Compounds with SHP2 proteolytic activity and medical uses thereof

Abstract

The present disclosure provides a compound of a specific chemical structure, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, which has excellent activity in terms of degradation of SHP2 protein. The present disclosure also provides a composition comprising such a compound, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof. The present disclosure also provides medical use of the compound according to the present disclosure, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a salt thereof and a composition comprising same, for the treatment or prevention of SHP2-associated diseases (for example, cancer). The present disclosure also provides a method for treating or preventing SHP2-associated diseases (for example, cancer), the method comprising administering, to a subject in need of treatment, an effective amount of the compound according to the present disclosure, an optical isomer, stereoisomer, isotopic variant, hydrate or solvate thereof, or a salt thereof, or a composition comprising same.

Description

Compounds having SHP2 proteolytic activity and their medicinal uses

[0001] This application claims priority to Korean Patent Application No. 10-2024-0021368, filed February 14, 2024, the entire disclosure of which is incorporated herein by reference.

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

[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 childhood myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia, and acute myeloid leukemia. Somatic activating mutations in SHP2 have been 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] SHP2 is known to be involved in various signaling processes in cancer cells, such as the RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB, and mTOR pathways. In the RAS-ERK pathway, SHP2 acts as a positive regulator upstream to promote the RAS-RAF-MEK-ERK kinase cascade signaling. Therefore, SHP2 inhibition inhibits the oncogenic function of the RAS-RAF-MEK-ERK pathway, resulting in cell growth inhibition and apoptosis in cancer cells. SHP2 also contributes to immune evasion as a key protein in the PD-1 / PD-L1-mediated T cell activation inhibitory signaling pathway in immune cells. In summary, SHP2 is a highly attractive cancer therapeutic target. For example, SHP099, a SHP2 inhibitor, was shown to selectively block SHP2 phosphatase activity and inhibit cancer cell growth in vitro and tumor growth in a xenograft mouse model (Chen et al.,Nature2016, 535, 148-152; Garcia Fortanet 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. Furthermore, CRISPR-Cas9-mediated SHP2 inactivation has been demonstrated to induce senescence and suppress tumor growth in xenograft models of KRAS-mutant tumors.

[0006] Deletion of the SHP2 protein may provide an alternative and more effective strategy for inhibiting SHP2 activity. Therefore, the present invention aims to provide a compound having Src homology 2 domain-containing phosphatase (SHP2) degrading activity, a pharmaceutical composition comprising the compound as an active ingredient, and a pharmaceutical use thereof for treating or preventing SHP2-related diseases (cancer, tumors, etc.).

[0007] Another problem to be solved by the present invention is to provide a method for treating or preventing a SHP2-related disease (preferably cancer or tumor), characterized in that the compound according to the present invention is characterized in that it decomposes SHP2 and consequently lowers the SHP2 level, and is administered to a patient in need of treatment, improvement or prevention of the SHP2-related disease.

[0008] The present disclosure relates to a SHP2 targeted protein degradation (TPD) compound capable of targeting and degrading SHP2 protein through ubiquitination by E3 ubiquitin ligase, a pharmaceutical composition comprising the same as an active ingredient, and a method for treating or preventing SHP2-related diseases using the same.

[0009] Compound of the present disclosure

[0010] According to one embodiment of the present invention, a compound is a target protein degradation compound of 'SHP2 binding ligand-linker(-WL-)-VHL ligand'. In one aspect, the present application relates to a bifunctional compound useful for modulating protein activity by inducing degradation of a target protein. In some embodiments, the bifunctional compound comprises a VHL ligand that is an E3 ubiquitin ligase binding moiety and a target protein binding moiety, preferably linked via a linker (linker) moiety, as otherwise described herein. E3 ubiquitin ligase refers to a group of proteins that target substrate proteins by transferring ubiquitin for degradation. VHL is an E3 ubiquitin ligase protein that, in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to lysine on a target protein, thereby inducing degradation by the proteasome. Thus, the bifunctional compound simultaneously binds to VHL and the target protein, thereby bringing the target protein into proximity with VHL, thereby inducing degradation via ubiquitination and consequently inhibiting / suppressing the activity of the target protein. In certain embodiments, the bifunctional compound comprises, for example, a SHP2 binding ligand and a VHL ligand covalently, directly or indirectly, linked to a chemical linker -WL-.

[0011] One aspect of the present invention provides a compound of the following chemical formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

[0012] [Chemical Formula 1]

[0013]

[0014] In the above chemical formula 1,

[0015] R1 is , , or And,

[0016] R 12a is H, C 1-6alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein aryl and heteroaryl are independent of each other and optionally one or more hydrogens in the ring are C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, or C 1-3 is substituted with alkoxy,

[0017] R 12b is amino, C 1-6 aminoalkyl, or C 1-6 It is alkylamino,

[0018] R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 It is alkoxy,

[0019] R 14 are independently H, C 1-6 alkyl, hydroxy, halogen, or CN,

[0020] Z is independently -O-, -S-, -NH-, or -CH2-,

[0021] Ring C is aryl or heteroaryl,

[0022] n is an integer from 0 to 3,

[0023] R2 is H, C 1-6 alkyl, or -NH2,

[0024] R3 is H, C 1-6 alkyl, C1-6 hydroxyalkyl, C 1-6 haloalkyl, -C(O)R 10a , -C(O)OR 10a , -C(O)NR 10a R 10b , or CN,

[0025] R4 is H, C 1-6 alkyl, halogen (preferably Cl), C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 It is haloalkoxy,

[0026] R5 is H, C 1-6 alkyl, C 2-6 alkynyl (preferably acetylenyl), halogen (preferably F, Cl), -CN, or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole, or triazole), wherein the heteroaryl optionally has one or more hydrogens in the ring atom(s) C 1-6 alkyl (preferably methyl, ethyl), halogen, or C 1-3 is substituted with haloalkyl,

[0027] R6 is -NHC(O)R7 or heteroaryl (preferably isoxazole, triazole, or pyrazole), wherein the heteroaryl optionally has one or more hydrogens in the ring at C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl,

[0028] R7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-10cycloalkyl, or heterocycle, wherein cycloalkyl and heterocycle are independently of each other and optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen (preferably F), or -CN,

[0029] R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl,

[0030] R 9a and R 9b are independently H, C 1-6 alkyl, C 1-6 alkoxy, or halogen,

[0031] X is -S-, -O-, -N(R 10a )-, or -CH2-,

[0032] Y is CH or N,

[0033] W is a direct bond, -O-, or -N(R 10a )-and,

[0034] V is CH or N,

[0035] R 10a and R 10b are independently H, C 1-6 alkyl, or C 1-6 It is haloalkyl,

[0036] L is the following chemical formula 2,

[0037] [Chemical Formula 2]

[0038]

[0039] In chemical formula 2,

[0040] A1 and A2 are directly bonded independently of each other, C 3-10cycloalkyl, heterocycle (preferably azetidine, pyrrolidine, piperidine, piperazine), aryl, or heteroaryl, wherein cycloalkyl, heterocycle, aryl, or heteroaryl optionally has one or more hydrogens in the ring at C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, -OH, or =O,

[0041] B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, -C(O)-, -C(O)N(R 11 )-, or -N(R 11 )C(O)-, where R 11 are independently H or C 1-6 It is alkyl,

[0042] q1, q2, q3, q4, and q5 are integers from 0 to 5, independently of each other.

[0043]

[0044] A preferred embodiment of the present invention is, in the chemical formula 1,

[0045] R1 is , , or And,

[0046] R 12a is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, or C 1-6 It is haloalkyl,

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

[0048] R 13a and R 13b are independently H, C 1-6alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 It is alkoxy,

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

[0050] Z is independently -O-, -S-, -NH-, or -CH2-,

[0051] Ring C is aryl or heteroaryl,

[0052] n is an integer from 0 to 3,

[0053] R2 is H, C 1-6 alkyl, or -NH2,

[0054] R3 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, -C(O)NR 10a R 10b , or CN,

[0055] R4 is H, C 1-6 alkyl, halogen (preferably Cl), C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 It is haloalkoxy,

[0056] R5 is H, C 1-6 alkyl, C 2-6 alkynyl (preferably acetylenyl), halogen (preferably F, Cl), -CN, or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole, or triazole), wherein the heteroaryl optionally has one or more hydrogens in the ring atom(s) C 1-6alkyl (preferably methyl, ethyl), halogen, or C 1-3 is substituted with haloalkyl,

[0057] R6 is -NHC(O)R7 or heteroaryl (preferably isoxazole, triazole, or pyrazole), wherein the heteroaryl optionally has one or more hydrogens in the ring at C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl,

[0058] R7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, or heterocycle, wherein cycloalkyl and heterocycle are independently of each other and optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen (preferably F), or -CN,

[0059] R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl,

[0060] R 9a and R 9b are independently H, C 1-6 alkyl, C 1-6 alkoxy, or halogen,

[0061] X is -S-, -O-, -N(R 10a )-, or -CH2-,

[0062] Y is CH or N,

[0063] W is a direct bond, -O-, or -N(R 10a )-and,

[0064] V is CH or N,

[0065] R 10a and R 10b are independently H, C 1-6 alkyl, or C 1-6 It is haloalkyl,

[0066] L is the following chemical formula 2,

[0067] [Chemical Formula 2]

[0068]

[0069] In chemical formula 2,

[0070] A1 and A2 are directly bonded independently of each other, C 3-10 cycloalkyl, heterocycle (preferably azetidine, pyrrolidine, piperidine, piperazine), aryl, or heteroaryl, wherein cycloalkyl, heterocycle, aryl, or heteroaryl optionally has one or more hydrogens in the ring at C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, -OH, or =O,

[0071] B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, -C(O)-, -C(O)N(R 11 )-, or -N(R 11 )C(O)-, where R 11 are independently H or C 1-6 It is alkyl,

[0072] q1, q2, q3, q4, and q5 are independently integers from 0 to 5,

[0073] Provided are compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0074]

[0075] The compounds of the present disclosure have desirable properties in terms of SHP2 degradation activity, stability in plasma, metabolic stability in the body, stability during storage, pharmacological properties, and physicochemical properties.

[0076] In addition, the compounds of the present invention have advantageous properties in addition to the aspects of the compounds of the present invention mentioned above, such as cancer cell proliferation inhibition activity, (water) solubility, cell permeability, dosage requirement (good effect is achieved even with low dosage due to good activity and solubility), bioavailability, body distribution, cancer tissue distribution, pharmacodynamic properties, pharmacodynamic activity, duration of effect, and drug interaction.

[0077]

[0078] More preferably, one aspect of the present invention is, in the above chemical formula 1,

[0079] R1 is , , or And,

[0080] R 12a is H, C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, or C 1-3 It is haloalkyl,

[0081] R 12b is amino, C 1-3 aminoalkyl, or C 1-3 It is alkylamino,

[0082] R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, or C 1-3 It is alkoxy,

[0083] R 14 are independently H, C 1-6alkyl, hydroxy, halogen, or CN,

[0084] Z is independently -O-, -NH-, or -CH2-,

[0085] Ring C is aryl or heteroaryl,

[0086] n is an integer from 0 to 3,

[0087] R2 is H, C 1-6 alkyl, or -NH2,

[0088] R3 is H, C 1-6 alkyl, C 1-3 hydroxyalkyl, -C(O)NR 10a R 10b , or CN,

[0089] R4 is H, C 1-6 alkyl, halogen (preferably Cl), or C 1-6 It is haloalkyl,

[0090] R5 is H, C 1-6 alkyl, C 2-6 alkynyl (preferably acetylenyl), halogen (preferably F, Cl), -CN, or heteroaryl (preferably thiazole, pyrazole, pyrrole, oxazole, or triazole), wherein the heteroaryl optionally has one or more hydrogens in the ring atom(s) C 1-6 alkyl (preferably methyl, ethyl), halogen, or C 1-3 is substituted with haloalkyl,

[0091] R6 is -NHC(O)R7 or heteroaryl (preferably isoxazole, triazole, or pyrazole), wherein the heteroaryl optionally has one or more hydrogens in the ring at C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C3-6 Substituted with cycloalkyl,

[0092] R7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, or C 3-10 cycloalkyl, where cycloalkyl is optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen (preferably F), or -CN,

[0093] R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl,

[0094] R 9a and R 9b are independently H, C 1-6 alkyl, or halogen,

[0095] X is -S-, -O-, -N(R 10a )-, or -CH2-,

[0096] Y is CH or N,

[0097] W is a direct bond, -O-, or -N(R 10a )-and,

[0098] V is CH or N,

[0099] R 10a and R 10b are independently H, C 1-6 alkyl, or C 1-6 It is haloalkyl,

[0100] L is the following chemical formula 2,

[0101] [Chemical Formula 2]

[0102]

[0103] In chemical formula 2,

[0104] A1 and A2 are directly bonded independently of each other, C3-10 cycloalkyl, or heterocycle (preferably azetidine, pyrrolidine, piperidine, piperazine), wherein cycloalkyl and heterocycle are independently of each other and optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, or -OH,

[0105] B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, or -C(O)-, where R 11 are independently H or C 1-6 It is alkyl,

[0106] q1, q2, q3, q4, and q5 are independently integers from 0 to 5,

[0107] Provided are compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0108]

[0109] Even more preferably, one aspect of the present invention is, in the chemical formula 1,

[0110] R1 is , , or And,

[0111] R 12a is H, C 1-6 alkyl, hydroxy, or C 1-3 It is hydroxyalkyl,

[0112] R 12b is amino or C 1-3 It is aminoalkyl,

[0113] R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, C1-3 hydroxyalkyl, or C 1-3 It is alkoxy,

[0114] R 14 are independently H, C 1-3 alkyl, hydroxy, halogen, or CN,

[0115] Z is independently -O-, -NH-, or -CH2-,

[0116] Ring C is aryl or heteroaryl,

[0117] n is an integer from 0 to 3,

[0118] R2 is H, C 1-6 alkyl, or -NH2,

[0119] R3 is H, C 1-6 alkyl, or C 1-3 It is hydroxyalkyl,

[0120] R4 is H, C 1-6 alkyl, halogen (preferably Cl), or C 1-3 It is haloalkyl,

[0121] R5 is H, C 1-6 alkyl, acetylenyl, halogen (preferably F, Cl), -CN, thiazole, pyrazole, pyrrole, oxazole, or triazole, wherein thiazole, pyrazole, pyrrole, oxazole, or triazole optionally has one or more hydrogens in the ring C 1-6 alkyl (preferably methyl, ethyl), halogen, or C 1-3 is substituted with haloalkyl,

[0122] R6 is -NHC(O)R7, isoxazole, triazole, or pyrazole, wherein isoxazole, triazole, or pyrazole optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl,

[0123] R7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, or C 3-6 cycloalkyl, where cycloalkyl is optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen (preferably F), or -CN,

[0124] R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl,

[0125] R 9a and R 9b are independently H, C 1-3 alkyl, or halogen,

[0126] X is -S- or -O-,

[0127] Y is CH or N,

[0128] W is a direct bond, -O-, or -N(R 10a )-and,

[0129] V is CH or N,

[0130] R 10a is H, C 1-3 alkyl, or C 1-3 It is haloalkyl,

[0131] L is the following chemical formula 2,

[0132] [Chemical Formula 2]

[0133]

[0134] In chemical formula 2,

[0135] A1 and A2 are independently a direct bond, cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, or 3-azabicyclo[3.1.1]heptane, wherein cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, and 3-azabicyclo[3.1.1]heptane are independently a direct bond, and optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, or -OH,

[0136] B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, or -C(O)-, where R 11 are independently H or C 1-3 It is alkyl,

[0137] q1, q2, q3, q4, and q5 are independently integers from 0 to 5,

[0138] Provided are compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0139]

[0140] Even more preferably, one aspect of the present invention is, in the chemical formula 1,

[0141] R1 is , , or And,

[0142] R 12a is H, C 1-6 alkyl, or hydroxy,

[0143] R 12b is amino or C 1-3 It is aminoalkyl,

[0144] R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, or C 1-3 It is hydroxyalkyl,

[0145] R 14 are independently H, C 1-3 alkyl, or halogen,

[0146] Z is independently -O- or -CH2-,

[0147] Ring C is aryl or heteroaryl,

[0148] n is an integer from 0 to 2,

[0149] R2 is H, C 1-6 alkyl, or -NH2,

[0150] R3 is H, C 1-6 alkyl, or C 1-3 It is hydroxyalkyl,

[0151] R4 is H, C 1-6 alkyl, halogen (preferably Cl), or C 1-3 It is haloalkyl,

[0152] R5 is H, C 1-6alkyl, acetylenyl, halogen (preferably F, Cl), -CN, thiazole, pyrazole, or pyrrole, wherein thiazole, pyrazole, or pyrrole optionally has one or more hydrogens in the ring C 1-6 alkyl (preferably methyl, ethyl), halogen, or C 1-3 is substituted with haloalkyl,

[0153] R6 is -NHC(O)R7, isoxazole, triazole, or pyrazole, wherein isoxazole, triazole, or pyrazole optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl,

[0154] R7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, or C 3-6 cycloalkyl, where cycloalkyl is optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen (preferably F), or -CN,

[0155] R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl,

[0156] R 9a and R 9b are independently H, C 1-3 alkyl, or halogen,

[0157] X is -S- or -O-,

[0158] Y is CH or N,

[0159] W is a direct bond, -O-, or -N(R 10a )-and,

[0160] V is CH,

[0161] R 10a is H, C 1-3 alkyl, or C 1-3 It is haloalkyl,

[0162] L is the following chemical formula 2,

[0163] [Chemical Formula 2]

[0164]

[0165] In chemical formula 2,

[0166] A1 and A2 are independently a direct bond, cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, or 3-azabicyclo[3.1.1]heptane, wherein cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, and 3-azabicyclo[3.1.1]heptane are independently a direct bond, and optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -OH,

[0167] B1 and B2 are independently a direct bond, -O-, or -C(O)-,

[0168] q1, q2, q3, q4, and q5 are independently integers from 0 to 3,

[0169] Provided are compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0170]

[0171] Even more preferably, one aspect of the present invention is, in the chemical formula 1,

[0172] R1 is or And,

[0173] R 12a is H or C 1-6 It is alkyl,

[0174] R 12b is amino or C 1-3 It is aminoalkyl,

[0175] R 13a and R 13b are independently H or C 1-6 It is alkyl,

[0176] Z is independently -O- or -CH2-,

[0177] R2 is H, C 1-6 alkyl, or -NH2,

[0178] R3 is H, C 1-6 alkyl, or C 1-3 It is hydroxyalkyl,

[0179] R4 is H, C 1-6 alkyl, halogen (preferably Cl), or C 1-3 It is haloalkyl,

[0180] R5 is H, C 1-6 alkyl, halogen (preferably F, Cl), -CN, thiazole, or pyrazole, wherein thiazole or pyrazole optionally has one or more hydrogens in the ring as C 1-3 alkyl (preferably methyl, ethyl), halogen, or C 1-3is substituted with haloalkyl,

[0181] R6 is -NHC(O)R7, isoxazole, or triazole, wherein isoxazole or triazole optionally has one or more hydrogens in the ring C 1-3 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl,

[0182] R7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, or C 3-6 cycloalkyl, wherein cycloalkyl is optionally substituted with one or more hydrogens in the ring by halogen (preferably F) or -CN,

[0183] R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl,

[0184] R 9a and R 9b are independently H, C 1-3 alkyl, or halogen,

[0185] X is -S-,

[0186] Y is CH or N,

[0187] W is a direct bond or -N(R 10a )-and,

[0188] V is CH,

[0189] R 10a is H, C 1-3 alkyl, or C 1-3 It is haloalkyl,

[0190] L is the following chemical formula 2,

[0191] [Chemical Formula 2]

[0192]

[0193] In chemical formula 2,

[0194] A1 and A2 are independently a direct bond, cyclohexane, cyclobutane, azetidine, piperidine, piperazine, or 3-azabicyclo[3.1.0]hexane, wherein cyclohexane, cyclobutane, azetidine, piperidine, piperazine, and 3-azabicyclo[3.1.0]hexane are independently of each other and optionally have one or more hydrogens in the ring C 1-3 substituted with alkyl, halogen, or -OH,

[0195] B1 and B2 are independently a direct bond or -C(O)-,

[0196] q1, q2, q3, q4, and q5 are independently integers from 0 to 3,

[0197] Provided are compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0198]

[0199] Preferably, in the SHP2 target protein degradation compound according to the present invention, the moiety (SHP2 ligand) on the left side of the linker (-WL-) has any of the following structures. When it has the structure as follows, not only is the SHP2 degradation activity excellent, but it is also suitable for various purposes of the present invention as mentioned above.

