 10, wherein the cancer is at least one selected from the following: blood cancer, acute lymphoblastic 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, sarcoma, papillary thyroid cancer, and combinations thereof.

12. A method for treating or preventing Src homology 2 domain-containing phosphatase (SHP2)-related diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 7, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts.

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

14. The method according to claim 13, wherein the cancer is at least one selected from the following: blood cancer, acute lymphoblastic 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, sarcoma, papillary thyroid cancer, and combinations thereof.

15. A method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), which comprises administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 7, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts.

16. A method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample, which comprises contacting the patient or the biological sample with the compound according to any one of claims 1 to 7, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts.

17. Use of the compound according to any one of claims 1 to 7, its optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts for producing a medicament for degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample.

18. Use of a compound according to any one of claims 1 to 7, an optical isomer, stereoisomer, isotopic variant, hydrate, solvate or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating Src homology 2 domain-containing phosphatase (SHP2)-related diseases.

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