[0200]

[0201]

[0202] In one preferred embodiment of the present invention, neither A1 nor A2 is a direct bond. In another preferred embodiment of the present invention, B1 is not a direct bond. In another preferred embodiment of the present invention, neither A1 nor A2 is a direct bond, and B1 is not a direct bond. In one preferred embodiment of the present invention, A1 and A2 are independently C 3-10 cycloalkyl or heterocycle, wherein the cycloalkyl or heterocycle optionally has one or more hydrogens in the ring as C 1-6 alkyl, halogen, C 1-3 is substituted with haloalkyl, -OH, or =O. In a preferred embodiment of the present invention, A1 and A2 are independently C 3-6 cycloalkyl or heterocycle, wherein the cycloalkyl or heterocycle optionally has one or more hydrogens in the ring as C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, -OH, or =O, and B1 is not a direct bond. In a preferred embodiment of the present invention, A1 and A2 are independently C 3-6 cycloalkyl or heterocycle, wherein the cycloalkyl or heterocycle optionally has one or more hydrogens in the ring as C 1-6 alkyl, halogen, C 1-3 is substituted with haloalkyl, -OH, or =O, and B1 is -C(O)-. In a preferred embodiment of the present invention, A1 and A2 are each independently a heterocycle, wherein the heterocycle optionally has one or more hydrogens in the ring substituted with C 1-3 alkyl, halogen, C 1-3is substituted with haloalkyl, -OH, or =O, and B1 is not a direct bond. In a preferred embodiment of the present invention, A1 and A2 are each independently a heterocycle, wherein the heterocycle optionally has one or more hydrogens in the ring C 1-3 alkyl, halogen, C 1-3 is substituted with haloalkyl, -OH, or =O, and B1 is -C(O)-. In a preferred embodiment of the present invention, A1 and A2 are each independently a heterocycle, wherein the heterocycle optionally has one or more hydrogens in the ring substituted with C 1-3 alkyl, halogen, C 1-3 haloalkyl, or -OH, B1 is not a direct bond, and the total number of carbon atoms of q4 and q5 is 3 or less, preferably 2 or less. In a preferred embodiment of the present invention, A1 and A2 are each independently a heterocycle, wherein the heterocycle optionally has one or more hydrogens in the ring as C 1-3 alkyl, halogen, C 1-3 haloalkyl, or -OH, B1 is -C(O)-, and the total number of carbon atoms of q4 and q5 is 3 or less, preferably 2 or less. The heterocycle included in the linker of the present invention is preferably azetidine, pyrrolidine, piperidine, or piperazine.

[0203] As described below, in preferred embodiments of the linker of the aforementioned paragraph, (i) SHP2 ligand moieties, (ii) W in the linker (-WL-), and (iii) VHL ligand moieties can be used in various examples mentioned herein to form compounds of formula 1 in various combinations.

[0204] Preferably, in the SHP2 target protein degradation compound according to the present invention, the linker (-WL-) is any one of the following linkers. When the compound has a linker as described below, not only is the compound excellent in SHP2 degradation activity, but it is also suitable for various purposes of the present invention as mentioned above, particularly metabolic stability and stability during storage.

[0205]

[0206]

[0207] Preferably, in the SHP2 target protein degradation compound according to the present invention, the moiety (VHL ligand) on the right side of the linker (-WL-) has any of the following structures. When it has the structure as follows, the SHP2 degradation activity is excellent and it is more suitable for the various purposes of the present invention mentioned above.

[0208]

[0209]

[0210] One aspect of the present invention provides various forms of SHP2 target protein degradation compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates or pharmaceutically acceptable salts thereof, which combine one of the aforementioned (i) SHP2 ligand moieties, (ii) one of the linker (-WL-) moieties, and (iii) one of the VHL ligand moieties.

[0211] Non-limiting examples of compounds of formula 1 according to the present disclosure are the compounds prepared in Examples 1 to 102 described below. Each Example number corresponds to a compound number. For example, the number of the final compound prepared in Example 51 is Compound 51.

[0212] One aspect of the present invention provides a compound described in the table below, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221] In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

[0222] If a substituent is described as "optionally substituted" or "optionally substituted," it means that the substituent is unsubstituted or substituted with one or more of the defined substituents. If a substitutable position is unsubstituted, the default substituent is hydrogen.

[0223] The term "alkyl" as used herein means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms or 1 to 6 carbon atoms (where the number of carbon atoms is not specifically limited). "Lower alkyl" means a straight-chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-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, and 2,2-diethylhexyl. In a preferred embodiment of the present invention, alkyl is methyl, ethyl, n-propyl, -isopropyl, or tert-butyl.

[0224] The term "alkynyl" as used herein means a straight-chain or branched non-cyclic hydrocarbon having 2 to 10 or 2 to 6 carbon atoms (where the number of carbon atoms is not particularly limited) and containing at least one carbon-carbon triple bond. Representative straight-chain or branched (C2-C 10) Alkynyl includes -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, and -9-decynyl. These alkynyl groups can be optionally substituted.

[0225] The term "alkoxy" as used herein means -O-(alkyl) including -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)2H, -OC(CH3)3, and the like, wherein alkyl is as defined above.

[0226] In this specification, “C 1-6 ”, “C1-6”, or “C1-C6”, this means that the number of carbon atoms is 1 to 6. For example, C 1-6 Alkyl refers to alkyl having 1 to 6 carbon atoms.

[0227] 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.

[0228] The term "haloalkyl" as used herein means an alkyl group in which one or more hydrogen atoms are each replaced by a halogen atom. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CCl3, -CHCl2, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CCl3, -CH2-CHCl2, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and the like. In a preferred embodiment of the present invention, haloalkyl is CF3. wherein alkyl and halogen are as defined above.

[0229] The term "hydroxyalkyl" as used herein refers to a linear or branched C substituted with one or more hydroxy groups. 1-10 Alkyl or C 1-6 Indicates alkyl, examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0230] The term "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Examples of polycyclic rings include, but are not limited to, fused bicyclic rings such as octahydropentalene, decahydronaphthalene, etc.; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, etc.; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The cycloalkyl group may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic ring. In a preferred embodiment of the present invention, the cycloalkyl is cyclopropyl.

[0231] As used herein, “heterocycle” or “heterocycloalkyl” means a saturated 5- to 7-membered monocyclic, or 7- to 12-membered bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Representative heterocycles include oxiran, oxetan, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidinone, hydantoine, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, morpholine, tetrahydropyridine, tetrahydropyrimidine, etc. Heterocycles include bicyclic rings in which some of the heterocycles are fused to a benzene or cyclopenta-1,3-diene ring. The heterocycles may be attached by heteroatoms or carbon atoms. Heterocycles also include fused bicyclic rings, spiro rings, and bridged bicyclic rings in which one or more carbon atoms of the aforementioned polycyclic rings are replaced by nitrogen, oxygen, or sulfur atoms. Examples of these include, for example, 3-azabicyclo[3.1.Fused heterobicyclic rings such as 0]hexane, octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, etc.; 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, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, Spiro rings such as 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, 3,9-diazaspiro[5.5]undecane, etc.; and bridged heterobicyclic rings such as 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane, etc. In a preferred embodiment of the present invention, the heterocycle is any one selected from azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.1]heptane, etc.

[0232] The term "aryl" as used herein refers to a carbon-cyclic aromatic group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The carbon-cyclic aromatic group may be optionally substituted.

[0233] As used herein, "heteroaryl" is a 5 to 10 membered aromatic heterocycle ring having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and at least one carbon atom, including mono- and bicyclic ring systems. Representative heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, ozaxole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, and the like. In a preferred embodiment of the present invention, the heteroaryl is thiazole, pyridine, or pyrazine.

[0234] In this specification, * or means connected to another moiety.

[0235]

[0236] The term "pharmaceutically acceptable salts" in the present invention includes salts of the active compounds prepared with relatively non-toxic acids and bases, depending on the specific substituents found in the compounds mentioned herein. When the compounds of the present disclosure contain relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present disclosure contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids, including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like, as well as salts derived from hydrochloric, hydrobromide, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide, or phosphorous acids and the like. Also included are salts of amino acids such as alginate and its analogs and analogs of organic acids such as glucuronic or galactunoric acids and their analogs.Certain specific compounds of the present invention possess both basic and acidic functionalities, allowing them to be converted into basic or acidic addition salts. Other examples of salts are well known in the art.

[0237] As used herein, the term "compound of the present disclosure" is meant to include not only each compound of Formula 1, but also optical isomers, stereoisomers, isotopic variants, hydrates, or solvates thereof. The term "compound of the present disclosure" is also meant to include pharmaceutically acceptable salts of the compounds of the present disclosure, unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, the compounds of the present disclosure can exist as stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than or equal to 85% ee, greater than or equal to 90% ee, greater than or equal to 95% ee, greater than or equal to 97% ee, or greater than or equal to 99% ee)). That is, when the compound of formula 1 according to the present invention or a salt thereof is a tautomeric isomer and / or a stereoisomer (e.g., a geometrical isomer and a conformational isomer), each of their separated isomers and mixtures are also included in the scope of the compound of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.

[0238] As used herein, the term "isomer" means compounds having the same molecular formula but differing in the nature or order of their atomic bonding or in the arrangement of their atoms in space.

[0239] As used herein, the term "stereoisomer" means an isomer having different arrangements of atoms in space.

[0240] 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, it can bond to four different groups, forming a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of the asymmetric center, described by the R and S sequencing rules, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures of them. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0241] As used herein, a pure enantiomeric compound is one in which the other enantiomer or stereoisomer of the compound is substantially free. This condition is called enantiomeric excess. In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, 99%, 99.2%, or greater than 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of the compound. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0242] As used herein, unless otherwise indicated, the term "enantiomerically pure (R)-compound" means at least about 95 wt % (R)-compound, no more than about 5 wt % (S), at least about 99 wt % (R)-compound and up to about 1 wt % (S)-compound, or at least about 99.9 wt % (R)-compound and up to about 0.1 wt % (S)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0243] As used herein, and unless otherwise indicated, the term "enantiomerically pure (S)-compound" means at least about 95 wt % of the (S)-compound, at most about 5 wt % of the (R)-compound, at least about 99 wt % of the (S)-compound and at most about 1 wt % of the (R)-compound, or at least about 99.9 wt % of the (S)-compound and at most about 0.1 wt % of the (R)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0244] In the compositions provided herein, the enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound can comprise, for example, about 90% excipients and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can comprise, for example, greater than or equal to about 95% (R)-compound and up to about 5% (S)-compound by total weight. weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound can comprise, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions may comprise, for example, at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0245] Unless otherwise specified, the description or designation of a particular compound in the specification and claims is intended to encompass both individual enantiomers and mixtures, racemates or other materials thereof.

[0246] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein contain one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0247] In certain embodiments, the compounds disclosed herein have one or more chiral centers, each center having an R configuration or an S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms, as well as corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0248] In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form pairs of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociative complexes are preferred. In certain embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are separated by exploiting these differences. In certain embodiments, diastereomers are separated by chiral chromatography, or, preferably, by separation / resolution techniques based on differences in solubility. In certain embodiments, the optically pure enantiomers are recovered along with the resolving agent.

[0249] In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein.

[0250] Tautomers are compounds that are interconvertible by the movement of hydrogen atoms, which involves the conversion of a single bond to an adjacent double bond. In bonding arrangements where tautomerism is possible, a chemical equilibrium of tautomers exists. The tautomeric form may be related to achieving optimal chemical reactivity and biological activity of the compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of this disclosure. The exact ratio of tautomers varies depending on several factors, including temperature, solvent, and pH.

[0251] As used herein, the term "isotopic variant" means a compound that contains an unusual ratio of isotopes at one or more atoms constituting the compound. For example, an isotopic variant of a compound may be radioactively labeled, for example, a hydrogen atom may be selected from hydrogen, deuterium, and tritium, and a carbon-13 ( 13 C), nitrogen-15( 15 N) may contain the following.

[0252] The term "solvent compound" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small amounts.

[0253] The term "hydrate" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0254] The term "purified" as used herein means that when separated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and in yet another embodiment at least 99.9% pure.

[0255]

[0256] Medicinal uses and therapeutic methods of the compounds of the present invention

[0257] One aspect of the present invention further provides a method for treating a disease or condition in a subject having or susceptible to the disease or condition by administering to the subject a therapeutically effective amount of one or more of the compounds described above. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.

[0258] As used herein, the term “prevention” or “preventing” describes preventing the onset of symptoms or complications of a disease, condition or disorder.

[0259] 1. Disease or condition

[0260] The compounds of the present disclosure are useful for various therapeutic or prophylactic applications (e.g., cancer). These compounds can be used to degrade SHP2 and thereby reduce SHP2 activity, and can also be used to treat or prevent the worsening of SHP2-associated diseases. Accordingly, one aspect of the present disclosure provides a method for degrading SHP2 in a cell. In such a method, the cell can be 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 comprises administering to a subject in need of treatment or prevention a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of the present disclosure.

[0261] In one aspect, an aspect of the present invention provides a method for degrading SHP2 within a cell of a SHP2-associated disease. For example, one embodiment of the present invention may provide a method for degrading SHP2 within a cell of an individual suffering from a SHP2-associated disease, as described below, thereby reducing SHP2 activity. In another aspect of the present invention, the compounds of the present disclosure may be used to degrade SHP2 within a cell of a cancer, particularly leukemia, lymphoma, lung cancer, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, pancreatic cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, melanoma, neuroblastoma, glioma, sarcoma, and the like.

[0262] In another aspect, a method of treating a SHP2-associated disorder is provided, comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. The method comprises administering to a subject in need thereof an amount of a compound of the present disclosure sufficient to degrade SHP2, i.e., a therapeutically effective amount. In such a method, the compound of the present disclosure may be administered to the subject in the form of a pharmaceutical composition as described herein.

[0263] In one specific embodiment of the present invention, the SHP2-related disease may be cancer, cancer metastasis, cardiovascular disease, immune disorder, or ocular disorder.

[0264] In one specific embodiment of the present invention, the SHP2-related disease is cancer. For example, it may be any one of the cancers described in Table 2 of International Patent Application Publication No. WO 2021 / 236775, but is not limited thereto. Specifically, it may be at least one selected from hematological cancer, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT-midline cancer, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, lymphoma, cervical cancer, head and neck cancer, head cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, melanoma, colon cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma, or sarcoma, papillary thyroid carcinoma, and combinations thereof. The disclosure of Table 2 of WO 2021 / 236775 is fully incorporated herein by reference. In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is a hematological cancer. Exemplary hematological 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 fully incorporated herein by reference. In another embodiment, the hematological cancer is acute lymphoblastic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. In another embodiment, the cancer is a leukemia, for example, a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In 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's 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 stomach 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 colon cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0265] In another embodiment, the cancer according to the present invention is selected from the group consisting of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, lymphoma, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, head and neck cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, melanoma, ovarian cancer, colon cancer, prostate cancer, breast cancer, bladder cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0266] That is, one aspect of the present invention provides a pharmaceutical use of a compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof for treating or preventing the above-described disease.

[0267] 2. Subjects

[0268] Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, and the like, and include mammals in utero.

[0269] In one aspect, the subject suitable for treatment according to the present invention is a human.

[0270] 3. Administration and Dosing

[0271] The compounds of the present disclosure are generally administered in therapeutically effective amounts.

[0272] As used herein, "effective amount" refers to an amount of a compound of the present disclosure sufficient to prevent, slow, or minimize the progression of a SHP2-associated disorder, or provide a therapeutic benefit in the treatment or management of a SHP2-associated disorder. An "effective amount" also refers to an amount sufficient to inhibit or reduce SHP2 activity, either in vitro or in vivo.

[0273] The compounds of the present disclosure may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg / kg body weight per day, preferably from about 0.01 to about 50 mg / kg / day, in single or divided doses. Dosage levels below the lower end of this range may be appropriate depending on age, species, and the disease or condition being treated. In other cases, still higher dosages may be used without harmful side effects. A larger dosage may be divided into several smaller doses for administration throughout the day.

[0274] 4. Other embodiments related to medicinal use

[0275] Based on the foregoing description, one aspect of the present invention provides a method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

[0276] Based on the foregoing description, one aspect of the present invention provides a method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample, comprising the step of contacting the patient or biological sample with a compound according to the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

[0277] Based on the foregoing description, one aspect of the present invention provides the use of a compound according to the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, for the production of a medicament for degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample.

[0278] Based on the foregoing description, one aspect of the present invention provides the use of a compound according to the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, for the production of a medicament for treating a Src homology 2 domain-containing phosphatase (SHP2)-associated disease.

[0279]

[0280] Pharmaceutical composition of the present disclosure compound

[0281] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect of the present invention, the use of the pharmaceutical composition is for the treatment or prevention of a SHP2-related disease, specifically cancer, as described below.

[0282] The term "pharmaceutically acceptable" means suitable for use in pharmaceutical preparations, generally considered safe for such use, and officially approved by a national regulatory agency for such use or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0283] As the pharmaceutically acceptable carrier or additive, any one or more of the carriers or additives mentioned in the composition or formulation described below may be used.

[0284]

[0285] Pharmaceutical compositions, dosage forms and routes of administration

[0286] For the treatment of the diseases or conditions described above, the compounds described herein may be administered as follows.

[0287] 1. Oral administration

[0288] The compounds of the present disclosure may be administered orally, including by swallowing. Oral administration allows the compounds of the present invention to enter the gastrointestinal tract, or, for example, may be absorbed directly into the bloodstream through the mouth, as in buccal or sublingual administration.

[0289] Suitable compositions for oral administration may be in the form of solids, liquids, gels, or powders, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0290] Compositions for oral administration may optionally be enteric coated, and may exhibit delayed or sustained release through the enteric coating. That is, the compositions for oral administration according to the present invention may be formulations having an immediate or modified release pattern.

[0291] Liquid formulations may include solutions, syrups, and suspensions, and these liquid compositions may be contained within soft or hard capsules. These formulations may include pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations may also include one or more emulsifying and / or suspending agents.

[0292] In tablet formulations, the active ingredient drug may be present in an amount of from about 0.05% to about 95% by weight of the total weight of the tablet, more typically from about 2% to about 50% by weight of the formulation. The tablets may also contain a disintegrant, which comprises from about 0.5% to about 35% by weight, more typically from about 2% to about 25% by weight of the formulation. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0293] Suitable lubricants included for manufacturing the tablets may be present in an amount of about 0.1 wt% to about 5 wt%, and talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, etc. may be used as lubricants, but the present invention is not limited to the types of these additives.

[0294] Gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. can be used as binders for manufacturing into tablets, and mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. can be used as suitable diluents for manufacturing into tablets, but the present invention is not limited to the types of these additives.

[0295] Solubilizing agents that may optionally be included in the tablet may be used in an amount of about 0.1 wt% to about 3 wt% based on the total weight of the tablet, and examples thereof include polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR. TM (Nikkol), oleic acid ester, gelucire TM ), caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, solutol HS TM Although these may be used in the pharmaceutical composition according to the present invention, the present invention is not limited to the specific types of these solubilizing agents.

[0296] 2. Parenteral Administration

[0297] The compounds of the present disclosure may be administered directly into the bloodstream, muscle, or viscera. Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, and intracranial injections. Suitable devices for parenteral administration include injectors (including needle and needle-less syringes) and infusion methods.

[0298] Most parenteral formulations are liquid compositions, which are aqueous solutions containing the active ingredient, salt, buffer, isotonic agent, etc. according to the present invention.

[0299] Parenteral formulations may also be prepared in dried form (e.g., lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle, such as sterile water.

[0300] 3. Topical Administration

[0301] The compounds of the present disclosure can be administered topically, either skin-wise or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be accomplished by electroporation, iontophoresis, phonophoresis, and the like.

[0302]

[0303] Combination administration

[0304] In one aspect of the present invention, the compound of the present invention may be administered in combination with a second active ingredient, preferably a second anticancer agent.

[0305] The terms "combination administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a different time than the administration of the additional therapeutic agent or agent), as long as the therapeutic agents are simultaneously present in the patient's body to some extent, preferably in an effective amount. In certain preferred embodiments, one or more compounds of the present disclosure described herein are co-administered in combination with at least one additional bioactive agent, particularly an anti-cancer agent. In certain preferred embodiments, the co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer therapy.

[0306] In one embodiment of the present invention, the compound of formula 1 of the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, may be usefully combined with another pharmacologically active compound or two or more other pharmacologically active compounds, particularly in the treatment of cancer. For example, the pharmaceutical ingredient of the present invention may be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapeutic agents, for example, mitotic inhibitors such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, for example, cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine. These combinations may provide important benefits in treatment, including synergistic, preferably synergistic, effects.

[0307] Accordingly, one aspect of the present invention provides a composition for treating or preventing cancer or cancer metastasis, comprising a compound of formula 1 of the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof as a first active ingredient, and another anticancer agent as a second active ingredient.

[0308] Another aspect of the present invention also provides a method for treating or preventing cancer or cancer metastasis, comprising administering to a subject in need thereof a therapeutically effective amount, particularly an amount effective to cause a synergistic effect, of a compound of formula 1 of the present invention as a first active ingredient, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and an anticancer agent as a second active ingredient.

[0309] Another aspect of the present invention also provides the use of a compound of formula 1 of the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, for the production of a medicament in combination with another anticancer agent for the treatment or prevention of cancer or cancer metastasis.

[0310] For example, in one aspect of the present invention, the compound of formula 1 of the present invention, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, may be administered in combination with any one or more of the second active ingredients described in Table 1 below.

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] In the above embodiments of the present invention, the anticancer agent may preferably be at least one of a Hormone or Nuclear receptor-related protein inhibitor or degrader; a Non-Receptor tyrosine kinase inhibitor or degrader; an RTK / RAS / MAPK pathway protein inhibitor or degrader; an immuno-oncology agent, an immunomodulatory drug or vaccine; a cytotoxic anticancer agent; or an antibody-drug conjugate of Table 1.

[0319] The present disclosure provides compounds having excellent SHP2 degrading activity and thus exhibiting various pharmacological activities, pharmaceutical compositions comprising these as active ingredients, their medicinal uses (particularly, cancer or tumors), and therapeutic methods comprising administering these to a subject in need of treatment or prevention. The compounds according to the present disclosure can provide compounds having excellent SHP2 degrading activity by linking an SHP2 binding ligand to a VHL ligand via the linker of the present disclosure, particularly by linking to a specific position of the VHL ligand, thereby providing an effective treatment option for tumor cells, particularly cancers having KRAS mutations. In addition, the compounds according to the present disclosure are excellent in various aspects, such as SHP2 degrading activity, plasma stability, metabolic stability, stability during storage, pharmacological properties, and physicochemical properties.

[0320] Hereinafter, the present invention will be described in detail, using examples and the like, to aid understanding. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0321]

[0322] Preparation of compounds of the present invention

[0323] Hereinafter, the synthetic processes of some compounds of the present disclosure are described, and compounds not mentioned below can be prepared by similar methods by replacing the starting materials, intermediates, and / or reactants.

[0324]

[0325] Intermediate 1. Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0326]

[0327] Step 1: Synthesis of Tert-butyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate

[0328] 3-Chloro-2-fluoro-4-iodopyridine (500 mg, 1.94 mmol), 1-Boc-3-aminoazetidine (669 mg, 3.88 mmol), and DIPEA (0.68 ml, 3.88 mmol) were suspended in DMSO (7.5 ml) and stirred at 100 °C for 2 hours. Distilled water (30 ml) was added to the reaction mixture 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 purified by MPLC (1-15% EtOAc / hexane) to obtain 540 mg (68%) of a white solid.

[0329] Step 2: Synthesis of N-(Azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine

[0330] 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 hour. The reaction mixture was concentrated under reduced pressure to obtain 800 mg (quant.) of brown oil.

[0331] Step 3: Synthesis of 2-(Trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate

[0332] N-(Azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine (800 mg, 1.07 mmol) and TEA (0.6 ml, 4.30 mmol) were suspended in DCM (3.8 ml), and 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (279 mg, 1.07 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. Distilled water (15 ml) was added to the reaction mixture, 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 purified by MPLC (1-15% EtOAc / hexane) to obtain 468 mg (96%) of a colorless oil.

[0333] Step 4: Synthesis of Tert-butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0334] Tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (504 mg, 2.21 mmol), 2,5-dibromopyrazine (500 mg, 2.10 mmol), and DIPEA (1.1 ml, 6.31 mmol) were suspended in NMP (2 ml) and stirred at 130 °C for 1 hour. Distilled water (20 ml) was added to the reaction mixture and 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 resulting residue was purified by MPLC (1-15% EtOAc / hexane) to give 705 mg (87%) of the title yellow solid.

[0335] Step 5: Synthesis of Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanoate

[0336] Tert-butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (705 mg, 1.83 mmol), methyl 3-mercaptopropionate (0.22 ml, 2.01 mmol), Pd2(dba)3 (84 mg, 0.09 mmol), Xantphos (106 mg, 0.18 mmol), and DIPEA (0.64 ml, 3.66 mmol) were suspended in 1,4-dioxane (3.6 ml) and stirred at 90 °C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (1-35% EtOAc / hexane) to obtain 680 mg (88%) of the title compound as a yellow oil.

[0337] Step 6: Synthesis of Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate

[0338] Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanoate (243 mg, 0.57 mmol) was suspended in THF (1.28 ml), and NaOEt (ca. 20% in EtOH, 0.21 ml, 0.63 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 278 mg (crude) of a yellow solid.

[0339] 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

[0340] 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), Pd2(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 h. Distilled water (15 ml) was added to the reaction mixture, 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 (1-40% EtOAc / hexane) to obtain 278 mg (95%) of a yellow solid.

[0341] 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

[0342] 2-(Trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate (37.8 mg, 0.06 mmol) and TBAF (1.0 M in THF, 0.17 ml, 0.17 mmol) were suspended in THF (0.43 ml) and stirred at 50 °C for 2 hours. Distilled water (5 ml) was added to the reaction mixture and extracted with DCM (5 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 28.5 mg (96%) of an ivory solid.

[0343]

[0344] Intermediates 2, 3, and 29 were synthesized using the same method as for synthesizing intermediate 1.

[0345]

[0346]

[0347] Intermediate 4. 1-(4-((5-(4-(((Tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid

[0348]

[0349] Step 1: Synthesis of Methyl 1-(3-chloro-4-iodopyridin-2-yl)piperidine-4-carboxylate

[0350] 3-Chloro-2-fluoro-4-iodopyridine (4.5 g, 17.46 mmol), methyl piperidine-4-carboxylate (5.0 g, 34.92 mmol), and DIPEA (9.0 ml, 52.38 mmol) were suspended in DMSO (58 ml) and stirred at 100 °C for 1 hour. Distilled water (100 ml) was added to the reaction mixture and extracted with EtOAc (100 ml x 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 purified by MPLC (0-10% EtOAc / hexane) to obtain 5.05 g (76%) of a white solid.

[0351] Step 2: Synthesis of Methyl 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate

[0352] Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (849 mg, 2.355 mmol), methyl 1-(3-chloro-4-iodopyridin-2-yl)piperidine-4-carboxylate (598 mg, 1.57 mmol), Pd2(dba)3 (18 mg, 0.078 mmol), Xantphos (91 mg, 0.157 mmol), and DIPEA (1.4 ml, 7.85 mmol) were suspended in 1,4-dioxane (5 ml) and stirred at 90 °C for 4 hours. Distilled water (20 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (15 ml x 2). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-50% EtOAc / hexane) to obtain 910 mg (98%) of a white solid.

[0353] Step 3: Synthesis of 1-(4-((5-(4-(((Tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid

[0354] Methyl 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate (908 mg, 1.53 mmol) and LiOH monohydrate (116 mg, 2.76 mmol) were suspended in THF:MeOH:H2O = 3:1:1 (10 ml) and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and extracted with DCM (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-100% EtOAc / hexane and 0-10% MeOH / DCM) to obtain 854 mg (97%) of an ivory solid.

[0355]

[0356] Intermediates 5, 6, 32, and 33 were synthesized using the same method as that for synthesizing intermediate 4.

[0357]

[0358]

[0359] Intermediate 7. 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

[0360]

[0361] Step 1: Synthesis of Methyl 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylate

[0362] Tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (4.63 g, 20.28 mmol), methyl 3,6-dibromopyrazine-2-carboxylate (5 g, 16.9 mmol), and TEA (4.7 ml, 33.8 mmol) were suspended in DMF (75 ml) and stirred at 80 °C for 2 hours. Distilled water (50 ml) was added to the reaction mixture and extracted with EtOAc (50 ml x 2). The organic layer was washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-15% EtOAc / hexane) to obtain 7.18 g (96%) of a yellow solid.

[0363] Step 2: Synthesis of Tert-butyl ((1-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate

[0364] Methyl 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylate (3 g, 6.77 mmol) was suspended in EtOH (16 ml), and NaBH4 (640 mg, 16.92 mmol) and CaCl2 (1.5 mg, 13.53 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 16 hours. Saturated NH4Cl aqueous solution (40 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (40 ml). The organic layer was washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (1-20% EtOAc / hexane) to obtain 1.08 g (39%) of a yellow solid.

[0365] Step 3: Synthesis of Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propanoate

[0366] Tert-butyl ((1-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (1.07 g, 2.58 mmol), methyl 3-mercaptopropionate (0.31 ml, 2.83 mmol), Pd2(dba)3 (118 mg, 0.13 mmol), Xantphos (149 mg, 0.26 mmol), and DIPEA (0.93 ml, 5.15 mmol) were suspended in 1,4-dioxane (10 ml) and stirred at 90 °C for 1 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (1-40% EtOAc / hexane) to obtain 1.07 g (82%) of yellow oil.

[0367] Step 4: Synthesis of Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate

[0368] Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propanoate (167 mg, 0.37 mmol) was suspended in THF (1.2 ml), and NaOEt (ca. 20% in EtOH, 0.16 ml, 0.40 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 143 mg (crude) of a yellow solid.

[0369] Step 5: 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

[0370] Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate (132 mg, 0.34 mmol), methyl 1-(3-chloro-4-iodopyridin-2-yl)piperidine-4-carboxylate (86 mg, 0.23 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol), and DIPEA (0.11 ml, 0.68 mmol) were suspended in 1,4-dioxane (1.1 ml) and stirred at 90 °C for 16 h. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to MPLC (0-50% EtOAc / hexane) to obtain 104 mg (74%) of an ivory solid.

[0371] Step 6: 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

[0372] 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 monohydrate (10 mg, 0.24 mmol) were suspended in THF:H2O = 3:1 (0.72 ml) and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and extracted with EtOAc (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 99 mg (99%) of an orange solid.

[0373]

[0374] Intermediates 8, 9, and 34 to 38 were synthesized using the same method as that for synthesizing intermediate 7.

[0375]

[0376]

[0377]

[0378] Intermediate 10. (S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid

[0379]

[0380] Step 1: Synthesis of Methyl (S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoate

[0381] (S)-3-(4-Bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoic acid (2.8 g, 8.13 mmol), MeOH (313 mg, 9.76 mmol), TBTU (3.13 g, 9.76 mmol), HOBt (1.32 g, 9.76 mmol), and DIPEA (4.2 ml, 24.4 mmol) were suspended in DCM (40 ml) and stirred at room temperature for 16 h. Distilled water (40 ml) was added to the reaction mixture and extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-35% EtOAc / hexane) to obtain 2.75 g (95%) of a white solid.

[0382] Step 2: Synthesis of Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate

[0383] Methyl (S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoate (2.75 g, 7.68 mmol) and 4-methylthiazole (1.4 ml, 15.4 mmol) were suspended in NMP (25 ml), KOAc (1.51 g, 15.4 mmol) and Pd(OAc)2 (35 mg, 0.15 mmol) were added, and the mixture was stirred at 90 ℃ for 4 hours. Distilled water (30 ml) was added to the reaction mixture, and then extracted with EtOAc (40 ml x 2). The organic layer was washed with a saturated aqueous solution of NaHCO3 (30 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0-66% EtOAc / hexane) to obtain 1.95 g (68%) of an ivory solid.

[0384] Step 3: Synthesis of Methyl (S)-3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate

[0385] Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate (1.9 g, 5.05 mmol) was suspended in DCM (30 ml), 4 M HCl in 1,4-dioxane (12.6 ml, 50.5 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 1.59 g (crude) of a white solid.

[0386] Step 4: Synthesis of Methyl (S)-3-((2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate

[0387] Methyl (S)-3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate (1.59 g, crude), (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.75 g, 5.07 mmol), EDCI (1.17 g, 6.09 mmol), HOBt (823 mg, 6.09 mmol), and DIPEA (2.6 ml, 15.23 mmol) were suspended in DCM (30 ml) and stirred at room temperature for 16 h. Distilled water (30 ml) was added to the reaction mixture, and the mixture was extracted with DCM (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to obtain 1.9 g (63%) of a white solid.

[0388] Step 5: Synthesis of Methyl (S)-3-((2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate

[0389] Methyl (S)-3-((2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate (200 mg, 0.33 mmol) was suspended in DCM (2.4 ml), 4 M HCl in 1,4-dioxane (0.83 ml, 3.3 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 179 mg (crude) of a white solid.

[0390] Step 6: Synthesis of Methyl (S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate

[0391] Methyl (S)-3-((2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate (179 mg, crude), acetic acid (0.02 ml, 0.33 mmol), EDCI (76.4 g, 0.4 mmol), HOBt (54 mg, 0.4 mmol), and DIPEA (0.17 ml, 1.0 mmol) were suspended in DMF (2 ml) and stirred at room temperature for 16 h. Distilled water (3 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (5 ml x 2). The organic layer was washed with brine (5 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-8% MeOH / DCM) to obtain 142 mg (79%) of a white solid.

[0392] Step 7: Synthesis of (S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid

[0393] Methyl (S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoate (140 mg, 0.26 mmol) and LiOH monohydrate (21.6 mg, 0.51 mmol) were suspended in THF:MeOH:H2O = 3:1:1 (2.5 ml) and stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and concentrated under reduced pressure to obtain 202 mg (crude) of a white solid.

[0394]

[0395] Intermediate 11 was synthesized using the same method as that for synthesizing intermediate 10.

[0396]

[0397]

[0398] Intermediate 12. 1-((S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylic acid

[0399]

[0400] Step 1: Synthesis of Ethyl 1-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylate

[0401] (S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (intermediate 10, 150 mg, 0.28 mmol), ethyl piperidine-4-carboxylate (49 mg, 0.31 mmol), EDCI (65.2 mg, 0.34 mmol), HOBt (46 mg, 0.34 mmol), and DIPEA (0.15 ml, 0.85 mmol) were suspended in DCM (3 ml) and stirred at room temperature for 16 h. Distilled water (4 ml) was added to the reaction mixture, and the mixture was extracted with DCM (6 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0-12% MeOH / DCM) to obtain 73 mg (39%) of a white solid.

[0402] Step 2: Synthesis of 1-((S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylic acid

[0403] Ethyl 1-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylate (70 mg, 0.11 mmol) and LiOH monohydrate (8.8 mg, 0.21 mmol) were suspended in THF:MeOH:H2O = 3:1:1 (2 ml) and stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and concentrated under reduced pressure to obtain 36 mg (crude) of a white solid.

[0404]

[0405] Intermediate 13 was synthesized using the same method as that for synthesizing intermediate 12.

[0406]

[0407]

[0408] Intermediate 14. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0409]

[0410] Step 1: Synthesis of Tert-butyl 4-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperazine-1-carboxylate

[0411] (S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (intermediate 10, 100 mg, 0.19 mmol), tert-butyl piperazine-1-carboxylate (35.6 mg, 0.23 mmol), EDCI (43.3 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol), and DIPEA (0.16 ml, 0.95 mmol) were suspended in DMF (3 ml) and stirred at room temperature for 16 h. Distilled water (5 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (5 ml x 2). The organic layer was washed with brine (5 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-8% MeOH / DCM) to obtain 77 mg (59%) of a white solid.

[0412] Step 2: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0413] Tert-butyl 4-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperazine-1-carboxylate (75 mg, 0.11 mmol) was suspended in DCM (3 ml), 4 M HCl in 1,4-dioxane (0.28 ml, 1.1 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 79 mg (crude) of a white solid.

[0414]

[0415] Intermediate 15 was synthesized using the same method as that for synthesizing intermediate 14.

[0416]

[0417]

[0418] Intermediate 16. 1-((S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid

[0419]

[0420] Step 1: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-3-(methoxy(methyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)pyrrolidine-2-carboxamide

[0421] (S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (intermediate 10, 194 mg, 0.37 mmol), N,O-dimethylhydroxylamine hydrochloride (43 mg, 0.44 mmol), EDCI (84 mg, 0.44 mmol), HOBt (59 mg, 0.44 mmol), and DIPEA (0.2 ml, 1.09 mmol) were suspended in DCM (1.8 ml) and stirred at room temperature for 16 h. Distilled water (15 ml) was added to the reaction mixture, 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 (0-5% MeOH / DCM) to obtain 130 mg (62%) of an ivory solid.

[0422] Step 2: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)pyrrolidine-2-carboxamide

[0423] (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-3-(methoxy(methyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)pyrrolidine-2-carboxamide (137 mg, 0.24 mmol) was suspended in THF (8 ml), and LiAlH4 (2.0 M in THF, 0.15 ml, 0.31 mmol) was added at 0 °C, followed by stirring at 0 °C for 1 h. Distilled water (12 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0-10% MeOH / DCM) to obtain 78 mg (63%) of an ivory solid.

[0424] Step 3: Synthesis of Ethyl 1-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylate

[0425] (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)pyrrolidine-2-carboxamide (78 mg, 0.15 mmol), ethyl 4-piperidinecarboxylate (0.05 ml, 0.30 mmol), NaBH(OAc)3 (96 mg, 0.45 mmol), and acetic acid (0.2 ml) were suspended in ACN (1.2 ml) and stirred at room temperature for 16 h. Saturated NaHCO3 aqueous solution (20 ml) was added to the reaction mixture, and the mixture was extracted with DCM (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to obtain 26 mg (26%) of an ivory solid.

[0426] Step 4: Synthesis of 1-((S)-3-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid

[0427] Ethyl 1-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylate (103 mg, 0.16 mmol) and LiOH monohydrate (10 mg, 0.24 mmol) were suspended in THF:H2O:MeOH = 4:1:1 (0.7 ml) and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and concentrated under reduced pressure to obtain 98 mg (crude) of an ivory-colored solid.

[0428]

[0429] Intermediates 17, 44, and 45 were synthesized using methods identical or similar to those used to synthesize intermediates 10 and 16.

[0430]

[0431]

[0432] Intermediate 18. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0433]

[0434]

[0435] Step 1: Synthesis of Tert-butyl (S)-(1-(4-bromophenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate

[0436] (S)-3-(4-Bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoic acid (5 g, 14.53 mmol), N,O-dimethylhydroxylamine hydrochloride (1.69 g, 17.43 mmol), EDCI (3.34 g, 17.43 mmol), HOBt (2.35 g, 17.43 mmol), and DIPEA (13 ml, 7.63 mmol) were suspended in DMF (24 ml) and stirred at room temperature for 5 hours. Distilled water (50 ml) was added to the reaction mixture and 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 (0-5% MeOH / DCM) to obtain 4.5 g (80%) of a colorless oil.

[0437] Step 2: Synthesis of Tert-butyl (S)-(3-(methoxy(methyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate

[0438] Tert-butyl (S)-(1-(4-bromophenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate (4.5 g, 11.62 mmol) and 4-methylthiazole (2.88 g, 29.05 mmol) were suspended in DMAC (20 ml), KOAc (2.28 g, 23.24 mmol) and Pd(OAc)2 (260 mg, 1.16 mmol) were added, and the mixture was heated and refluxed for 16 hours. Distilled water (100 ml) was added to the reaction mixture, and extracted with EtOAc (100 ml x 2). The organic layer was washed with brine (100 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0-40% EtOAc / hexane) to obtain 2.89 g (crude) of a yellow solid.

[0439] Step 3: Synthesis of (S)-3-Amino-N-methoxy-N-methyl-3-(4-(4-methylthiazol-5-yl)phenyl)propanamide

[0440] Tert-butyl (S)-(3-(methoxy(methyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate (3.45 g, 8.45 mmol) was suspended in DCM (42 ml), 4 M HCl in 1,4-dioxane (21 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 3.7 g (crude) of a yellow solid.

[0441] Step 4: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(3-(methoxy(methyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate

[0442] (S)-3-Amino-N-methoxy-N-methyl-3-(4-(4-methylthiazol-5-yl)phenyl)propanamide (3.7 g, 8.50 mmol) and TEA (4.7 ml, 33.79 mmol) were suspended in DCM (28 ml), and 1-[2-(trimethylsilyl)ethoxycarbonyloxy]-pyrrolidin-2,5-dione (2.41 g, 9.29 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 16 hours. Distilled water (50 ml) was added to the reaction mixture, and the mixture was extracted with DCM (50 ml x 2). The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.87 g (75%) of an ivory solid.

[0443] Step 5: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate

[0444] 2-(Trimethylsilyl)ethyl (S)-(3-(methoxy(methyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate (3 g, 6.67 mmol) was suspended in THF (222 ml) and LiAlH4 (2.0 M in THF, 4.3 ml, 8.67 mmol) was added at 0 °C, followed by stirring at 0 °C for 30 minutes. Distilled water (30 ml) was added to the reaction mixture and extracted with EtOAc (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-50% EtOAc / hexane) to obtain 2.32 g (89%) of a yellow solid.

[0445] Step 6: Synthesis of Tert-butyl (S)-4-(3-(4-(4-methylthiazol-5-yl)phenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate

[0446] 2-(Trimethylsilyl)ethyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)carbamate (2.32 g, 5.94 mmol) and 1-Boc-piperazine (2.22 ml, 11.88 mmol) were suspended in ACN (50 ml) and stirred at room temperature for 1 hour. NaBH(OAc)3 (3.78 g, 17.82 mmol) was added to the reaction solution and stirred at room temperature for 16 hours. Saturated NaHCO3 aqueous solution (50 ml) was added to the reaction solution and extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0-50% EtOAc / hexane) to obtain 3.01 g (90%) of a yellow solid.

[0447] Step 7: Synthesis of Tert-butyl (S)-4-(3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate

[0448] Tert-butyl (S)-4-(3-(4-(4-methylthiazol-5-yl)phenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate (720 mg, 1.28 mmol) and TBAF (1.0 M in THF, 3.85 ml, 3.85 mmol) were suspended in THF (13 ml) and stirred at 50 °C for 2 hours. Distilled water (30 ml) was added to the reaction mixture and extracted with DCM (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 534 mg (crude) of brown oil.

[0449] Step 8: Synthesis of Benzyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0450] Benzyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (10 g, 38.80 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (9 g, 38.80 mmol), EDCI (8.9 g, 45.60 mmol), HOBt (6.3 g, 45.60 mmol), and DIPEA (33 ml, 194 mmol) were suspended in DCM (60 ml) and stirred at room temperature for 16 h. Distilled water (80 ml) was added to the reaction mixture and extracted with DCM (100 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-66% EtOAc / hexane) to obtain 9 g (54%) of a white solid.

[0451] Step 9: Synthesis of Benzyl (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0452] Benzyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (9 g, 20.76 mmol) was suspended in DCM (80 ml), 4 M HCl in 1,4-dioxane (26 ml, 103.8 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 8 g (crude) of a white solid.

[0453] Step 10: Synthesis of Benzyl (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0454] Benzyl (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (3.85 g, 10.38 mmol), acetic acid (0.6 ml, 10.38 mmol), EDCI (2.40 g, 12.5 mmol), HOBt (1.69 g, 12.5 mmol), and DIPEA (8.9 ml, 51.9 mmol) were suspended in DCM (50 ml) and stirred at room temperature for 16 h. Distilled water (30 ml) was added to the reaction mixture and extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% MeOH / DCM) to obtain 3 g (80%) of a white solid.

[0455] Step 11: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid

[0456] Benzyl (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (3 g, 7.97 mmol) was suspended in MeOH (16 ml), 10% Pd / C (300 mg) was added, and the mixture was stirred at room temperature for 1 hour under a stream of hydrogen. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to MPLC (1-10% MeOH / DCM) to obtain 1.8 g (80%) of a white solid.

[0457] Step 12: Synthesis of Tert-butyl 4-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate

[0458] Tert-butyl (S)-4-(3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (534 mg, 1.28 mmol), (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (380 mg, 1.28 mmol), EDCI (295 mg, 1.54 mmol), HOBt (208 mg, 1.54 mmol), and DIPEA (1.11 ml, 6.42 mmol) were suspended in DCM (4.3 ml) and stirred at room temperature for 16 h. Distilled water (20 ml) was added to the reaction mixture, 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 (0-10% MeOH / DCM) to obtain 888 mg (99%) of a yellow solid.

[0459] Step 13: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0460] Tert-butyl 4-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (880 mg, 1.27 mmol) was suspended in DCM (12 ml), 4 M HCl in 1,4-dioxane (3 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 947 mg (crude) of a yellow solid.

[0461]

[0462] Intermediate 19 was synthesized using the same method as that for synthesizing intermediate 18.

[0463]

[0464]

[0465] Intermediate 20. 1-((R)-2-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylic acid

[0466]

[0467] Step 1: Synthesis of Tert-butyl (R)-(1-(4-bromophenyl)-2-hydroxyethyl)carbamate

[0468] (R)-2-Amino-2-(4-bromophenyl)ethanol (2 g, 7.92 mmol) and TEA (2.8 ml, 19.80 mmol) were suspended in DCM (50 ml), di-tert-butyl dicarbonate (2.7 ml, 11.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Distilled water (50 ml) was added to the reaction mixture, and the mixture was extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.24 g (89%) of a white solid.

[0469] Step 2: Synthesis of Tert-butyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate

[0470] Tert-butyl (R)-(1-(4-bromophenyl)-2-hydroxyethyl)carbamate (1.74 g, 5.49 mmol) and 4-methylthiazole (1.08 g, 10.98 mmol) were suspended in DMAC (35 ml), KOAc (1.07 g, 10.98 mmol) and Pd(OAc)2 (123 mg, 0.55 mmol) were added, and the mixture was heated and refluxed for 16 hours. Distilled water (70 ml) was added to the reaction mixture, and extracted with EtOAc (70 ml x 2). The organic layer was washed with brine (70 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC (0-40% EtOAc / hexane) to obtain 827 mg (45%) of an ivory solid.

[0471] Step 3: Synthesis of (R)-2-((Tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl methanesulfonate

[0472] Tert-butyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (300 mg, 0.90 mmol) and TEA (0.14 ml, 0.99 mmol) were suspended in DCM (2.2 ml), methanesulfonyl chloride (0.08 ml, 0.99 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 2 hours. Distilled water (10 ml) was added to the reaction mixture, and the mixture was extracted with DCM (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0-40% EtOAc / hexane) to obtain 343 mg (93%) of an ivory solid.

[0473] Step 4: Synthesis of Ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylate

[0474] (R)-2-((Tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl methanesulfonate (343 mg, 0.83 mmol), K2CO3 (230 mg, 1.67 mmol), and ethyl 4-piperidinecarboxylate (0.64 ml, 4.17 mmol) were suspended in THF (3 ml) and heated to reflux for 16 hours. Distilled water (15 ml) was added to the reaction mixture and extracted with EtOAc (15 ml x 2). The organic layer was washed with brine (15 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by MPLC (0-40% EtOAc / hexane) to obtain 167 mg (42%) of an ivory solid.

[0475] Step 5: Synthesis of Ethyl (R)-1-(2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylate

[0476] Ethyl (R)-1-(2-((tert-butoxycarbonyl)amino)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylate (94 mg, 0.99 mmol) was suspended in DCM (2 ml), 4 M HCl in 1,4-dioxane (0.5 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 81 mg (crude) of a white solid.

[0477] Step 6: Synthesis of Ethyl 1-((R)-2-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylate

[0478] Ethyl (R)-1-(2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylate (81 mg, 0.20 mmol), (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (57 mg, 0.20 mmol), HATU (90 mg, 0.24 mmol), and DIPEA (0.07 ml, 0.40 mmol) were suspended in DMF (0.7 ml) and stirred at room temperature for 2 hours. Distilled water (20 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 ml). The organic layer was washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to obtain 105 mg (83%) of an ivory solid.

[0479] Step 7: Synthesis of 1-((R)-2-((2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylic acid

[0480] Ethyl 1-((R)-2-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylate (104 mg, 0.17 mmol) and LiOH monohydrate (8 mg, 0.19 mmol) were suspended in THF:H2O:MeOH = 4:1:1 (0.9 ml) and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and concentrated under reduced pressure to obtain 104 mg (crude) of an ivory-colored solid.

[0481]

[0482] Intermediates 46 and 47 were synthesized using a method identical or similar to that used to synthesize intermediate 20.

[0483]

[0484]

[0485] Intermediate 21. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide

[0486]

[0487] Step 1: Synthesis of (R)-2-Amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol

[0488] Tert-butyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (100 mg, 0.30 mmol) was suspended in DCM (3 ml), 4 M HCl in 1,4-dioxane (0.75 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 81 mg (crude) of a white solid.

[0489] Step 2: Synthesis of 2-(Trimethylsilyl)ethyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate

[0490] (R)-2-Amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol (81 mg, 0.30 mmol) and TEA (0.17 ml, 1.20 mmol) were suspended in DCM (1 ml), and 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (78 mg, 0.30 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 1 hour. Distilled water (15 ml) was added to the reaction mixture, and the mixture was extracted with DCM (15 ml x 2). The organic layer was washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC (0-50% EtOAc / hexane) to obtain 97 mg (86%) of an ivory solid.

[0491] Step 3: Synthesis of (R)-2-(4-(4-Methylthiazol-5-yl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl methanesulfonate

[0492] 2-(Trimethylsilyl)ethyl (R)-(2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (95 mg, 0.25 mmol) and TEA (0.04 ml, 0.28 mmol) were suspended in DCM (0.6 ml), methanesulfonyl chloride (0.02 ml, 0.28 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 1 hour. Distilled water (15 ml) was added to the reaction mixture, and the mixture was extracted with DCM (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to obtain 106 mg (93%) of an ivory solid.

[0493] Step 4: Synthesis of Tert-butyl (R)-4-(2-(4-(4-methylthiazol-5-yl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)piperazine-1-carboxylate

[0494] (R)-2-(4-(4-Methylthiazol-5-yl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl methanesulfonate (360 mg, 0.95 mmol), K2CO3 (691 mg, 4.75 mmol), and 1-Boc-piperazine (1.77 g, 9.5 mmol) were suspended in DMF (2 ml) and stirred at 70 °C for 16 hours. Distilled water (15 ml) was added to the reaction mixture and extracted with EtOAc (15 ml x 2). The organic layer was washed with brine (15 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to obtain 209 mg (40%) of an ivory solid.

[0495] Step 5: Synthesis of Tert-butyl (R)-4-(2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperazine-1-carboxylate

[0496] Tert-butyl (R)-4-(2-(4-(4-methylthiazol-5-yl)phenyl)-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)piperazine-1-carboxylate (202 mg, 0.37 mmol) and TBAF (1.0 M in THF, 1.11 ml, 1.11 mmol) were suspended in THF (3.7 ml) and stirred at 50 °C for 2 hours. Distilled water (20 ml) was added to the reaction mixture and extracted with DCM (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 81 mg (55%) of an ivory solid.

[0497] Step 6: Synthesis of Tert-butyl 4-((R)-2-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperazine-1-carboxylate

[0498] Tert-butyl (R)-4-(2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperazine-1-carboxylate (80 mg, 0.20 mmol), (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (57 mg, 0.20 mmol), EDCI (46 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol), and DIPEA (0.17 ml, 1.00 mmol) were suspended in DCM (0.7 ml) and stirred at room temperature for 16 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, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to obtain 101 mg (76%) of a yellow solid.

[0499] Step 7: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide

[0500] Tert-butyl 4-((R)-2-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperazine-1-carboxylate (98 mg, 0.15 mmol) was suspended in DCM (1.5 ml), 4 M HCl in 1,4-dioxane (0.37 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 94 mg (crude) of a yellow solid.

[0501]

[0502] Intermediate 22. (2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0503]

[0504] Step 1: Synthesis of Benzyl (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylate

[0505] 3-Methyl-2-(3-methylisoxazol-5-yl)butanoic 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 h. 1 M HCl aqueous solution was added to the reaction mixture, and the mixture was extracted with EtOAc (200 ml x 2). The organic layer was washed with saturated NaHCO3 aqueous solution (200 ml) and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0-100% EtOAc / petroleum ether). The obtained mixture was purified by SFC (column: REGIS (S,S) WHELK - O1 (250 mm x 25 mm x 10 um); mobile phase: [CO2- EtOH (0.1% NH4OH)]; B%: 25%, isocratic elution mode) to obtain P1 1.50 g (16%, 100%ee) and P2 2.00 g (20%, 98.8%ee) as yellow solids, respectively.

[0506] Step 2: Synthesis of (2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid

[0507] Benzyl (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylate (P2 of Step 1, 2.00 g, 5.00 mmol) was suspended in MeOH (20 ml), 10% Pd / C (484 mg) was added, and the mixture was stirred at room temperature for 2 hours under a stream of hydrogen. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 mm x 70 mm x 10 um); mobile phase: [water(FA) - ACN]; B%: 5%-35%, 188 min) to give 1.00 g (65%) of a yellow solid.

[0508] Step 3: Synthesis of Tert-butyl 4-((S)-3-((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate

[0509] (2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxylic acid (380 mg, 1.28 mmol), tert-butyl (S)-4-(3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (533 mg, crude, 1.28 mmol), EDCI (295 mg, 1.54 mmol), HOBt (208 mg, 1.54 mmol), and DIPEA (1.11 ml, 6.42 mmol) were suspended in DCM (4.3 ml) and stirred at room temperature for 16 h. Distilled water (20 ml) was added to the reaction mixture, 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 (0-10% MeOH / DCM) to obtain 888 mg (99%) of a yellow solid.

[0510] Step 4: Synthesis of (2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0511] Tert-butyl 4-((S)-3-((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (880 mg, 1.27 mmol) was suspended in DCM (12 ml), 4 M HCl in 1,4-dioxane (3 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 947 mg (quant.) of a yellow solid.

[0512]

[0513] Intermediate 23. (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0514]

[0515] Step 1: Synthesis of N'-(1,1-Dimethoxypropan-2-ylidene)-4-methylbenzenesulfonohydrazide

[0516] 1,1-Dimethoxypropan-2-one (34 g, 287 mmol) and 4-methylbenzenesulfonohydrazide (48.7 g, 261 mmol) were suspended in MeOH (340 ml), degassing and N2 purging were repeated three times, and the mixture was stirred at room temperature for 1 hour. The reaction solution was used immediately in the next reaction.

[0517] Step 2: Synthesis of Ethyl (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoate

[0518] N'-(1,1-Dimethoxypropan-2-ylidene)-4-methylbenzenesulfonohydrazide (74.92 g, 261 mmol) was suspended in MeOH (340 ml), ethyl L-valinate hydrochloride (57 g, 313 mmol) and TEA (36.4 ml, 261 mmol) were added, and degassing and N2 purging were repeated three times, followed by stirring at 75 °C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue obtained was subjected to MPLC (2-20% EtOAc / petroleum ether) to obtain 39.20 g (69%) of yellow oil.

[0519] Step 3: Synthesis of (S)-3-Methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoic acid

[0520] Ethyl (S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoate (10 g, 47.3 mmol) was suspended in distilled water (50 ml), conc. HCl (50 ml) was added, and the mixture was stirred at 50°C for 5 hours. The reaction solution was concentrated under reduced pressure to obtain 12.80 g (crude) of yellow oil.

[0521] 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

[0522] (S)-3-Methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoic acid (6.20 g, 27.2 mmol), benzyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (7.03 g, 27.2 mmol), and DIPEA (14.2 ml, 81.8 mmol) were suspended in DMF (60 ml), and degassing and N2 purging were repeated three times. HATU (12.4 g, 32.7 mmol) was added and stirred at room temperature for 2 hours. Distilled water (150 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 ml x 3). The organic layer was washed with distilled water (150 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (2-10% EtOAc / petroleum ether). The resulting mixture was purified by prep-HPLC (column: Phenomenex luna C18 (250 mm x 70 mm x 10 um); mobile phase: [H2O (FA) - ACN]; B%: 30%-60%, 20 min) to obtain 1.70 g (16%, 100%ee) of a white solid.

[0523] 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

[0524] Benzyl (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylate (1.70 g, 4.40 mmol) was suspended in MeOH (15 ml), 10% Pd / C (170 mg) was added, and the mixture was stirred at room temperature for 3 hours under a stream of hydrogen. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 1.05 g (81%) of a white solid.

[0525] Step 6: Tert-butyl Synthesis of 4-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate

[0526] (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (195 mg, 0.66 mmol), tert-butyl (S)-4-(3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (274 mg, crude, 0.66 mmol), EDCI (152 mg, 0.79 mmol), HOBt (107 mg, 0.79 mmol), and DIPEA (0.34 ml, 1.98 mmol) were suspended in DCM (1.3 ml) and stirred at room temperature for 16 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, filtered, and concentrated under reduced pressure. The residue obtained was subjected to MPLC (0-8% MeOH / DCM) to obtain 357 mg (78%) of an ivory solid.

[0527] Step 7: Synthesis of (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0528] Tert-butyl 4-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (357 mg, 0.51 mmol) was suspended in DCM (5.1 ml), 4 M HCl in 1,4-dioxane (1.28 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 412 mg (quant.) of a yellow solid.

[0529]

[0530] Intermediate 24. (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0531]

[0532] Step 1: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(3-hydroxy-1-phenylpropyl)carbamate

[0533] (S)-3-Amino-3-phenylpropan-1-ol (500 mg, 3.31 mmol) and TEA (1.39 ml, 91 mmol) were suspended in DCM (12 ml), 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (858 mg, 3.31 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 1 hour. Distilled water (10 ml) was added to the reaction mixture, and the mixture was extracted with DCM (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to obtain 874 mg (90%) of a colorless oil.

[0534] Step 2: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(3-oxo-1-phenylpropyl)carbamate

[0535] 2-(Trimethylsilyl)ethyl (S)-(3-hydroxy-1-phenylpropyl)carbamate (300 mg, 1.02 mmol) was suspended in DCM (3.6 ml), and DMP (517 mg, 1.22 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous Na2S2O3 solution (4 ml) was added to the reaction mixture, and the mixture was extracted with DCM (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-25% EtOAc / hexane) to obtain 303 mg (100%) of a white solid.

[0536] Step 3: Synthesis of Tert-butyl (S)-4-(3-phenyl-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate

[0537] 2-(Trimethylsilyl)ethyl (S)-(3-oxo-1-phenylpropyl)carbamate (300 mg, 1.02 mmol) and tert-butyl piperazine-1-carboxylate (229 mg, 1.23 mmol) were suspended in DCM (6 ml) and stirred at room temperature for 30 min. NaBH(OAc)3 was added to the reaction solution and stirred at room temperature for 16 h. Saturated NaHCO3 aqueous solution (5 ml) was added to the reaction solution and extracted with DCM (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (0-55% EtOAc / hexane) to obtain 308 mg (78%) of a colorless oil.

[0538] Step 4: Synthesis of Tert-butyl (S)-4-(3-amino-3-phenylpropyl)piperazine-1-carboxylate

[0539] Tert-butyl (S)-4-(3-phenyl-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate (71 mg, 0.15 mmol) was suspended in THF (2 ml), TBAF (0.46 ml, 0.46 mmol) was added, and the mixture was stirred at 50 °C for 2 hours. Distilled water (2 ml) was added to the reaction mixture, and the mixture was extracted with DCM (5 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 72 mg (crude) of brown oil.

[0540] Step 5: Synthesis of Tert-butyl 4-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-phenylpropyl)piperazine-1-carboxylate

[0541] Tert-butyl (S)-4-(3-amino-3-phenylpropyl)piperazine-1-carboxylate (72 mg, crude), (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (30 mg, 0.10 mmol), EDCI (24 mg, 0.12 mmol), HOBt (17 mg, 0.12 mmol), and DIPEA (0.05 ml, 0.30 mmol) were suspended in DCM (3 ml) and stirred at room temperature for 16 h. Distilled water (5 ml) was added to the reaction mixture, and the mixture was extracted with DCM (3 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to obtain 60 mg (99%) of a white solid.

[0542] Step 6: Synthesis of (2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide

[0543] Tert-butyl 4-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-phenylpropyl)piperazine-1-carboxylate (58 mg, 0.10 mmol) was suspended in DCM (1 ml), 4 M HCl in 1,4-dioxane (0.25 ml, 1.0 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 60 mg (crude) of a white solid.

[0544]

[0545] Intermediate 25. (2S,4R)-N-((S)-1-(4-Chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0546]

[0547] Step 1: Synthesis of (S)-2-(Trimethylsilyl)ethyl (1-(4-chlorophenyl)-3-hydroxypropyl)carbamate

[0548] (S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (500 mg, 2.69 mmol) and TEA (1.5 ml, 10.77 mmol) were suspended in DCM (9 ml), 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (768 mg, 2.96 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 2 hours. Distilled water (20 ml) was added to the reaction mixture, and the mixture was extracted with DCM (20 ml x 2). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by MPLC (0-50% EtOAc / hexane) to obtain 830 mg (93%) of an ivory solid.

[0549] Step 2: Synthesis of (S)-3-(4-Chlorophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl methanesulfonate

[0550] (S)-2-(Trimethylsilyl)ethyl (1-(4-chlorophenyl)-3-hydroxypropyl)carbamate (100 mg, 0.30 mmol) and TEA (0.04 ml, 0.33 mmol) were suspended in DCM (1 ml), methanesulfonyl chloride (0.02 ml, 0.33 mmol) was added at 0 ℃, and the mixture was stirred at room temperature for 1 hour. Distilled water (15 ml) was added to the reaction mixture, and the mixture was extracted with DCM (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to obtain 122 mg (98%) of an ivory solid.

[0551] Step 3: Synthesis of Tert-butyl (S)-4-(3-(4-chlorophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate

[0552] (S)-3-(4-Chlorophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl methanesulfonate (568 mg, 1.39 mmol) and 1-Boc-piperazine (2.59 g, 13.92 mmol) were suspended in a mixture of THF (28 ml) and DMF (2.7 ml) and stirred at 90 °C for 16 hours. Distilled water (20 ml) was added to the reaction mixture and extracted with EtOAc (20 ml x 2). The organic layer was washed with brine (20 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to obtain 478 mg (69%) of an ivory solid.

[0553] Step 4: Synthesis of Tert-butyl (S)-4-(3-amino-3-(4-chlorophenyl)propyl)piperazine-1-carboxylate

[0554] Tert-butyl (S)-4-(3-(4-chlorophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate (60 mg, 0.12 mmol) and TBAF (1.0 M in THF, 0.36 ml, 0.36 mmol) were suspended in THF (1.2 ml) and stirred at 50 °C for 2 hours. Distilled water (10 ml) was added to the reaction mixture and extracted with DCM (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 43 mg (crude) of an ivory solid.

[0555] Step 5: Synthesis of Tert-butyl 4-((S)-3-(4-chlorophenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperazine-1-carboxylate

[0556] Tert-butyl (S)-4-(3-amino-3-(4-chlorophenyl)propyl)piperazine-1-carboxylate (43 mg, 0.12 mmol), (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (30 mg, 0.10 mmol), EDCI (16 mg, 0.08 mmol), HOBt (11 mg, 0.08 mmol), and DIPEA (0.06 ml, 0.34 mmol) were suspended in DCM (0.2 ml) and stirred at room temperature for 16 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, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-10% MeOH / DCM) to obtain 59 mg (93%) of a yellow solid.

[0557] Step 6: Synthesis of (2S,4R)-N-((S)-1-(4-Chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0558] Tert-butyl 4-((S)-3-(4-chlorophenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperazine-1-carboxylate (58 mg, 0.09 mmol) was suspended in DCM (0.92 ml), 4 M HCl in 1,4-dioxane (0.23 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 56 mg (crude) of an ivory-colored solid.

[0559]

[0560] Intermediate 26. (2S,4R)-N-((S)-1-(4-Cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0561]

[0562] Step 1: Synthesis of Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate

[0563] (S)-3-((Tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (1 g, 3.44 mmol), EDCI (792 mg, 4.13 mmol), HOBt (559 mg, 4.13 mmol), and DIPEA (1.8 ml, 10.33 mmol) were suspended in DCM:MeOH = 2:1 (10.3 ml) and stirred at room temperature for 16 h. Distilled water (50 ml) was added to the reaction mixture and extracted with DCM (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% EtOAc / hexane) to obtain 821 mg (78%) of a colorless oil.

[0564] Step 2: Synthesis of Methyl (S)-3-amino-3-(4-cyanophenyl)propanoate hydrochloride

[0565] Methyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate (821 mg, 2.70 mmol) was suspended in DCM (27 ml), 4 M HCl in 1,4-dioxane (6.7 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 635 mg (quant.) of a white solid.

[0566] Step 3: Synthesis of Methyl (S)-3-(4-cyanophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate

[0567] Methyl (S)-3-amino-3-(4-cyanophenyl)propanoate hydrochloride (635 mg, 2.64 mmol) and TEA (1.1 ml, 7.91 mmol) were suspended in DCM (5.4 ml), 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (700 mg, 2.70 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Distilled water (20 ml) was added to the reaction mixture, 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 purified by MPLC (0-20% EtOAc / hexane) to obtain 935 mg (99%) of a colorless oil.

[0568] Step 4: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(1-(4-cyanophenyl)-3-hydroxypropyl)carbamate

[0569] Methyl (S)-3-(4-cyanophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propanoate (500 mg, 1.43 mmol) was suspended in Et2O (25 ml), LiBH4 (94 mg, 4.30 mmol) was added at 0 °C, and the mixture was stirred for 1 hour at 0 °C under a nitrogen stream. Saturated NH4Cl aqueous solution (10 ml) was added to the reaction mixture, stirred for 20 minutes, and extracted with Et2O (25 ml x 2). The organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-50% EtOAc / hexane) to obtain 323 mg (70%) of a white solid.

[0570] Step 5: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(1-(4-cyanophenyl)-3-oxopropyl)carbamate

[0571] 2-(Trimethylsilyl)ethyl (S)-(1-(4-cyanophenyl)-3-hydroxypropyl)carbamate (299 mg, 0.93 mmol) and DMP (791 g, 1.87 mmol) were suspended in DCM (4.2 ml) and stirred at room temperature for 2 hours. Saturated aqueous Na2S2O3 solution (10 ml) was added to the reaction mixture and extracted with DCM (10 ml). The organic layer was washed with distilled water (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-30% EtOAc / hexane) to obtain 255 mg (86%) of a colorless oil.

[0572] Step 6: Synthesis of Tert-butyl (S)-4-(3-(4-cyanophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate

[0573] 2-(Trimethylsilyl)ethyl (S)-(1-(4-cyanophenyl)-3-oxopropyl)carbamate (255 mg, 0.80 mmol), Boc-piperazine (224 mg, 1.20 mmol), and acetic acid (0.25 ml, 3.20 mmol) were suspended in ACN: DCM = 1:1 (3.6 ml), NaBH(OAc)3 (509 mg, 2.40 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 aqueous solution (30 ml) was added to the reaction mixture, and the mixture was extracted with DCM (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-40% EtOAc / hexane) to obtain 221 mg (57%) of a white solid.

[0574] Step 7: Synthesis of Tert-butyl (S)-4-(3-amino-3-(4-cyanophenyl)propyl)piperazine-1-carboxylate

[0575] Tert-butyl (S)-4-(3-(4-cyanophenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate (54 mg, 0.11 mmol) was suspended in THF (0.76 ml), TBAF (1.0 M in THF, 0.33 ml, 0.33 mmol) was added, and the mixture was stirred at 50 °C for 1 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, filtered, and concentrated under reduced pressure to obtain 51.2 mg (quant.) of brown oil.

[0576] Step 8: Synthesis of Tert-butyl 4-((S)-3-(4-cyanophenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperazine-1-carboxylate

[0577] Tert-butyl (S)-4-(3-amino-3-(4-cyanophenyl)propyl)piperazine-1-carboxylate (51.2 mg, 0.11 mmol), (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (30 mg, 0.10 mmol), EDCI (23 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol), and DIPEA (0.053 ml, 0.30 mmol) were suspended in DCM (0.2 ml) and stirred at room temperature for 16 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, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-5% MeOH / DCM) to obtain 47 mg (75%) of a white solid.

[0578] Step 9: Synthesis of (2S,4R)-N-((S)-1-(4-Cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0579] Tert-butyl 4-((S)-3-(4-cyanophenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperazine-1-carboxylate (47 mg, 0.08 mmol) was suspended in DCM (0.76 ml), 4 M HCl in 1,4-dioxane (0.19 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 53 mg (quant.) of a white solid.

[0580]

[0581] Intermediates 48 and 49 were synthesized using the same method as that for synthesizing intermediate 26.

[0582]

[0583]

[0584] Intermediate 27. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0585]

[0586] Step 1: Synthesis of Tert-butyl (S)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate

[0587] Tert-butyl (S)-(1-(4-bromophenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate (851 mg, 2.20 mmol), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (634 mg, 2.86 mmol), Pd(PPh3)4 (254 mg, 0.22 mmol), and K2CO3 (911 mg, 6.59 mmol) were suspended in 1,4-dioxane : H2O = 5 : 1 (15 ml) and stirred at 70 °C for 2 hours. Distilled water (30 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-60% EtOAc / hexane) to obtain 915 mg (crude) of a yellow solid.

[0588] Step 2: Synthesis of (S)-3-Amino-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-N-methoxy-N-methylpropanamide

[0589] Tert-butyl (S)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate (915 mg, 2.27 mmol) was suspended in DCM (23 ml), 4 M HCl in 1,4-dioxane (5.7 ml) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 solution (20 ml) was added to the reaction mixture, and the mixture was extracted with DCM (20 ml x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-3% MeOH / DCM) to obtain 609 mg (92%) of a colorless oil.

[0590] Step 3: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate

[0591] (S)-3-Amino-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-N-methoxy-N-methylpropanamide (609 mg, 2.01 mmol) and TEA (0.84 ml, 6.04 mmol) were suspended in DCM (4 ml), 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (575 mg, 2.21 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Distilled water (20 ml) was added to the reaction mixture, 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 purified by MPLC (0-50% EtOAc / hexane) to obtain 838 mg (93%) of the title compound as a white solid.

[0592] Step 4: Synthesis of 2-(Trimethylsilyl)ethyl (S)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-oxopropyl)carbamate

[0593] 2-(Trimethylsilyl)ethyl (S)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(methoxy(methyl)amino)-3-oxopropyl)carbamate (838 mg, 1.88 mmol) was suspended in THF (64 ml), LiAlH4 (2.0 M in THF, 1.4 ml, 2.81 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Saturated NH4Cl aqueous solution (50 ml) was added to the reaction mixture, and the mixture was extracted with DCM (50 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-50% EtOAc / hexane) to obtain 690 mg (95%) of a colorless oil.

[0594] Step 5: Synthesis of Tert-butyl (S)-4-(3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate

[0595] 2-(Trimethylsilyl)ethyl (S)-(1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-oxopropyl)carbamate (690 mg, 1.78 mmol), Boc-piperazine (497 mg, 2.67 mmol), and acetic acid (0.54 ml, 7.12 mmol) were suspended in ACN: DCM = 1:1 (7.8 ml), then NaBH(OAc)3 (1.13 g, 5.34 mmol) was added and stirred at room temperature for 1 hour. Saturated NaHCO3 aqueous solution (30 ml) was added to the reaction mixture, and then extracted with DCM (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-50% EtOAc / hexane) to obtain 562 mg (57%) of a white solid.

[0596] Step 6: Synthesis of Tert-butyl (S)-4-(3-amino-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)piperazine-1-carboxylate

[0597] Tert-butyl (S)-4-(3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)propyl)piperazine-1-carboxylate (305 mg, 0.55 mmol) was suspended in THF (3.6 ml), TBAF (1.0 M in THF, 1.64 ml, 1.64 mmol) was added, and the mixture was stirred at 50 °C for 1 hour. Distilled water (20 ml) was added to the reaction mixture, and the mixture was extracted with DCM (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 325 mg (quant.) of brown oil.

[0598] Step 7: Synthesis of Tert-butyl 4-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)piperazine-1-carboxylate

[0599] Tert-butyl (S)-4-(3-amino-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (325 mg, 0.55 mmol), (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (157 mg, 0.55 mmol), EDCI (126 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol), and DIPEA (0.29 ml, 1.64 mmol) were suspended in DCM (1.1 ml) and stirred at room temperature for 16 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, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-8% MeOH / DCM) to obtain 357 mg (96%) of an ivory solid.

[0600] Step 8: Synthesis of (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0601] Tert-butyl 4-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)piperazine-1-carboxylate (357 mg, 0.52 mmol) was suspended in DCM (5.2 ml), 4 M HCl in 1,4-dioxane (1.3 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 376 mg (quant.) of a white solid.

[0602]

[0603] Intermediates 28 and 50 were synthesized using the same method as that for synthesizing intermediate 27.

[0604]

[0605]

[0606] Intermediate 30. 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

[0607]

[0608] Step 1: Synthesis of Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate

[0609] Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)propanoate (978 mg, 2.15 mmol) was suspended in THF (7 ml), NaOEt (ca. 20% in EtOH, 0.92 ml, 2.37 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 840 mg (crude) of a yellow solid.

[0610] Step 2: Synthesis of 2-(Trimethylsilyl)ethyl 4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carboxylate

[0611] Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate (840 mg, 2.15 mmol), 2-(trimethylsilyl)ethyl 4-((3-chloro-4-iodopyridin-2-yl)amino)piperidine-1-carboxylate (691 mg, 1.43 mmol), Pd2(dba)3 (66 mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol), and DIPEA (0.5 ml, 2.87 mmol) were suspended in 1,4-dioxane (5 ml) and stirred at 90 °C for 16 h. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to MPLC (0-50% EtOAc / hexane) to obtain 800 mg (77%) of an ivory solid.

[0612] Step 3: Synthesis of 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

[0613] 2-(Trimethylsilyl)ethyl 4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carboxylate (800 mg, 1.11 mmol) and TBAF (1.0 M in THF, 3.32 ml, 3.32 mmol) were suspended in THF (11.1 ml) and stirred at 50 °C for 2 hours. Distilled water (20 ml) was added to the reaction mixture and extracted with DCM (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 489 mg (85%) of an ivory solid.

[0614]

[0615] Intermediate 31 was synthesized using the same method as that for synthesizing intermediate 30.

[0616]

[0617]

[0618] Intermediate 39. 1-(3-((5-(4-(((Tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid

[0619]

[0620] Step 1: Synthesis of tert-butyl (3-bromo-2-chlorophenyl)(tert-butoxycarbonyl)carbamate

[0621] 3-Bromo-2-chloroaniline (2 g, 9.69 mmol) and DMAP (118 mg, 0.97 mmol) were suspended in THF (17 ml), di-tert-butyl dicarbonate (6.3 mg, 29.06 mmol) was added, and the mixture was heated and refluxed for 1 hour. Distilled water (50 ml) was added to the reaction mixture, and then extracted with EtOAc (50 ml). 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 (0-15% EtOAc / Hexane) to obtain 3.55 g (90%) of a white solid.

[0622] Step 2: Synthesis of Tert-butyl (3-bromo-2-chlorophenyl)carbamate

[0623] Tert-butyl (3-bromo-2-chlorophenyl)(tert-butoxycarbonyl)carbamate (3.55 g, 8.73 mmol) and K2CO3 (3.6 g, 26.19 mmol) were suspended in MeOH (15.5 ml) and refluxed for 1 hour. Distilled water (50 ml) was added to the reaction mixture and extracted with EtOAc (50 ml). 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 (0-5% EtOAc / Hexane) to obtain 2.55 g (95%) of an ivory solid.

[0624] Step 3: Synthesis of Ethyl 1-(3-((tert-butoxycarbonyl)amino)-2-chlorophenyl)piperidine-4-carboxylate

[0625] Tert-butyl (3-bromo-2-chlorophenyl)carbamate (1.20 g, 3.91 mmol), ethyl piperidine-4-carboxylate (1.23 g, 7.83 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), BINAP (244 mg, 0.39 mmol), and Cs2CO3 (2.6 g, 7.83 mmol) were suspended in 1,4-dioxane (12.7 ml) and stirred at 90 °C for 16 h. Distilled water (50 ml) was added to the reaction mixture and extracted with EtOAc (50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-10% EtOAc / Hexane) to give 1.09 mg (73%) of an ivory solid.

[0626] Step 4: Synthesis of Ethyl 1-(3-amino-2-chlorophenyl)piperidine-4-carboxylate

[0627] Ethyl 1-(3-((tert-butoxycarbonyl)amino)-2-chlorophenyl)piperidine-4-carboxylate (1.22 g, 3.19 mmol) was suspended in DCM (32 ml), TFA (7.9 ml) was added, and the mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 9 with 20% NaOH aqueous solution, and then extracted with DCM (30 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 882 mg (98%) of an ivory solid.

[0628] Step 5: Synthesis of Ethyl 1-(2-chloro-3-iodophenyl)piperidine-4-carboxylate

[0629] Ethyl 1-(3-amino-2-chlorophenyl)piperidine-4-carboxylate (882 mg, 3.12 mmol) was suspended in 2 M HCl aqueous solution: 1,4-dioxane = 2:1 (20.2 ml), and sodium nitrite (237 mg, 3.43 mmol) and H2O (0.7 ml) were added at 0 °C, and the mixture was stirred at 0 °C for 15 min. Sodium iodide (514 mg, 3.43 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Distilled water (30 ml) was added to the reaction mixture, 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 (0-5% EtOAc / Hexane) to obtain 570 mg (46%) of a brown solid.

[0630] Step 6: Synthesis of Ethyl 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylate

[0631] Ethyl 1-(2-chloro-3-iodophenyl)piperidine-4-carboxylate (190 mg, 0.48 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazine-2-thiolate (crude, 0.58 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), Xantphos (28 mg, 0.05 mmol), and DIPEA (0.17 ml, 0.97 mmol) were suspended in 1,4-dioxane (1.1 ml) and stirred at 90 °C for 1 h. Distilled water (10 ml) was added to the reaction mixture, and the mixture 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 (0-30% EtOAc / Hexane) to obtain 231 mg (77%) of an ivory solid.

[0632] Step 7: Synthesis of 1-(3-((5-(4-(((Tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylic acid

[0633] Ethyl 1-(3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carboxylate (231 mg, 0.37 mmol) was suspended in THF:MeOH:H2O = 3:2:1 (2.58 ml), LiOHH2O (31 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 2 with 1 M HCl aqueous solution, and then extracted with EtOAc (10 ml). The organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 200 mg (100%) of an ivory solid.

[0634]

[0635] Intermediate 40. 1-(4-((3-Amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid

[0636]

[0637] Step 1: Synthesis of Methyl 3-((3-amino-5-chloropyrazin-2-yl)thio)propanoate

[0638] 3-Bromo-6-chloropyrazin-2-amine (500 mg, 2.40 mmol), methyl 3-mercaptopropionate (0.28 ml, 2.64 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), Xantphos (139 mg, 0.24 mmol), and DIPEA (0.84 ml, 4.80 mmol) were suspended in 1,4-dioxane (8 ml) and stirred at 90 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by MPLC (0-20% EtOAc / hexane) to obtain 508 mg (86%) of an ivory solid.

[0639] Step 2: Synthesis of Sodium 3-amino-5-chloropyrazine-2-thiolate

[0640] Methyl 3-((3-amino-5-chloropyrazin-2-yl)thio)propanoate (398 mg, 1.61 mmol) was suspended in THF (5.4 ml), NaOEt (ca. 20% in EtOH, 0.7 ml, 1.77 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 295 mg (crude) of a yellow solid.

[0641] Step 3: Synthesis of Ethyl 1-(4-((3-amino-5-chloropyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate

[0642] Ethyl 1-(3-chloro-4-iodopyridin-2-yl)piperidine-4-carboxylate (422 mg, 1.07 mmol), sodium 3-amino-5-chloropyrazine-2-thiolate (295 mg, crude, 1.61 mmol), Pd2(dba)3 (49 mg, 0.05 mmol), Xantphos (62 mg, 0.11 mmol), and DIPEA (0.37 ml, 2.14 mmol) were suspended in 1,4-dioxane (3.6 ml) and stirred at 90 °C for 1 h. Distilled water (15 ml) was added to the reaction mixture, 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 (0-50% EtOAc / hexane) to obtain 394 mg (86%) of a pink solid.

[0643] Step 4: Synthesis of Ethyl 1-(4-((3-amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate

[0644] Ethyl 1-(4-((3-amino-5-chloropyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate (104 mg, 0.24 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (60 mg, 0.27 mmol), and DIPEA (0.21 ml, 1.21 mmol) were suspended in NMP (0.2 ml) and stirred at 90 °C for 16 h. Distilled water (30 ml) was added to the reaction mixture 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 purified by MPLC (0-50% EtOAc / hexane) to give 128 mg (85%) of the title yellow solid.

[0645] Step 5: Synthesis of 1-(4-((3-Amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid

[0646] Ethyl 1-(4-((3-amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylate (126 mg, 0.20 mmol) and LiOH monohydrate (16 mg, 0.41 mmol) were suspended in THF:MeOH:H2O = 3:1:1 (1 ml) and stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 1-2 with 1 M HCl aqueous solution and extracted with DCM (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-100% EtOAc / hexane and 0-10% MeOH / DCM) to obtain 107 mg (89%) of an ivory solid.

[0647]

[0648] Intermediates 41 to 43 were synthesized using the same method as that for synthesizing intermediate 40.

[0649]

[0650]

[0651] Intermediate 51. (2S,4R)-N-((S)-1-(4-(1-Ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0652]

[0653] Step 1: Synthesis of (R,E)-N-(4-Bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[0654] 4-Bromo-3-fluorobenzaldehyde (2 g, 9.85 mmol), (R)-2-methylpropane-2-sulfinamide (1.3 g, 10.84 mmol), and Cs2CO3 (3.9 g, 11.82 mmol) were suspended in DCM (42 ml) and stirred at room temperature for 16 h. Distilled water (100 ml) was added to the reaction mixture and extracted with DCM (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.2 g (quant.) of colorless oil.

[0655] Step 2: Synthesis of Ethyl (S)-3-(4-bromo-3-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0656] (R,E)-N-(4-Bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (3.2 g, 9.85 mmol) and EtOAc (1.4 ml, 14.78 mmol) were suspended in THF (60 ml). Ti(Oi-Pr)3Cl (4.7 ml, 19.70 mmol) and 1 M LHMDS in THF (15 ml, 14.78 mmol) were added at -70 °C, and the mixture was stirred at -70 °C for 1 h. Saturated NH4Cl aqueous solution (50 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (50 ml x 2). 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 (0-40% EtOAc / hexane) to obtain 1.37 g (35%) of an ivory solid.

[0657] Step 3: Synthesis of Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propanoate

[0658] Ethyl (S)-3-(4-bromo-3-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (1.37 g, 3.47 mmol), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.54 g, 6.95 mmol), Pd(PPh3)4 (803 mg, 0.69 mmol), and K2CO3 (1.44 g, 10.42 mmol) were suspended in 1,4-dioxane : H2O = 5 : 1 (35 ml) and stirred at 80 °C for 4 h. Distilled water (100 ml) was added to the reaction mixture, and the mixture was extracted with EtOAc (100 ml). 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 (0-60% EtOAc / Hexane) to obtain 857 mg (60%) of an ivory solid.

[0659] Step 4: Synthesis of (R)-N-((S)-1-(4-(1-Ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide

[0660] Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propanoate (167 g, 0.41 mmol) was suspended in DCM (2.7 ml) at -78 °C, 1 M DIBAL-H in toluene (1 ml, 1.02 mmol) was added, and the mixture was stirred at -78 °C for 1 h. Distilled water (10 ml) was added to the reaction mixture, and the mixture was extracted with DCM (10 ml x 2). The organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (0-80% EtOAc / hexane) to obtain 72 mg (48%) of a colorless oil.

[0661] Step 5: Synthesis of Tert-butyl 4-((S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propyl)piperazine-1-carboxylate

[0662] (R)-N-((S)-1-(4-(1-Ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (72 mg, 0.20 mmol) and 1-Boc-piperazine (55 mg, 0.30 mmol) were suspended in DCM:ACN = 1:1 (1 ml), AcOH (0.06 ml, 0.79 mmol) and NaBH(OAc)3 (125 mg, 0.59 mmol) were added, and the mixture was stirred at room temperature for 1 h. Saturated NaHCO3 aqueous solution (10 ml) was added to the reaction mixture, and the mixture was extracted with DCM (10 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-80% EtOAc / hexane) to obtain 80 mg (76%) of a white solid.

[0663] Step 6: Synthesis of Tert-butyl (S)-4-(3-amino-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propyl)piperazine-1-carboxylate

[0664] Tert-butyl 4-((S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propyl)piperazine-1-carboxylate (80 mg, 0.15 mmol) and iodine (26.6 mg, 0.10 mmol) were suspended in THF: H2O = 5:1 (1.04 ml) and stirred at 60 °C for 6 hours. Saturated NaHCO3 aqueous solution (5 ml) was added to the reaction mixture and extracted with EtOAc (5 ml x 2). The organic layer was washed with saturated Na2S2O3 aqueous solution (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 75 mg (quant.) of brown oil.

[0665] Step 7: Tert-butyl 4-((S)-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4- methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperazine-1-carboxylate synthesis

[0666] Tert-butyl (S)-4-(3-amino-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propyl)piperazine-1-carboxylate (75 mg, 0.15 mmol), (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxylic acid (45 mg, 0.15 mmol), EDCI (34 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), and DIPEA (0.1 ml, 0.60 mmol) were suspended in DCM (0.5 ml) and stirred at room temperature for 16 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, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-8% MeOH / DCM) to obtain 88 mg (83%) of an ivory solid.

[0667] Step 8: (2S,4R)-N-((S)-1-(4-(1-Ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide synthesis

[0668] Tert-butyl 4-((S)-3-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperazine-1-carboxylate (88 mg, 0.12 mmol) was suspended in DCM (1.2 ml), 4 M HCl in 1,4-dioxane (0.31 ml) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 138 mg (quant.) of an ivory solid.

[0669]

[0670] Intermediates 52 to 54 were synthesized using a method identical or similar to that used to synthesize intermediate 51.

[0671]

[0672]

[0673] Example 1. (2S,4R)-N-((S)-3-(3-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidin-1-yl)-1-(4-(4-me thylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0674]

[0675] Step 1: Tert-butyl ((1-(5-((3-chloro-2-((1-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxami do)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)azetidin-3-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate synthesis

[0676] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1, 72 mg, 0.0653mmol), (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11, 25 mg, 0.0435 mmol), EDCI (10 mg, 0.0522 mmol), HOBt (7 mg, 0.0522 mmol), and DIPEA (0.02 ml, 0.130 mmol) was suspended in DMF (1 ml) and stirred at room temperature for 16 hours. Distilled water (3 ml) was added to the reaction mixture and extracted with EtOAc (5 ml x 2). The organic layer was washed with brine (5 ml x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (0-8% MeOH / DCM) to obtain 27 mg (58%) of an ivory solid.

[0677] Step 2: (2S,4R)-N-((S)-3-(3-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidin-1-yl)-1-(4-(4-met hylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide synthesis

[0678] Tert-butyl ((1-(5-((3-chloro-2-((1-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)azetidin-3-yl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (25 mg, 0.023 mmol) was suspended in DCM (2.3 ml), 4 M HCl in 1,4-dioxane (0.06 ml) was added, and the mixture was stirred at 0 °C for 1 h. Saturated NaHCO3 aqueous solution (2 ml) was added to the reaction mixture, and the mixture was extracted with DCM (5 ml x 3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by MPLC (amine-silica, 0-6% MeOH / DCM) to obtain 17 mg (76%) of an ivory solid.

[0679]

[0680] Example 2. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chlor opyridin-2-yl)amino)azetidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-4-hydroxypyrrolidine-2-carboxamide

[0681]

[0682] Example 2 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylic acid (Intermediate 12).

[0683]

[0684] Example 3.(2S,4R)-N-((S)-3-(4-(3-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)piperidin-1-y l)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0685]

[0686] Example 3 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylic acid (Intermediate 13).

[0687]

[0688] Example 4. (2S,4R)-N-((S)-3-(4-(3-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)piperidin-1 -yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0689]

[0690] Example 4 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 17).

[0691]

[0692] Example 5. (2S,4R)-N-((S)-3-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidin-1-yl)-1-(4-(4-me thylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0693]

[0694] Example 5 was synthesized in the same manner as in Example 1, using tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1).

[0695]

[0696] Example 6. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloro pyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-4-hydroxypyrrolidine-2-carboxamide

[0697]

[0698] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 6 was synthesized in the same manner as in Example 1 using 1-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylic acid (Intermediate 12) instead of (Intermediate 11).

[0699]

[0700] 실시예 7.(2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0701]

[0702] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 7 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoyl)piperidine-4-carboxylic acid (Intermediate 13) instead of (Intermediate 11).

[0703]

[0704] 실시예 8. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0705]

[0706] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 8 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 16) instead of (Intermediate 11).

[0707]

[0708] 실시예 9.(2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0709]

[0710] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 9 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 17) instead of (Intermediate 11).

[0711]

[0712] 실시예 10. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-2-(4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0713]

[0714] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 10 was synthesized in the same manner as in Example 1, using 1-((R)-2-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylic acid (Intermediate 20) instead of (Intermediate 11).

[0715]

[0716] Example 11.(2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-2-(4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)- 3-chloropyridin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0717]

[0718] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperazin-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 3) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 11 was synthesized in the same manner as in Example 1, using 1-((R)-2-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylic acid (Intermediate 20) instead of (Intermediate 11).

[0719]

[0720] 실시예 12. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-4-hydroxypyrrolidine-2-carboxamide

[0721]

[0722] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 12 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 14).

[0723]

[0724] 실시예 13. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0725]

[0726] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 13 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 15).

[0727]

[0728] 실시예 14. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0729]

[0730] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 14 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 18).

[0731]

[0732] 실시예 15.(2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0733]

[0734] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 15 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 19).

[0735]

[0736] 실시예 16. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-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)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0737]

[0738] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 16 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide (Intermediate 21).

[0739]

[0740] 실시예 17. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

[0741]

[0742] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 17 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 22) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0743]

[0744] 실시예 18.(2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0745]

[0746] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 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 4) was used, Example 18 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0747]

[0748] Example 19. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chlo ropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0749]

[0750] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 19 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 18).

[0751]

[0752] 실시예 20. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

[0753]

[0754] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 20 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 22) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0755]

[0756] 실시예 21. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0757]

[0758] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 21 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0759]

[0760] Example 22. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)p iperazin-1-yl)-1-phenylpropyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0761]

[0762] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 22 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 24) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0763]

[0764] Example 23. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)pipera zin-1-yl)-1-(4-chlorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0765]

[0766] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 23 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 25) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0767]

[0768] 실시예 24. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-cyanophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0769]

[0770] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 24 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 26) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0771]

[0772] 실시예 25. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0773]

[0774] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 6) was used, Example 25 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 18).

[0775]

[0776] 실시예 26. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-2-(4-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0777]

[0778] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 6) was used, Example 26 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide (Intermediate 21).

[0779]

[0780] 실시예 27. (2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

[0781]

[0782] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 6) was used, Example 27 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 22) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0783]

[0784] 실시예 28. (2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0785]

[0786] Instead of Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 6) was used, Example 28 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0787]

[0788] 실시예 29.(2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0789]

[0790] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 29 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 18).

[0791]

[0792] 실시예 30.(2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-2-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0793]

[0794] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 30 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide (Intermediate 21).

[0795]

[0796] 실시예 31. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

[0797]

[0798] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 31 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 22) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0799]

[0800] 실시예 32.(2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0801]

[0802] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 32 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0803]

[0804] 실시예 33.(2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-phenylpropyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0805]

[0806] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 33 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 24) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0807]

[0808] 실시예 34. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-chlorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0809]

[0810] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 34 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 25) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0811]

[0812] 실시예 35.(2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-cyanophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0813]

[0814] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 35 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 26) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0815]

[0816] 실시예 36. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0817]

[0818] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 36 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 27).

[0819]

[0820] 실시예 37. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0821]

[0822] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 37 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0823]

[0824] 실시예 38.(2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0825]

[0826] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 38 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 18).

[0827]

[0828] 실시예 39.(2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-2-(4-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0829]

[0830] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 39 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide (Intermediate 21).

[0831]

[0832] 실시예 40. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

[0833]

[0834] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 40 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 22) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0835]

[0836] 실시예 41. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0837]

[0838] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 41 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0839]

[0840] 실시예 42. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-phenylpropyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0841]

[0842] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 42 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 24) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0843]

[0844] 실시예 43. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-chlorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0845]

[0846] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 43 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 25) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0847]

[0848] 실시예 44.(2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-cyanophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0849]

[0850] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 44 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 26) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0851]

[0852] 실시예 45. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0853]

[0854] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 45 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxypyrrolidine-2-carboxamide (Intermediate 27).

[0855]

[0856] 실시예 46. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0857]

[0858] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 46 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0859]

[0860] 실시예 47. (2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxypyrrolidine-2-carboxamide

[0861]

[0862] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 47 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 18).

[0863]

[0864] 실시예 48.(2S,4R)-1-((S)-2-Acetamido-3,3-dimethylbutanoyl)-N-((R)-2-(4-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0865]

[0866] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 48 was synthesized in the same manner as in Example 1, using (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-(piperazin-1-yl)ethyl)pyrrolidine-2-carboxamide (Intermediate 21).

[0867]

[0868] 실시예 49.(2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide

[0869]

[0870] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 49 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 22) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0871]

[0872] 실시예 50. (2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0873]

[0874] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 50 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0875]

[0876] 실시예 51. (2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-phenylpropyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0877]

[0878] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 51 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 24) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0879]

[0880] 실시예 52. (2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-chlorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0881]

[0882] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 52 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 25) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0883]

[0884] 실시예 53.(2S,4R)-N-((S)-3-(4-(1-(4-((5-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-cyanophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0885]

[0886] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 9) was used, Example 53 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 26) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0887]

[0888] 실시예 54. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0889]

[0890] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 54 was synthesized in the same manner as in Example 1 using 1-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 44) instead of (Intermediate 11).

[0891]

[0892] 실시예 55. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0893]

[0894] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 55 was synthesized in the same manner as in Example 1 using 1-((S)-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperidine-4-carboxylic acid (Intermediate 45) instead of (Intermediate 11).

[0895]

[0896] 실시예 56. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0897]

[0898] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 56 was synthesized in the same manner as in Example 1 using 1-((R)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylic acid (Intermediate 46) instead of (Intermediate 11).

[0899]

[0900] 실시예 57. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0901]

[0902] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 2) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 57 was synthesized in the same manner as in Example 1 using 1-((R)-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 47) instead of (Intermediate 11).

[0903]

[0904] Example 58. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbon yl)piperazin-1-yl)-1-phenylpropyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0905]

[0906] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 4) was used, Example 58 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-phenyl-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 24) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0907]

[0908] 실시예 59. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-chlorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0909]

[0910] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 4) was used, Example 59 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-chlorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 25) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0911]

[0912] 실시예 60. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-cyanophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0913]

[0914] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 4) was used, Example 60 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-cyanophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 26) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0915]

[0916] 실시예 61. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0917]

[0918] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 4) was used, Example 61 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0919]

[0920] 실시예 62. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0921]

[0922] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 4) was used, Example 62 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-N-((S)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 50) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0923]

[0924] 실시예 63. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0925]

[0926] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 63 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0927]

[0928] 실시예 64. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0929]

[0930] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 64 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-N-((S)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 50) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0931]

[0932] 실시예 65. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0933]

[0934] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 5) was used, Example 65 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 51) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0935]

[0936] 실시예 66. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0937]

[0938] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 66 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-fluorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 48) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0939]

[0940] 실시예 67. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(pyridin-3-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0941]

[0942] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 67 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-3-(piperazin-1-yl)-1-(pyridin-3-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 49) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0943]

[0944] 실시예 68. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0945]

[0946] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 68 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-N-((S)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 50) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0947]

[0948] 실시예 69. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(2-methyl-4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0949]

[0950] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 69 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2-methyl-4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 52) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0951]

[0952] 실시예 70. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0953]

[0954] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 70 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 53) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0955]

[0956] 실시예 71. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(5-fluoro-2-methyl-4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0957]

[0958] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 7) was used, Example 71 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(5-fluoro-2-methyl-4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 54) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0959]

[0960] 실시예 72. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0961]

[0962] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 72 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-N-((S)-1-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 50) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0963]

[0964] 실시예 73. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0965]

[0966] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 8) was used, Example 73 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-3-fluorophenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 51) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0967]

[0968] 실시예 74. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0969]

[0970] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 74 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 44) instead of (Intermediate 11).

[0971]

[0972] 실시예 75. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0973]

[0974] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 75 was synthesized in the same manner as in Example 1 using 1-((S)-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperidine-4-carboxylic acid (Intermediate 45) instead of (Intermediate 11).

[0975]

[0976] 실시예 76. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0977]

[0978] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 76 was synthesized in the same manner as in Example 1 using 1-((R)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)ethyl)piperidine-4-carboxylic acid (Intermediate 46) instead of (Intermediate 11).

[0979]

[0980] 실시예 77. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0981]

[0982] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 29) is used, (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid Example 77 was synthesized in the same manner as in Example 1 using 1-((R)-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 47) instead of (Intermediate 11).

[0983]

[0984] 실시예 78. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0985]

[0986] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of 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 30) was used, Example 78 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 44).

[0987]

[0988] 실시예 79. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0989]

[0990] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of 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 30) was used, Example 79 was synthesized in the same manner as in Example 1, using 1-((S)-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperidine-4-carboxylic acid (Intermediate 45) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0991]

[0992] 실시예 80. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0993]

[0994] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of 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 30) was used, Example 80 was synthesized in the same manner as in Example 1, using 1-((R)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0995]

[0996] 실시예 81. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[0997]

[0998] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of 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 30) was used, Example 81 was synthesized in the same manner as in Example 1, using 1-((R)-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 47) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[0999]

[1000] 실시예 82. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1001]

[1002] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 31), Example 82 was synthesized in the same manner as in Example 1, using 1-((S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of 1-((S)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propyl)piperidine-4-carboxylic acid (Intermediate 44).

[1003]

[1004] 실시예 83. (2S,4R)-N-((S)-3-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1005]

[1006] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 31), Example 83 was synthesized in the same manner as in Example 1, using 1-((S)-3-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)propyl)piperidine-4-carboxylic acid (Intermediate 45) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1007]

[1008] 실시예 84. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1009]

[1010] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 31), Example 84 was synthesized in the same manner as in Example 1, using 1-((R)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)-2-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1011]

[1012] 실시예 85. (2S,4R)-N-((R)-2-(4-(4-((4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)piperidin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1013]

[1014] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead of tert-butyl (1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate (Intermediate 31), Example 85 was synthesized in the same manner as in Example 1, using 1-((R)-2-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamido)ethyl)piperidine-4-carboxylic acid (Intermediate 47) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1015]

[1016] 실시예 86. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1017]

[1018] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 32) was used, Example 86 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1019]

[1020] 실시예 87. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1021]

[1022] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 32) was used, Example 87 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1023]

[1024] 실시예 88. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1025]

[1026] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 33) was used, Example 88 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1027]

[1028] 실시예 89. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1029]

[1030] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 33) was used, Example 89 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1031]

[1032] 실시예 90. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-fluoropiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1033]

[1034] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-fluoropyridin-4-carboxylic acid (Intermediate 34) was used, Example 90 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1035]

[1036] 실시예 91. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1037]

[1038] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 35) was used, Example 91 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1039]

[1040] 실시예 92. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1041]

[1042] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 35) was used, Example 92 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1043]

[1044] 실시예 93. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-Amino-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1045]

[1046] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 36) was used, Example 93 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1047]

[1048] 실시예 94. (2S,4R)-N-((S)-3-(4-(1-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1049]

[1050] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-methylpiperidine-4-carboxylic acid (Intermediate 37) was used, Example 94 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1051]

[1052] 실시예 95. (2S,4R)-N-((S)-3-(4-((1R,5S,6r)-3-(4-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1053]

[1054] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead (1R,5S,6r)-3-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 38) use it, Example 95 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1055]

[1056] 실시예 96. (2S,4R)-N-((S)-3-(4-(1-(3-((5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-2-chlorophenyl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1057]

[1058] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 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 39) was used, Example 96 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1059]

[1060] 실시예 97. (2S,4R)-N-((S)-3-(4-(1-(4-((3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1061]

[1062] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((3-amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 40) was used, Example 97 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1063]

[1064] 실시예 98. (2S,4R)-N-((S)-3-(4-(1-(4-((3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1065]

[1066] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((3-amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 40) was used, Example 98 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1067]

[1068] 실시예 99. (2S,4R)-N-((S)-3-(4-(1-(4-((3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(4-methylthiazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1069]

[1070] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((3-amino-5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used, Example 99 was synthesized in the same manner as in Example 1, using (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)pyrrolidine-2-carboxamide (Intermediate 23) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1071]

[1072] 실시예 100. (2S,4R)-N-((S)-3-(4-(1-(4-((3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1073]

[1074] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((3-amino-5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (Intermediate 41) was used, Example 100 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1075]

[1076] 실시예 101. (2S,4R)-N-((S)-3-(4-(1-(4-((3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1077]

[1078] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((3-amino-5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 42) was used, Example 101 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1079]

[1080] 실시예 102. (2S,4R)-N-((S)-3-(4-(1-(4-((3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperazin-1-yl)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide

[1081]

[1082] Tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (Intermediate 1) instead 1-(4-((3-amino-5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid (Intermediate 43) was used, Example 102 was synthesized in the same manner as in Example 1, using (2S,4R)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(piperazin-1-yl)propyl)-4-hydroxy-1-((S)-3-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)butanoyl)pyrrolidine-2-carboxamide (Intermediate 28) instead of (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl)propanoic acid (Intermediate 11).

[1083]

[1084] The NMR and MASS measurement results of the previously synthesized example compounds are summarized and shown in Table 2 below.

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100] Evaluation of the compounds disclosed herein

[1101] Experimental Example 1: Measurement of SHP2 protein degradation in NCI-H358 cells.

[1102] The synthesized compound was treated in H358 cells, and the amount of SHP2 protein present in the cells was measured using Western blotting. The protocol for the experiment using H358 cells is as follows.

[1103] [Culture] Resuspend H358 cells in RPMI1640 with 25 mM HEPES (Hyclone, SH30255.01), 10% FBS (Hyclone, SV30207.02), 1% Penicillin-streptomycin (Welgene, LS 202-02) media and seed 3 x 10 5 After seeding 1 mL per 12-well plate at / mL, it was cultured for 24 hours.

[1104] [Compound treatment] Before compound treatment, the media was changed to 1 mL media, and then the 12-well plate was treated as follows. A 10 mM stock dissolved in DMSO was serially diluted 1 / 100 or 1 / 10 with media, and the cells were treated with compounds at final concentrations of 0.001, 0.01, and 0.1 μM, and harvested after 24 hours. For the negative control group, DMSO diluted 1 / 1000 in media was added (1 μL DMSO + 999 μL media).

[1105] [Harvest] After 24 hours of compound treatment, each well was scraped with a cell lifter (SPL, 90040), pipetted with a 1 mL pipette, collected in a 1.5 mL microtube, and centrifuged (500 g, 5 min, 4 °C). The supernatant was removed, washed with PBS, and centrifuged again (500 g, 5 min, 4 °C). The supernatant was then removed to prepare a pellet.

[1106] [Cell lysis and sample preparation] Lysis buffer was prepared as follows. RIPA buffer (Biosesang, RC2038-050-00) + 0.5 mM PMSF (SIGMA, P7626) + 1x Protease / Phosphatase Inhibitor (Cell signaling, 5872S) was added at 30 μL per tube, vortexed, and incubated on ice for 30 minutes. After sonication (10-second pulse, 30-second rest, 5 cycles, 70% amplification), centrifugation (15,000 g, 15 min, 4°C) was performed, and only the supernatant was transferred to a microtube. A 96-well plate was diluted to 1 / 4 with 7.5 μL of RIPA buffer and 2.5 μL of sample, and then 200 μL each of A and B of the BCA Protein Assay Kit (iNtRON, 21071) were mixed at a ratio of 50:1. The plate was incubated at 37°C for 30 minutes and left at room temperature for 10 minutes. After shaking for 10 seconds with a BioTek SYNERGY H1 microplate reader, the absorbance was measured at 562 nm. The protein was quantified using the measured value, and the sample was incubated at 70°C for 10 minutes. The sample buffer used here was a mixture of NuPAGE or Bolt 4x sample buffer (Invitrogen) and each 10x sample reducing agent depending on the gel to be used, and the protein was diluted using RIPA buffer.

[1107] [Western blotting detection method] Equal amounts of samples were loaded onto NuPAGE or Bolt Bis-tris 4-12% gradient gels and run (200 V, 35 min). The membranes were transferred to 0.2 mm NC membranes using Trans-blot Turbo (BIO-RAD) (1.3 A constant, 25 V limit, 15 min). The membranes were blocked with 5% skim milk / 0.2% TBST for 45 min at room temperature. Anti-SHPTP2 Mouse (1:1,000 in 5% skim milk / 0.2% TBST, size: 70 kDa, Santa Cruz sc-7384) and Anti-GAPDH Rabbit (1:2,000 in 5% skim milk or 5% BSA / 0.2% TBST, size: 37 kDa, CST #2118) were added and incubated overnight at 4°C. The slides were washed three times for 5 minutes each with 0.2% TBST washing buffer, and secondary antibodies, Anti-Mouse IgG (1:5,000 in 5% skim milk / 0.2% TBST, CST) and IRDye® 680RD Goat anti-Rabbit IgG Secondary Antibody (1:10,000 in 5% skim milk / 0.2% TBST, LI-COR 926-68071), were added, and incubated on a rocker at room temperature for 45 minutes. The slides were washed five times for 5 minutes each with 0.2% TBST washing buffer, and detected with LI-COR's Odyssey. GAPDH was detected with a 700 nm channel, and SHPTP2 was detected using SuperSignal West Pico PLUS Chemiluminescent Substrate.

[1108] The results of evaluating the SHP2 protein degradation ability of the compounds of the present invention according to the above Experimental Example 1 are summarized and shown in Table 3 below. As shown in Table 3 below, the compounds of the present invention exhibited excellent activity in SHP2 protein degradation.

[1109]

[1110]

[1111]

Claims

1. A compound of the following chemical formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is , , or And, R 12a is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein aryl and heteroaryl are independent of each other and optionally one or more hydrogens in the ring are C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, or C 1-3 is substituted with alkoxy, R 12b is amino, C 1-6 aminoalkyl, or C 1-6 It is alkylamino, R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 It is alkoxy, R 14 are independently H, C 1-6 alkyl, hydroxy, halogen, or CN, Z is independently -O-, -S-, -NH-, or -CH2-, Ring C is aryl or heteroaryl, n is an integer from 0 to 3, R2 is H, C 1-6 alkyl, or -NH2, R3 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, -C(O)R 10a , -C(O)OR 10a , -C(O)NR 10a R 10b , or CN, R4 is H, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 It is haloalkoxy, R5 is H, C 1-6 alkyl, C 2-6 alkynyl, halogen, -CN, or heteroaryl, wherein the heteroaryl is optionally a group in which one or more hydrogens in the ring are C 1-6 alkyl, halogen, or C 1-3 is substituted with haloalkyl, R6 is -NHC(O)R7 or heteroaryl, where heteroaryl is optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl, R7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, or heterocycle, wherein cycloalkyl and heterocycle are independently of each other and optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -CN, R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl, R 9a and R 9b are independently H, C 1-6 alkyl, C 1-6 alkoxy, or halogen, X is -S-, -O-, -N(R 10a )-, or -CH2-, Y is CH or N, W is a direct bond, -O-, or -N(R 10a )-and, V is CH or N, R 10a and R 10b are independently H, C 1-6 alkyl, or C 1-6 It is haloalkyl, L is the following chemical formula 2, [Chemical Formula 2] In chemical formula 2, A1 and A2 are directly bonded independently of each other, C 3-10 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, -OH, or =O, B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, -C(O)-, -C(O)N(R 11 )-, or -N(R 11 )C(O)-, where R 11 are independently H or C 1-6 It is alkyl, q1, q2, q3, q4, and q5 are integers from 0 to 5, independently of each other.

2. In paragraph 1, R1 is , , or And, R 12a is H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, or C 1-6 It is haloalkyl, R 12b is amino, C 1-6 aminoalkyl, or C 1-6 It is alkylamino, R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, halogen, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 It is alkoxy, R 14 are independently H, C 1-6 alkyl, hydroxy, halogen, or CN, Z is independently -O-, -S-, -NH-, or -CH2-, Ring C is aryl or heteroaryl, n is an integer from 0 to 3, R2 is H, C 1-6 alkyl, or -NH2, R3 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, -C(O)NR 10a R 10b , or CN, R4 is H, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 It is haloalkoxy, R5 is H, C 1-6 alkyl, C 2-6 alkynyl, halogen, -CN, or heteroaryl, wherein the heteroaryl is optionally a group in which one or more hydrogens in the ring are C 1-6 alkyl, halogen, or C 1-3 is substituted with haloalkyl, R6 is -NHC(O)R7 or heteroaryl, where heteroaryl is optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl, R7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, or heterocycle, wherein cycloalkyl and heterocycle are independently of each other and optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -CN, R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl, R 9a and R 9b are independently H, C 1-6 alkyl, C 1-6 alkoxy, or halogen, X is -S-, -O-, -N(R 10a )-, or -CH2-, Y is CH or N, W is a direct bond, -O-, or -N(R 10a )-and, V is CH or N, R 10a and R 10b are independently H, C 1-6 alkyl, or C 1-6 It is haloalkyl, L is the following chemical formula 2, [Chemical Formula 2] In chemical formula 2, A1 and A2 are directly bonded independently of each other, C 3-10 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, -OH, or =O, B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, -C(O)-, -C(O)N(R 11 )-, or -N(R 11 )C(O)-, where R 11 are independently H or C 1-6 It is alkyl, q1, q2, q3, q4, and q5 are independently integers from 0 to 5, A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

3. In paragraph 2, R1 is , , or And, R 12a is H, C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, or C 1-3 It is haloalkyl, R 12b is amino, C 1-3 aminoalkyl, or C 1-3 It is alkylamino, R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, halogen, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, or C 1-3 It is alkoxy, R 14 are independently H, C 1-6 alkyl, hydroxy, halogen, or CN, Z is independently -O-, -NH-, or -CH2-, Ring C is aryl or heteroaryl, n is an integer from 0 to 3, R2 is H, C 1-6 alkyl, or -NH2, R3 is H, C 1-6 alkyl, C 1-3 hydroxyalkyl, -C(O)NR 10a R 10b , or CN, R4 is H, C 1-6 alkyl, halogen, or C 1-6 It is haloalkyl, R5 is H, C 1-6 alkyl, C 2-6 alkynyl, halogen, -CN, or heteroaryl, wherein the heteroaryl is optionally a group in which one or more hydrogens in the ring are C 1-6 alkyl, halogen, or C 1-3 is substituted with haloalkyl, R6 is -NHC(O)R7 or heteroaryl, where heteroaryl is optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl, R7 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, or C 3-10 cycloalkyl, where cycloalkyl is optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -CN, R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl, R 9a and R 9b are independently H, C 1-6 alkyl, or halogen, X is -S-, -O-, -N(R 10a )-, or -CH2-, Y is CH or N, W is a direct bond, -O-, or -N(R 10a )-and, V is CH or N, R 10a and R 10b are independently H, C 1-6 alkyl, or C 1-6 It is haloalkyl, L is the following chemical formula 2, [Chemical Formula 2] In chemical formula 2, A1 and A2 are directly bonded independently of each other, C 3-10 cycloalkyl, or heterocycle, where cycloalkyl and heterocycle are independently of each other and optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, or -OH, B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, or -C(O)-, where R 11 are independently H or C 1-6 It is alkyl, q1, q2, q3, q4, and q5 are independently integers from 0 to 5, A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

4. In paragraph 3, R1 is , , or And, R 12a is H, C 1-6 alkyl, hydroxy, or C 1-3 It is hydroxyalkyl, R 12b is amino or C 1-3 It is aminoalkyl, R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, C 1-3 hydroxyalkyl, or C 1-3 It is alkoxy, R 14 are independently H, C 1-3 alkyl, hydroxy, halogen, or CN, Z is independently -O-, -NH-, or -CH2-, Ring C is aryl or heteroaryl, n is an integer from 0 to 3, R2 is H, C 1-6 alkyl, or -NH2, R3 is H, C 1-6 alkyl, or C 1-3 It is hydroxyalkyl, R4 is H, C 1-6 alkyl, halogen, or C 1-3 It is haloalkyl, R5 is H, C 1-6 alkyl, acetylenyl, halogen, -CN, thiazole, pyrazole, pyrrole, oxazole, or triazole, wherein thiazole, pyrazole, pyrrole, oxazole, or triazole optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, or C 1-3 is substituted with haloalkyl, R6 is -NHC(O)R7, isoxazole, triazole, or pyrazole, wherein isoxazole, triazole, or pyrazole optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl, R7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, or C 3-6 cycloalkyl, where cycloalkyl is optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -CN, R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl, R 9a and R 9b are independently H, C 1-3 alkyl, or halogen, X is -S- or -O-, Y is CH or N, W is a direct bond, -O-, or -N(R 10a )-and, V is CH or N, R 10a is H, C 1-3 alkyl, or C 1-3 It is haloalkyl, L is the following chemical formula 2, [Chemical Formula 2] In chemical formula 2, A1 and A2 are independently a direct bond, cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, or 3-azabicyclo[3.1.1]heptane, wherein cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, and 3-azabicyclo[3.1.1]heptane are independently a direct bond, and optionally one or more hydrogens in the ring are C 1-6 alkyl, halogen, C 1-3 substituted with haloalkyl, or -OH, B1 and B2 are independently bonded directly, -O-, -N(R 11 )-, or -C(O)-, where R 11 are independently H or C 1-3 It is alkyl, q1, q2, q3, q4, and q5 are independently integers from 0 to 5, A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

5. In paragraph 4, R1 is , , or And, R 12a is H, C 1-6 alkyl, or hydroxy, R 12b is amino or C 1-3 It is aminoalkyl, R 13a and R 13b are independently H, C 1-6 alkyl, hydroxy, or C 1-3 It is hydroxyalkyl, R 14 are independently H, C 1-3 alkyl, or halogen, Z is independently -O- or -CH2-, Ring C is aryl or heteroaryl, n is an integer from 0 to 2, R2 is H, C 1-6 alkyl, or -NH2, R3 is H, C 1-6 alkyl, or C 1-3 It is hydroxyalkyl, R4 is H, C 1-6 alkyl, halogen, or C 1-3 It is haloalkyl, R5 is H, C 1-6 alkyl, acetylenyl, halogen, -CN, thiazole, pyrazole, or pyrrole, wherein thiazole, pyrazole, or pyrrole optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, or C 1-3 is substituted with haloalkyl, R6 is -NHC(O)R7, isoxazole, triazole, or pyrazole, wherein isoxazole, triazole, or pyrazole optionally has one or more hydrogens in the ring C 1-6 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl, R7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, or C 3-6 cycloalkyl, where cycloalkyl is optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -CN, R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl, R 9a and R 9b are independently H, C 1-3 alkyl, or halogen, X is -S- or -O-, Y is CH or N, W is a direct bond, -O-, or -N(R 10a )-and, V is CH, R 10a is H, C 1-3 alkyl, or C 1-3 It is haloalkyl, L is the following chemical formula 2, [Chemical Formula 2] In chemical formula 2, A1 and A2 are independently a direct bond, cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, or 3-azabicyclo[3.1.1]heptane, wherein cyclohexane, cyclopentane, cyclobutane, azetidine, pyrrolidine, piperidine, piperazine, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 3-azabicyclo[3.1.0]hexane, and 3-azabicyclo[3.1.1]heptane are independently a direct bond, and optionally one or more hydrogens in the ring are C 1-6 substituted with alkyl, halogen, or -OH, B1 and B2 are independently a direct bond, -O-, or -C(O)-, q1, q2, q3, q4, and q5 are independently integers from 0 to 3, A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

6. In paragraph 5, R1 is or And, R 12a is H or C 1-6 It is alkyl, R 12b is amino or C 1-3 It is aminoalkyl, R 13a and R 13b are independently H or C 1-6 It is alkyl, Z is independently -O- or -CH2-, R2 is H, C 1-6 alkyl, or -NH2, R3 is H, C 1-6 alkyl, or C 1-3 It is hydroxyalkyl, R4 is H, C 1-6 alkyl, halogen, or C 1-3 It is haloalkyl, R5 is H, C 1-6 alkyl, halogen, -CN, thiazole, or pyrazole, wherein thiazole or pyrazole optionally has one or more hydrogens in the ring C 1-3 alkyl, halogen, or C 1-3 is substituted with haloalkyl, R6 is -NHC(O)R7, isoxazole, or triazole, wherein isoxazole or triazole optionally has one or more hydrogens in the ring C 1-3 alkyl, halogen, C 1-3 haloalkyl, or C 3-6 Substituted with cycloalkyl, R7 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 cyanoalkyl, or C 3-6 cycloalkyl, wherein cycloalkyl is optionally substituted with one or more hydrogens in the ring by halogen or -CN, R8 is H, C 1-6 alkyl, or C 3-6 It is cycloalkyl, R 9a and R 9b are independently H, C 1-3 alkyl, or halogen, X is -S-, Y is CH or N, W is a direct bond or -N(R 10a )-and, V is CH, R 10a is H, C 1-3 alkyl, or C 1-3 It is haloalkyl, L is the following chemical formula 2, [Chemical Formula 2] In chemical formula 2, A1 and A2 are independently a direct bond, cyclohexane, cyclobutane, azetidine, piperidine, piperazine, or 3-azabicyclo[3.1.0]hexane, wherein cyclohexane, cyclobutane, azetidine, piperidine, piperazine, and 3-azabicyclo[3.1.0]hexane are independently of each other and optionally have one or more hydrogens in the ring C 1-3 substituted with alkyl, halogen, or -OH, B1 and B2 are independently a direct bond or -C(O)-, q1, q2, q3, q4, and q5 are independently integers from 0 to 3, A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, neither A1 nor A2 are direct bonds. A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, B1 is not a direct bond, A compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, the compound is a compound of formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, which is any one of the following compounds.

10. A composition comprising a compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

12. In claim 11, the pharmaceutical composition for inhibiting or degrading the Src homology 2 domain-containing phosphatase (SHP2) is a pharmaceutical composition for treating or preventing cancer, cancer metastasis, cardiovascular disease, immune disorder, eye disorder, Noonan syndrome, or Leopard syndrome.

13. A pharmaceutical composition according to claim 12, wherein the cancer is at least one selected from hematological cancer, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT-midline cancer, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, lymphoma, cervical cancer, head and neck cancer, head cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, melanoma, colon cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma, or sarcoma, papillary thyroid carcinoma, and combinations thereof.

14. A pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is for the treatment or prevention of cancer or cancer metastasis, and the composition further comprises an anticancer agent other than a compound of any one of claims 1 to 9 as a second active ingredient.

15. A pharmaceutical composition according to claim 14, wherein the anticancer agent is at least one of a hormone or nuclear receptor-related protein inhibitor or decomposer; a non-receptor tyrosine kinase inhibitor or decomposer; an RTK / RAS / MAPK pathway protein inhibitor or decomposer; an immuno-oncology agent, an immunomodulatory drug or vaccine; a cytotoxic anticancer agent; or an antibody-drug conjugate.

16. A method for treating or preventing a disease associated with Src homology 2 domain-containing phosphatase (SHP2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

17. A method for treating or preventing, in claim 16, 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.

18. A method for treating or preventing cancer according to claim 17, wherein the cancer is at least one selected from blood cancer, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, NUT-midline cancer, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, lymphoma, cervical cancer, head and neck cancer, head cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, melanoma, colon cancer, colon cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, glioma, or sarcoma, papillary thyroid carcinoma, and combinations thereof.

19. In claim 17, the method is a method for treating or preventing cancer or cancer metastasis, and the method comprises a step of administering to a subject a second active ingredient that is an anticancer agent other than a compound of any one of claims 1 to 9.

20. A method for treatment or prevention according to claim 19, wherein the anticancer agent is at least one of a hormone or nuclear receptor-related protein inhibitor or decomposer; a non-receptor tyrosine kinase inhibitor or decomposer; an RTK / RAS / MAPK pathway protein inhibitor or decomposer; an immuno-oncology agent, an immunomodulatory drug or vaccine; a cytotoxic anticancer agent; or an antibody-drug conjugate.

21. A method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

22. A method for inhibiting or degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample, comprising contacting the patient or biological sample with a compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

23. Use of a compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, for the production of a medicament for degrading Src homology 2 domain-containing phosphatase (SHP2) in a patient or a biological sample.

24. Use of a compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, for the production of a medicament for treating a disease associated with Src homology 2 domain-containing phosphatase (SHP2).

25. In claim 24, the use is for the treatment or prevention of cancer or cancer metastasis, and the compound of any one of claims 1 to 9, an optical isomer, a stereoisomer, an isotope variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof is used in combination with another anticancer agent.

26. The use according to claim 25, wherein the anticancer agent is at least one of a hormone or nuclear receptor-related protein inhibitor or decomposer; a non-receptor tyrosine kinase inhibitor or decomposer; an RTK / RAS / MAPK pathway protein inhibitor or decomposer; an immuno-oncology agent, an immunomodulatory drug or vaccine; a cytotoxic anticancer agent; or an antibody-drug conjugate.

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